Down-regulation of {beta}-adrenergic receptors on mononuclear leukocytes induced by dobutamine treatment in patients with congestive heart failure

(±)-Dobutamine is a positive inotropic drug usually usedto improve ventricular function in patients with congestiveheart failure (CHF). However, it has been found that haemodynamicresponses to dobutamine become blunted during continuous treatment.In this study we determined the time-dependent changes of ß-adrenergicreceptors in CHF patients treated with dobutamine. Seven CHFpatients received a continuous intravenous infusion of dobutamine(5 µg.kg^–1. min^–1) for 96 h. Blood sampleswere obtained before and every 24 h after starting the therapy.The density of ß-adrenergic receptors on mononuclearleukocytes and the plasma concentrations of norepinephrine andepinephrine were determined. During dobutamine treatment thereceptor density (fmol.mg^–1, mean±SEM) graduallydecreased from 42.8±4.4 (baseline) to 31.4±3.3(P<0.05), 25.2±4.0 (P<0.01), 18.8±5.5 (P<0.01)and 13.4±3.4 (P<0.01) at 24, 48, 72 and 96 h, respectively.However, the plasma concentrations of norepinephrine and epinephrinewere not significantly changed during the 96 h period of treatment.Thus, the ß-adrenergic receptors down-regulated asearly as 24 h after the dobutamine treatment was begun in CHFpatients. This receptor down-regulation was not associated withchanges of plasma catechol-amine concentrations, but was relatedrather to the development of drug tolerance to dobutamine.     

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.     

Platelet function, thrombin and fibrinolytic activity in patients with heart failure

Assays which detect the release of platelet proteins and ofpep tides during thrombogenesis and are considered markers ofactivation of platelets and the coagulation system have recentlybeen developed. This study was designed to utilize these haemostasis-relatedmarkers to lest the hypothesis that a prethrombotic state isrelated to the presence, aetiology and severity of heart failure.Seventy patients with heart failure were evaluated and datawere compared with 36 normal volunteers and 41 patients withcoronary artery disease without heart failure (CAD). Thrombogenesiswas documented using assays which measure platelet function,thrombin activity and fibrinolysis. Platelet function was measuredby determining plasma concentrations of platelet factor 4 (PF4)and beta-thromboglobulin (BTG). Thrombin antithrombin III complexes(TAT) and fibrinopeptide A (FPA) were determined to evaluatethrombin activity. Fibrinolyric activity was assessed by measuringD-Dimer levels. Patients with heart failure, when compared tonormals, had increased plasma levels of BTG (89±62 IU.ml^–1 vs 50±59 IU. ml^–1, P<0.01), TAT (4.6±4.3µg. l^–1 vs 2.3±0.64 µg. l^–1,P<0.005 and D-Dimer levels (506±444 IU. ml^–1vs 191±144 IU. ml^–1, P < 0.0001). Patients withheart failure, when compared to the CAD group, had increasedplasma levels of D-Dimer (506±444 ng. ml^–1 vs 191±144ng. ml^–1, P <0.05). Aetiology of heart failure didnot affect these measurements. Patients with severe heart failure,as determined by high plasma norepinephrine concentration orlow ejection fraction, were more likely to have activation ofplatelets and the coagulation system. Our study indicates thatpatients with heart failure have evidence of increased plateletand thrombin activation and fibrinolytic activity. These abnormalitiesare most pronounced in patients with severe heart failure.     

Isolated in-vitro perfusion of pig hearts obtained from the abattoir: an alternative to animal experiments?

Isolated pig hearts (German farm pigs) were characterized afterglobal in-vivo ischaemia as a potential alternative to in-vivoanimal studies. Hearts were harvested from adult farm swineat the abattoir 10.3 ±2.1 min after incision of the carotidartery. They were immediately perfused and thereafter storedin ice-cold cardioplegic (St Thomas's) solution. After 38 ±3min, retrograde perfusion was started with oxygenated pig blood(37°C; 5000 U Heparin.1^–1; pH 7.38 ± 0.1; 11mmol glucose. l^–1) at a flow rate of 85 ml. min^–1100 g^–1 wet weight (gww^–1) for 30 min (n=10). Additionally,shortly after obtaining the hearts, ATP and CP content weremeasured by enzymatic tests in 10 pigs at the beginning andafter 15 and 30 min of reperfusion. Heart rate was 90 ± 14 min^–1 with little variationduring 30 min. Perfusion pressure increased from 89 ±17 mmHg to 100 ± 17 mmHg (NS). Wet weight rose from 488± 33 to 548 ±45 g (P<0.002). CK increased from2180 ± 558 to 5900 ±1018 U.1^–1 (P<0.001).Calcium in the perfusate decreased from 2.45 ±0.15 to2.2 ±0.25 mmol. 1^–1 and magnesium increased from0.85 ± 0.2 to 1.79 ± 0.35 mmol. l^–1 (bothP<0.001). The transmural ATP and CP content was 2.8 ±0.48 and 5.08 ± 0.88 µmol. gww^–1. ATP fellmoderately during reperfusion to 2.6 ± 0.35 µmol(NS) and CP rose to 6.0 ±1.2 µmol (P<0.04).O₂ consumption started at 2.0 ± 0.9 µmol. min^–1.gww^–1 and measured 0.90 ± 0.6 µmol after30 min (P<0.001). Left ventricular developed pressure (LVDP)fell from 88 ±6 mmHg after 5 min to 68 ±4 mmHgwithin 30 min (P<0.001). The isolated perfusion of pig hearts after in-vivo ischaemiais no overall substitute for in-vivo animal experimentation,but may be useful for morphological studies with ultrasound,or for investigating new diagnostic or therapeutic devices.     

Once daily felodipine in preventing ergonovine-induced myocardial ischaemia in Prinzmetal's variant angina

The efficacy of extended-release felodipine in preventing ergonovine-inducedmyocardial ischaemia was assessed in 14 patients (12 male, twofemale, aged 56±7 years) with Prinzmetal's variant angina.Four of the patients had normal coronary arteries, eight hadone-vessel and two had two-vessel disease. The ergonovine testwas performed once in basal conditions and twice 5 days afterbeginning the oral administration of felodipine 20 mg o.d.,4 and 24 h after the last administration. During a continuous6-lead ECG recording, ergonovine was injected at doses of 25,50, 100, 200, and 400 µg at 5 min intervals. Blood samplesfor felodipine plasma concentrations were drawn at the timeof the tests. The basal ergonovine test was positive in all 14 patients (sevenwith anterior and seven with inferior ST segment elevation >0•1m V) at a mean ergonovine dose of 162±138 µg. Thetest was repeated 4 h after the last felodipine administrationand was negative in 13 patients (93%), but 24 h after the lastdrug administration, eight patients (57%) had a positive testresponse (five with anterior, three with inferior ST segmentelevation) at a higher ergonovine dose than at baseline (150vs 97 µg, P=0•042). The only dtfferences betweenpatients with a negative and a positive test were the mean valuesof the left ventricular end-diastolic pressure (9•3 vs14•9 mmHg, P=0•002) and the ergonovine doses usedin the baseline tests (250 vs 97 µg, P=0•034). Themean felodipine plasma level 4 h after dosing was 18•0±12•2nmol. l^–1; 24 h post-dosing plasma concentrations weregenerally very low (<3 nmol. l^–1 in eight cases). Noacute side effects were observed during the trial. In conclusion, extended-release felodipine, given once daily,appears to be highly effective in preventing ergonovine-inducedischaemia in patients with Prinzmetal's variant angina, maintaininggood efficacy even 24 h post-dosing.     

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.     

Serum C-reactive protein concentration in acute myocardial infarction and its relationship to mortality during 24 months of follow-up in patients under thrombolytic treatment

Objectives We studied the relationship between serum C-reactiveprotein and mortality in acute myocardial infarction. Background Early recanalization of an infarct-related coronaryartery is considered to be an essential prerequisite for reducingmortality by thrombolytic treatment in acute myocardial infarction.It also reduces the inflammatory reaction caused by acute myocardialinfarction and is measurable by determination of serum C-reactiveprotein concentrations. We therefore studied the prognosticvalue of determining serum C-reactive protein in acute myocardialinfarction. Methods We measured serum C-reactive protein concentrationsdaily for 6 days and creatine kinase, as well as its MB isoenzymeconcentrations twice a day, for 3 days after a myocardial infarct,in 188 consecutive patients selected for thrombolytic therapyand treated in the same University Hospital Coronary Care Unit.The highest serum concentrations were related to total mortalityas well as to the causes of death 3, 3–6, 6–12 and12–24 months after the onset of the myocardial infarction. Results The highest serum concentrations of serum C-reactiveprotein were observed 2 to 4 days after the onset of myocardialinfarction. The mean value of the highest serum concentrationof C-reactive protein in patients who survived the whole 24-monthstudy period was 65 mg. l^–1 with the 95% confidence intervalsfor the mean ranging from 58 to 71. The corresponding valuesin those who died within 3, 3–6, 6–12 and 12–24months were 166 (139–194), 136 (88–184), 85 (52–119)and 74 (38–111) mg.l^–1 respectively. The valuesin those who died within 3 and 3–6 months of the infarctiondiffered statistically significantly from the values in thosewho survived the whole period (P<0.001 and P<0.05, respectively).In patients who died due to congestive heart failure the meanhighest serum C-reactive protein concentration was 226 (189–265)mg . l^–1 In those who suffered sudden cardiac death andthose who died from a new myocardial infarction or non-cardiaccauses, the respective values were 167 (138–196), 64 (38–89)and 48 (10–86) mg. l^–1. The values in those whodied due to congestive heart failure and those suffering suddencardiac death differed statistically significantly (P<0.001)from the values of those who survived or died due to other causes.The highest serum concentrations of creatine kinase or its MBisoenzyme were not associated with mortality in this study. Conclusions High serum C-reactive protein concentrations inacute myocardial infarction patients treated with thrombolyticdrugs predict increased mortality up to 6 months following theinfarction. Accordingly, reduction of inflammatory reactionby successful thrombolytic treat ment may make an importantcontribution to the survival benefit of thrombolytic treatmentof acute myocardial infarction.     

The influence of intravenous magnesium sulphate on the occurrence of atrial fibrillation after coronary artery by-pass operation

To examine the influence of (Mg) on hypomagnesaemia and atrialfibrillation (AF) following coronary artery by-pass surgery,140 consecutive patients were randomized to receive 70 mmolof magnesium sulphate intravenously (n = 69) or placebo (n =71). Serum magnesium concentrations fell to 0.77 ± 0.10mmol. l^–1 in the control group but rose to 1.09 ±0.17 mmol. l^–1 in the Mg group (P <0.001). The incidenceof AF was 29% in the Mg group and 26% in the placebo group (NS).The AF patients were older, more of them had had prior AF episodes,their sinus rates (SR) were slower (78 ± 10 vs 86 ±12 beats. Min^–1; P <0.01) and serum Mg concentrationshigher (0.89 ± 0.21 vs 0.11 mmol. ^l–1; P <0.05)The incidence of AF was 43% in the highest quartile of serumMg and 23% among the rest (P = 0.056). In patients experiencingAF during the first three post-operative days, serum Mg concentrationswere higher and SR slower on each day compared with non-AF patients.SR increased post-operatively less with high Mg levels (P =0.044). In the Mg group, serum Mg and SR were the only independentpredictors of AF. In conclusion, the incidence of post-operativeAF is not decreased with magnesium. High Mg levels are likelyto provoke AF probably by mechanisms that modify SR.     

Hyperhomocysteinaemia in heart transplant recipients

The aim of this study was to determine the prevalence of hyperhomocysteinaemiain cardiac transplant recipients, Three groups of subjects werestudied: 27 heart transplant recipients, 14 to 63 months (mean=36.5)after transplantation; 10 patients with moderate chronic renalinsufficiency without clinical evidence of vascular disease;17 apparently healthy individuals. Twenty-five out of 27 transplantedpatients had a coronaroangiography within 6 months of homocysteinemeasurement. Plasma homocysteine was measured both while thesubject was fasting (tO) and 6 h after administration of 0.1g. kg^–1 of methionine (t6). Hyperhomocysteinaemia waspresent in 14127 fasting transplanted patients and after methionineloading. Mean plasma levels of homocysteine at tO were higher(P=0.03) in transplanted heart recipients (15.4 ± 7µmol.l^–1 than in the renal patients (9.9±5µmol.l^–1) despite similar mean plasma creatinin. In eight transplantedpatients with angiographic coronary abnormalities of the cardiacgraft, homocysteinaemia was at tO 17.1 ±9 µmol.l^–1 and at t6 47.8 ±25 µmol. l^–1. In17 transplanted patients with angiographically normal coronaryarteries, plasma homocysteine levels were at tO, 13.2 ±4µmol.l^–1 and at t6, 46.8±25µmol. l^–1. We conclude that hyperhomocysteinaemia is common in transplantedheart recipients, and partly related to renal insufficiency.No correlation was found between hyperhomocysteinaemia and angiographicevidence of coronary atherosclerosis of the graft, but the populationof the study was possibly too small to establish this correlation.     

Serum myoglobin for the early non-invasive detection of coronary reperfusion in patients with acute myocardial infarction

The ideal non-invasive method for detectmg coronary reperfusionhas not yet been established. In 63 patients with acute myocardialinfarction, serum myoglobin and creatine kinase-MB were measuredevery 15mm. Thrombolytic treatment was given (n=52) and acutecoronary angiography showed a patent infarct-related arteryin 49 patients while 14 patients had no coronary reperfusion.Median time to peak serum myoglobin was shorter (reperfusiongroup 178 mm vs no reperfusion group 480 min, P<0·0001)than time to peak serum creatine kinase-MB (reperfusion group550 mm vs no reperfusion group 1080 min, P<0·0001),P<0·0001. Myoglobin appearance rate, calculated asthe concentration at 2 h divided by baseline values (Mb₂/Mb₀)was highest in the reperfusion group (4·0 vs 1·6),P<0·001. An earlier proposed index, Mb₂/Mb₀>2·4 for identificationof reperfusion 2 h after thrombolytic therapy, showed predictivevalues of positive and negative tests of 0·94 and 0·44,respectively. Combining this mdex with signs of medium to largerinfarct size (Mb₂>200 µg . 1^–1)increased thepredictive value of the negative test to 1·00. In patientswith signs of minor mfarcts (Mb₂ <200 .µg .1^–1)the predictive values of positive and negative tests were 0·94and 0·79 respectively, 5 h after onset of thrombolytictherapy. An early rise and a peak in serum myoglobin values seems tobe a reliable and simple non-invasive indicator of successfuland unsuccessful reperfusion therapy. (Eur Heart J 1996; 17: 399–406)     

Hemodynamic and cardiac metabolic effects of inotropic stimulation with dobutamine in patients with coronary artery disease

The hemodynamic and myocardial metabolic effects of two intravenousdoses (5 and 10 ug/kg/min) of dobutamine were measured in 15patients with congestive heart failure secondary to coronaryartery disease. Dobutamine at 5 µg/kg/min induced an increasein peak rate of left ventricular pressure rise (dp/dt_max) from1004 ± 261 to 1386 ± 469 mm Hg x s^–1, coronarysinus blood flow (CSF) from 98 ± 34 to 128 ± 60ml/min and myocardial oxygen consumption (MVO₂) from 10.5 ±3.8 to 14.3 ± 6.9 ml/min. It decreased mean left ventricularend-diastolic pressure (LVEDP) from 24 ± 6 to 20 ±8 mm Hg. All changes were significant (P < 0.01). No significantchanges occurred in mean heart rate, left ventricular systolicpressure, arterio-coronary venous oxygen content differenceand mean myocardial lactate extraction rate. Dobutamine at 10 µg/kg/min further increased dp/dt_maxto 1545 ± 408 mm Hg x s^–1, CSF to 146 ±75 ml/min and MVO₂ to 17 ± 9.1 ml/min. Because mean heartrate also increased significantly from 73 ± 15 to 90± 23 beats/min it is possible that the concomitant increasein myocardial oxygen demand was no longer offset by the reductionin preload (further decrease of LVEDP to 18 ± 7 mm Hg).Thus, myocardial oxygen demand was inadequately met, myocardiallactate extraction rate decreased significantly (34 ±16 to 14 ± 20%, P < 0.01) and signs of myocardialischemia developed in three of the 15 patients. For this reason, heart rate should be monitored closely if dobutamineis given to patients with limited capacity to increase myocardialblood flow and oxygen delivery to the myocardium.     

Clinical cardiac electrophysiologic evaluation of the positive inotropic agent, DPI 201-106

DPI 201–106 is a new positive inotropic agent. The cardiacelectrophysiology of 16 patients was studied before and duringDPI 201–106 administration (loading dose of intravenousDPI 201–106, 1·8 mg kg^–1 h^–1 administeredover 10 min, followed by a maintenance dose of 0·2 mgkg^–1 h^–1). DPI 201–106 had no effect on thesinus node. The AH interval during fixed-rate atrial pacingbecame prolonged during DPI 201–106 infusion. There wasa significant prolongation of the QT interval [QT (corrected),417 ± 22 to 502 ± 35 ms, P<0·05; QT(atrial pacing at 600 ms), 374 ±17 to 419 ± 23ms, P<0·05; QT (ventricular pacing at 600 ms), 409± 37 to 449 ± 30 ms, P<0·05]. The ventriculareffective refractory period significantly prolonged during DPI201–106 administration (242 ± 21 to 287 ±56 ms, P < 0·05), but the supernormal-period durationdecreased. The atrial effective refractory period was shortenedin four patients and prolonged in one (261 ± 67 to 240± 53 ms, NS). The corrected atrial repolarization time(PT_ac) shortened significantly during DPI 210–106 infusion(479 ± 26 to 445 ± 22 ms at 20 min of the maintenancedose, P<0·05). Atrial fibrillation was initiated infive patients during DPI infusion, but no ventricular arrhythmiawas provoked. These findings suggest that DPI 201–106has novel differential electrophysiological effects on atriaand ventricles.     

Influence of nifedipine on left ventricular dysfunction at rest and during exercise

In order to determine the acute hemodynamic effect of nifedipineat rest and during a standardized supine bicycle exercise test(3 min, 50 W), 14 patients with left ventricular dysfunctionwere studied before and 60 min after taking 30 mg nifedipinesublingually. At rest (R) and during exercise (E), nifedipine produced a significantincrease in left ventricular systolic performance in terms ofstroke volume index (R: 33±6 to 38±4 ml/m², P<0.005;E: 32±5 to 37±6 ml/m², P<0.005) and cardiacindex (R: 2.9±0.4 to 3.6±0.5 l/min/m², P<0.001;E: 4.1±0.7 to 4.9±0.9 l/min/m², P<0.001) dueto a marked reduction in systemic vascular resistance (R: 1517±246to 1129±247 dynes s cm^–5, P<0.001; E: 1170±176to 908±129 dynes s cm^–5, P< 0.01). Pulmonary artery pressures did not change at rest, but droppedsignificantly during exercise, probably due to a shift in theleft ventricular pressure-volume relationship. The findingsof this study indicate that acute hemodynamic improvement canbe achieved by the sublingual use of nifedipine both at restand during exercise in patients with left ventricular dysfunction.Because the hemodynamic response in individual subjects mayvary, careful clinical observation or hemodynamic control isrecommended.     

Effects of simvastatin on plasma lipid, lipoprotein and apolipoprotein concentrations in hypercholesterolaemia

The effect of 24 weeks of treatment with simvastatin, a newHMG coenzyme A reductase inhibitor (dosages of 20 and40 mg day^–1)on serum lipid, lipoprotein and apolipoprotein A-I and B concentrationsas well as safety parameters and subjective side effects werestudied in 11 patients with familial (FH) and 10 patients withpolygenic hypercholesterolaemia (P-HC). The effects on plasmalipoprotein and apolipoprotein concentrations had already beenachieved after four weeks in both groups and then remained duringthe study. In FH, mean fasting plasma total cholesterol concentrationdecreased from 10·51 to 6·71 mmol l^–1 (36%),and in P-HC from 6·55 to 4·54 mmol l^–1 (31%)at 24 weeks (P<0·001). Mean plasma low density lipoprotein(LDL) cholesterol concentrations also decreased, in FH from8·87 to 5·05 mmol l^–1 (43%) and in P-HCfrom 4–97 to 3–12 mmol l^–1 (37%) at 24 weeks(P<0·001). Furthermore, apolipoprotein B concentrationsdecreased significantly from 2·21 to 1·57 g l^–1(29%)(P<0·001) in FH and from 1·53 to 1·09g l^–1 (29%) (P<0·01) in P-HC. Plasma high densitylipoprotein (HDL) cholesterol increased in both FH and P-HCduring treatment. Increases were seen in both the subfractionsHDL₂ and HDL₃. Simvastatin was well tolerated. No serious clinicalor laboratory adverse effects were observed. It is concludedthat 24 weeks of treatment with simvastatin in doses up to 40mg day^–1 effectively reduces plasma total and LDL cholesterolconcentrations without causing subjective or significant objectiveside effects. Thus, simvastatin may be of great interest infuture studies for prevention of coronary heart disease dueto hypercholesterolaemia.     

Skeletal muscle function at low work level as a model for daily activities in patients with chronic heart failure

AIM: Metabolic exercise abnormalities have been reported in chronicheart failure patients. This study sought to evaluate whetherthese abnormalities affected daily activity. METHODS AND RESULTS: In 16 patients with moderate-to-severe chronic heart failureand in eight controls we measured femoral flow (thermodilution)and metabolism (glucose, lactate, free fatty acids, blood gasvalues) at rest and during a constant load of 20 W, which maymimic a daily activity. At rest, chronic heart failure patientshad a leg flow similar to controls, but showed a higher legoxygen consumption (4·6±0· vs 2·6±0·4ml. min^–1; P>0·05), a higher arteriovenous oxygendifference (7·2±0·5 vs 5·4±0·7ml . d1^–1; P>0·05), and a lower femoral veinpH (7·37±5·–03 vs 7·42±0·01;P=0·01). At 20 W, chronic heart failure patients hada leg flow similar to controls, but showed increased lactaterelease (from resting 11·7±33 to 142+125 µg. min^–1 P>0·0001 vs controls, from resting 5·7±15·4to 50±149 µg . min^–1 ns), higher arterialconcentration of free fatty acids (781±69 vs 481±85µmol . 1^–1; P>0·01), lower femoral veinHCO₃ (24·1+2·6 vs 26·3±1·7mmol .1^–1;P>0·05) and base excess (–2·3+2·3vs –0·24±1·7 mmol . 1^–1 P=0·01 CONCLUSION: In chronic heart failure patients, the important cellular metabolicalterations already present at rest partially affect daily activities,owing to a further decrease in the efficiency of muscle metabolicprocesses, and may preclude tolerance of heavier activities.Such alterations appear, at least in part, independent of peripheralhaemodynamic responses to exercise.     

Effects of adrenaline on ventricular function and coronary haemodynamics in relation to catecholamine handling in transplanted human hearts

We investigated cardiovascular and coronary responses to intravenousinfusions of adrenaline, which raised arterial concentrationsin a stepwise fashion from basal to about 5–6 nmol. l^–1,in 11 non-rejecting heart transplanted patients, and in eightintact innervated subjects. Cardiac adrenaline extraction andnoradrenaline release rate were also measured. The transplanted patients showed larger increases in heart rate(36±11% vs 16±6%, P<0.0001 and cardiac index(80±30% vs 56±19%, P<0.05), while stroke volumeincrements were similar in the two groups (32±17% vs35±13%). The study groups did not differ with respectto changes in arterial pressure, cardiac work or peripheralresistances. Coronary sinus blood flow increased to a greaterextent in the transplanted group (75±35% vs 48±31%,P <0.05) and myocardial oxygen consumption also tended toincrease more in these patients (78±42% vs 48±34%,NS). Myocardial adrenaline extraction was greatly reduced inthe transplant patients (–6±25% vs 64±18%,P<0.001), while forearm adrenaline extraction was similarin the two groups (41±22% vs 40±23%, NS). Cardiacnoradrenaline overflow tended to be lower in the transplantedgroup (12±62 vs 48±43 pmol. min^–1, NS).There was a wide range of noradrenaline overflow values (–64to 147 pmol. min^–1) and definite high values in threepatients. Cardiac noradrenaline overflow was not correlatedto heart rate responsiveness to adrenaline. We conclude that patients with cardiac transplantation respondto adrenaline with exaggerated increases in heart rate and thusin cardiac output. High values of cardiac noradrenaline overfloware seen in some transplant recipients and may suggest reinnervation.Signs of reinnervation are not associated with consistentlylower heart rate responses to ß-adrenergic stimulation.     

Effects of antianginal therapy with a calcium antagonist and nitrates on dobutamine--atropine stress echocardiography: Comparison with exercise electrocardiography

BACKGROUND: Anti-ischaemic therapy with nitrates and/or calcium channelblockers profoundly affects the results of pharmacological stressechocardiography with coronary vasodilators but the influenceon catecholamine stress testing remains unsettled. AIMS: The present study aimed to assess the effects of non-beta-blockerantianginal therapy on dobutamine (up to 40 µg.kg^–1.min^–1)-atropine(up to 1 mg) stress echocardiography and to evaluate whetherdrug-induced changes in the dobutamine-atropine stress echocardiographyresponse may predict variations in exercise tolerance. METHODS: Twenty six patients with angiographically assessed coronaryartery disease (seven patients with single-, 10 with double-,and nine with triple-vessel disease) performed a dobutamine-atropinestress echocardiography and an exercise electrocardiographytest in random order both off and on antianginal drugs (nitratesand calcium antagonists). In dobutamine-atropine stress echocardiography,we evaluated: dobutamine time (i.e. the time from initiationof the dobutamine infusion to obvious dyssynergy), wall motionscore index (in a 16-segment model of the left ventricle, eachsegment ranging from 1=normal, to 4=dyskinetic), and rate-pressureproduct at peak stress. RESULTS: Dobutamine-atropine stress echocardiography positivity occurredin 26 out of 26 patients off and in 23 patients on therapy (100vs 88%, P=ns). Atropine coadministration was needed to evokeecho positivity in no patient off and in five out of 26 on therapy(0 vs 19%, P<0·01). The achieved rate-pressure productduring dobutamine-atropine stress echocardiography was comparableon and off therapy (17±4 vs 19±5x10³ mmHgxheartrate. min^–1, Pns). Therapy induced an increase in dobutaminetime (on=16±3 vs off=13±3 min, P<0·01)and a decrease in peak wall motion score index (on=1·3±0·2vs off=1·5±0·3, P<0·01). Thetherapy-induced changes in exercise time during the exerciseelectrocardiography test were not significantly correlated todobutamine-atropine stress echocardiography variations in eitherdobutamine time (r=0·07, P=ns), or peak rate-pressureproduct (r=0·24, P=ns), or peak wall motion score index(r=0·02, P=ns). CONCLUSION: (1) non-beta-blocker antianginal therapy only modestly reducesdobutamine-atropine stress echocardiography sensitivity, althoughatropine coadministration is more often required to reach stressecho positivity under therapy; (2) therapy reduces the severityof dobutamine-atropine stress echocardiography ischaemia stratifiedin the time and space domain, but these changes are only poorlycorrelated to variations in exercise tolerance.     

Left ventricular filling pattern in {beta}-thalassaemia major -- a Doppler echocardiographic study

The pattern of left ventricular filling was assessed by Dopplerechocardiography in 38 adult ß-thalassaemia majorpatients; 28 with normal (age 25.2±5.3 years) and 10with abnormal (age 24.5±8.8 years) left ventricular systolicfunction. The findings were compared with those obtained from38 age and sex matched normal individuals. In patients with normal left ventricular systolic function,peak flow velocity in early diastole was higher than in thecontrols (94±16 vs 79±12 cm. s^–1 P <0.001).The peak flow velocity in late diastole was also greater (60±18vs 46±9cm. s^–1 P <0.001) but the ratio betweenthe early and late (atrial) peaks was approximately the samein both groups (1.74±0.72 vs 1.70±0.30 There wasno difference in deceleration time and rate between the twogroups (152±32 vs 151±21 ms and 504±93vs 508±115 cm. s^–2 respectively). None of the patientshad atrial predominant left ventricular inflow pattern. In patients with congestive heart failure the peak flow velocityin early diastole was greater than in the controls (96±10vs 79±2 cm. s^–1 P < 0.001) while in late diastoleit was smaller (39±6 vs 44±2 cm. s^–1 P <0.05).The ratio between the early and late peaks was greater in thepatients than in the controls (2.5±0.35 vs 1.8±0.08,P <0.001). The deceleration time and rate were not significantlydifferent in the two groups (153±33 vs 152±17msand 617±219 vs 550±56 cm. s^–2 respectively),until the end stage of congestive heart failure. Thus, leftventricular filling pattern in ß-thalassaemia majorpatients with normal left ventricular systolic function, issimilar to that seen in conditions of an increased preload.Patterns compatible with abnormally prolonged relaxation orrestriction do not appear.     

Effects of positive inotropic stimulation (post-extrasystolic potentiation) on non-uniformity of left ventricular contraction in patients with coronary artery disease

In patients with chronic coronary artery disease, post-extrasystolicpotentiation (PESP) slightly worsens relaxation, increasingthe constant of ventricular pressure decay. However, it doesnot negatively influence left ventricular (LV) diastolic filling.To our knowledge, no data are available on the effects of PESPon segmental relaxation in chronic coronary artery disease. The effects of PESP on the LV pressure–volume (P/V) relationshipand on segmental pressure–length loops (P/L) were studiedin eight patients with coronary artery disease submitted toLV angiography. P/V loops were constructed by means of frame-to-frame analysisof ventriculograms and simultaneous high-fidelity LV pressuretracings; P/L loops were calculated by the endocardial movementof 45 chords intersecting the LV outline (centreline method).PESP was produced by programmed stimulation during ventriculography.P/V and P/L loops were studied in basal conditions and afterPESP. Results showed enhanced LV pump function (ejection fractionfrom 0.45 ± 0.14 to 0.54 ± 0.13, P<0.01; LVstroke work index from 62±29 to 79±28 g. m^–1.m^–2,P<0.01; the LV end-systolic pressure–volume relationfrom 2.9±1 to 3.2±2 mmHg.ml^–1, P<0.05)associated with impaired relaxation (time constant _w, from 40±9to 48±8 ms, P<0.01; time constant _m from 53±11to 61±10 ms, P<0.05;peak filling rate from 3.7 ±1 to 2.3 ± 1 EDV.s^–1, P<0.01; minimal diastolicpressure from 6±6 to 7.5±6 mmHg, P<0.05) andwith increased preload (EDVI from 97±27 to 106±27ml.m^–2, P<0.01; LVEDP from 16 ± 9 to 19 ±7 mmHg, P<0.01). P/L loops showed increased non-unformityof LV relaxation after PESP. The effects were more evident inthe segments showing P/L loops inclined to the left, where PESPincreased or caused the appearance of post-systolic shortening.PESP showed only slight or no effect in the segments showingP/L loops inclined towards the right. PESP slightly impaired early left ventricular filling by decreasingthe rate of fall of intraventricular pressure and increasingthe non-unformity of contraction and relaxation. However, itdid not change the isovolumic phases of pressure–lengthloops of normal segments, while worsened relaxation of hypokinetic(probably ischaemic) segments with the appearance of post-systolicshortening in the loops inclined to the left.     

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.