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.     

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.     

Evidence of oxidative stress in chronic heart failure in humans

Chronic heart failure (CHF) due to coronary artery disease (CAD)has been shown to be associated with increased plasma thiobarbituricreactive substances (TBARS) and reduced plasma thiol (PSH) concentrations,suggesting oxidative stress (OS). The aims of the present studieswere (a) to determine whether OS is due to CAD or CHF per seand (b) to determine if a wider range of more specific markersof OS are abnormal in CHF. In the first study, two groups of patients (n = 15 each) werecompared. Group 1 (11 male, mean age 56 years) had CHF due toCAD and group 2 (12 male, mean age 53 years) had non-CAD CHF.Median plasma TBARS in controls was 7.6 nmol . ml^–1 ,10.0 nmol . m^–1 in group 1 and 9.3 nmol. ml^–1 ingroup 2 (P < 0.01 both groups vs control). Median PSH was505 384 and 364 nmol. ml^–1 (P < 0.05 and P < 0.01vs control) respectively. Fifty-three patients with CHF were recruited in the second study.Malondialdehyde and PSH were 10.3 and 409 nmol. ml^–1 respectively,compared to control values of 7.9 and 560 nmol. ml^.1 (both P< 0.001). The median values for the following additionalmeasures of OS in controls and patients were: erythrocyte superoxidedismustase 131 vs 114 U . l^–1 (P = 0.005); caeruloplasminoxidase 97 vs 197 U. l^–1 (P < 0.01); erythrocyte glutathione1.56 nmol . ml^–1 vs 1.77 nmol . ml^–1 (P < 0.02);plasma conjugated dienes 0.28 vs 0.33 optical density units(P = ns). Chronic heart failure, regardless of aetiology, is associatedwith abnormalities of a range of markers of OS.     

Pattern of left ventricular filling in hypertrophic cardiomyopathy: Assessment by Doppler echocardiography and radionuclide angiography

Aims The left ventricle in hypertrophic cardiomyopathy is anatomicallyand functionally non-uniform. This study was undertaken to verifywhether a heterogeneity in the pattern of diastolic fillingcan be detected along the left ventricular inflow tract in hypertrophiccardiomyopathy. Methods and results Early (E) and late (A) diastolic velocitieswere recorded by Doppler echocardiography at mitral and at mid-ventricularlevel in 16 normal volunteers and 30 patients with hypertrophiccardiomyopathy. Patients with hypertrophic cardiomyopathy alsounderwent radionuclide angiography to assess left ventricularfunction. E wave decreased significantly in normal volunteers(80±15 to 60±14cm.s^–1;P<0·001),but it increased in hypertrophic cardiomyopathy (76±22to 87±28cm.s^–1;P=0·04), whereas the A wavedecreased similarly in both. By multivariate analysis, systolicasynchrony and the ejection fraction of left ventricular lateralwall were directly related to the pattern of early filling progression(r=0·656; F=9·467;P<0·002). Moreover,systolic asynchrony showed a univariate direct correlation withchanges in E velocity (r=0·42;P=0·02). Conclusion Many patients with hypertrophic cardio-myopathy havean acceleration of filling within the left ventricular inflowtract; this phenomenon is directly related to systolic asynchronyand ejection fraction of the left ventricular lateral wall,suggesting increased suction.     

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.     

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.     

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.     

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.     

Role of endogenous opioids and catecholamines in vasovagal syncope

Head-up tilt testing demonstrates vasovagal mechanisms as acause for syncope, but the pathophysiology underlying this conditionremains unclear. The aim of this study was (i) to measure plasmaß-endorphins, adrenocorticotrophic hormone, cortisol,catecholamines, and brain natriuretic peptide during head-uptilt, and (ii) to assess the effect of naloxone infusion duringhead-up tilt in subjects with reproducible vasovagal syncope.During the assessment of unexplained syncope, 71 subjects underwenta total of 93 tilt tests (60–70° head upwards for40–45 min or until syncope occurred) during which frequentblood sampling was performed. Subjects with a positive tilttest (n=56) (mean duration to syncope 23.6 min) showed a largerrise in ß-endorphin levels prior to syncope (baseline4.7 ± 2.2 vs syncope onset 6.9 ± 3.2 pmol . 1^–1,P=0.0001) than those with a negative test (n=37) (baseline 39± 3.9 vs end of test 4.9 ± 2.3 pmol. 1^–1,P=0.03). During tilting, adrenocorticotrophic hormone, cortisol,and noradrenaline increased; adrenaline and brain natriureticpeptide remained unchanged; and these responses were similarin positive and negative test groups. Naloxone (2.6 mg. kg^–1i.v. bolus followed by 20 µg. kg ^–1. min ^–1infusion), administered in a double-blind fashion during head-uptilt in nine subjects, failed tomodify either the time to syncopeor the vasodepressor response. Thus, endogenous opioids appearnot to be an important trigger for vasovagal syncope, and otherpathophysiological mechanisms should be considered.     

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.     

Altered autonomic cardiac control in hypertrophic cardiomyopathy: Role of outflow tract obstruction and myocardial hypertrophy

Aim The goal of this study was to investigate the role of leftventricular outflow tract obstruction and myocardial hypertrophyon autonomic cardiac function in patients with hypertrophiccardiomyopathy. Methods and results The sympatho-vagal function was evaluatedby spectral analysis of heart rate variability in 28 patientswith hypertrophic obstructive cardiomyopathy, 22 patients withhypertrophic non-obstructive cardiomyopathy, 12 with systemichypertension and left ventricular hypertrophy and 28 healthysubjects. Left ventricular outflow tract pressure gradient inpatients with hypertrophic cardiomyopathy was evaluated by echo-Dopplermethods and the quantitative assessment of left ventricularhyper-trophy was based on an echocardiographic index. At rest,patients with hypertrophic non-obstructive cardiomyop-athy showednormal spectral patterns, while in patients with hypertrophicobstructive cardiomyopathy and in patients with systemic hypertensionwe observed, respectively, a significant reduction and increasein the low frequency component relative to the control (P<0·05).During tilt, the physiological increases in the low frequencycomponent, and in the low to high frequency ratio were markedlyblunted, or even reverted, only in patients with hypertrophicobstructive cardiomyopathy. In these patients, the heart rateincrease during tilt was delayed in comparison to the othergroups. Finally, in the hypertrophic obstructive cardiomyopathygroup, the impairment of sympathetic activation (lack of increasein the low frequency component during tilt) was significantlycorrelated to the echocardiographic index of left ventricularhypertrophy (r=–0·800,P<0·001) ratherthan to the left ventricular outflow tract pressure gradient(r=0·295,P: ns). Conclusion Among patients with hypertrophic cardiomyopathy,only those with outflow tract obstruction show spectral signsof altered autonomic cardiac control. Within this group, theautonomic dysfunction appears to be correlated to myocardialhypertrophy rather than to left ventricular outflow tract obstruction.     

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.     

Platelet aggregability to platelet activating factor at rest and after exercise in patients with coronary artery disease

The platelet response to the aggregatory effect of platelet-activatingfactor (PAF) in relation to blood PAF levels, serum PAF-acetylhydrolase(PAF-AH) activity and to their lipidoemic profile, was studiedin 44 patients with coronary artery disease undergoing exercisetests. The PAF EC₅₀ values in 21 patients with positive exercisetest results were found to be significantly decreased at restcompared with 21 normal subjects (126±3•9 nM and24•9±11•7 nM respectively) (P<0•0001).Moreover, the maximal percentage of aggregation to 50 nM PAFwas found to be significantly increased (20•0±4•3%vs 13•5±3•6% respectively) (P<0•0001).By contrast, the PAF EC₅₀ values and the maximal percentageof aggregation in 23 patients with negative exercise test resultswere not statistically significantly different from the controlgroup (25•2±11•4 nM and 14•1±4•7%,respectively). At the end of exercise, the PAF EC₅₀ values and the maximalpercentage of aggregation did not change in any group, and therewere no significant differences in the whole-blood PAF levelseither at rest or at the end of exercise. In patients with positiveexercise test results, the PAF-AH activity at rest was significantlyhigher compared with the control group (37•2±8•0nmol. ml^–1. min^–1 vs 32•4±4•3 nmol.ml^–1. min^–1), (P<0•03), whereas the enzymeactivity did not differ in patients with negative exercise testresults compared to controls (33•6±6•1 nmol.ml^–1. min^–1). There was no change in PAF-AH activity during exercise in anygroup. The enzyme activity was positively correlated to theserum total and low density lipoprotein (LDL) cholesterol levelsin the control group and in patients with negative exercisetest results, whereas no correlation was found between PAF-AHactivity and total or LDL cholesterol levels in patients withpositive exercise test results. Our results suggest that platelethyper-reactivity to PAF may play a pathophysiological role inmyocardial ischaemia observed during exercise in coronary arterydisease patients.     

Hyperleptinaemia in chronic heart failure: Relationships with insulin

Background Leptin, a product of theobgene, is known to increaseenergy expenditure. Given that chronic heart failure is a hypercatabolicstate, we sought to determine whether congestive heart failureinvolves elevations in plasma leptin levels. Since leptin secretionis up-regulated by insulin, we also explored whether in congestiveheart failure, a hyperinsulinaemic state, plasma leptin levelsrelate to plasma insulin levels. Methods Male patients with weight-stable congestive heart failure(n=25, aged 55·5±2·0, mean±SEM,body mass index=27·4±0·8, radionuclideleft ventricular ejection fraction=29·3±3·0%)and 18 controls, matched for age, sex and body fat (dual energyX-ray absorp-tiometry), underwent measurement of fasting plasmaleptin (radioimmunoassay) and insulin levels. Results Compared to controls, patients with congestive heartfailure had higher plasma leptin [8·12 (–1·12,+1·31)vs 4·48 (–0·61,+0·70) ng.ml^–1,mean±asymmetrical SEM,P=0·003], 41·5% higherplasma leptin per percent body fat mass (P<0·001),and higher fasting insulin levels [67·8 (–11·1,+13·3)vs 32·9 (–5·7,+6·9) pmol.l^–1,P=0·010].In the congestive heart failure group, plasma leptin correlatedwith total body fat (r=0·66) and fasting insulin (r=0·68)(bothP<0·001). In multivariate regression analysesof the congestive heart failure group, fasting insulin (standardizedcoefficient=0·41,P=0·011) emerged as a predictorof plasma leptin levels, independent of total body fat (standardizedcoefficient=0·73,P=0·002, R²=0·66,P<0·001). Conclusions Plasma leptin levels are raised in patients withcongestive heart failure. The observation of a positive relationshipbetween plasma leptin and insulin concentrations suggests thatthe insulin–leptin axis may be related to the increasedenergy expenditure observed in patients with congestive heartfailure.     

Pharmacokinetics and additional anti-ischaemic effectiveness of amlodipine, a once-daily calcium antagonist, during acute and long-term therapy of stable angina pectoris in patients pre-treated with a beta-blocker

Amlodipine 10 mg was evaluated/or additional anti-ischaemicand anti-anginal efficacy in 14 patients pre-treated with aßblocker who had documented coronary artery disease,stable angina pectoris, and 2 mm of exercise-induced ST segmentdepression. For 2 days the patients received open-label amlodipineand then, according to a randomized, placebo controlled, cross-overand double-blind protocol, they were treated with amlodipineor placebo, respectively, once a day for 3 weeks each. Exercisetests and blood sampling for plasma concentrations of amlodipinewere performed at 8 and at 24 h after dosing on both days ofacute testing as well as on day 18 of chronic treatment. During chronic treatment, when plasma concentrations fluctuatedbetween 23.5 ng. ml^–1 at 8 h and 14 ng.ml^–1 at 24h post-dosing, ST segment depression at an individually comparableworkload was significantly decreased by 28% compared with placebo(P < 0.005) at both points in time. Increases in ischaemia-freeworkload capacity amounted to 76% (P < 0.005) and to 81%(P < 0.01) at 8 and at 24 h, respectively. The number ofanginal attacks was reduced by 39% (P < 0.05). Conversely,after initial dosing, i.e. when plasma concentrations declinedfrom 4.7 ng.ml^–1 to 3.9ng.ml^–1, influences uponischaemic parameters compared to control values were markedlyless at 24 h as opposed to 8 h. There were no untoward sideeffects observed at any point in time. Thus, a combination of amlodipine 10 mg with a ß-blockerenables additional anti-ischaemic and anti-anginal therapeuticcoverage for 24 h during long-term treatment, facilitating patientcompliance through once-daily administration.     

Late activation of the fibrinolytic system in myocardial infarction treated with thrombolytic therapy: Influence of the coronary anatomical substrate

Procoagulant activity, thrombin and fibrinolytic system activationhave been demonstrated in the first 24–48 h after acutemyocardial infarction treated with thrombolytic therapy. Littleis known about what happens in the subsequent days, during whichthe incidence of ischaemic recurrence is high. In 21 patients treated with streptokinase and in 20 patientstreated with urokinase we evaluated, with multiple plasma determinations,D-dimer and fibrinogen plasma levels in the first week aftermyocardial infarction. From the 2nd hour after the begrnningof thrombolysis to the 4th day, all patients received intravenousheparin in doses sufficient to raise the partial thromboplastintime to twice its normal level; subcutaneous calcium heparin(12 000 U/day) was subsequently substituted for the intravenousroute. Coronary angiography was performed 7 days after infarction.From the basal values 2·22 ± 1·44 nmol.1^–1 in the strep tokinase group and 3·28 ±3·05 nmol . 1^–1 in the urokinase group, D-dimerrose consistently in the 1st hour after thrombolysis 269·4± 206·7 nmol . 1^–1 and 44·5 ±35·5 nmol . 1^–1 in the streptokinase and urokinasegroups, respectively; P<0·00l. After the peak value,which in both groups was reached after 5 h, D-dimer slowly decreasedduring the study period. It reverted to normal values only in10/21 patients in the streptokinase group; in the urokinasegroup normalization was attained in 14/20 patients between the3rd and 6th days. After withdrawal of i.v. heparin in patientsof both groups with TIMI 0 or 1 grade of coronary patency, D-dimerrose to levels four to seven times greater than normal; in patientsof both groups with TIMI 2 or 3 grade coronary flow, D-dimershowed a monophasic pat tern of progressive normalization (P<0·05and P<0·0l at the 6th and 7th days, respectively,for differences between TIMI 0–1 and TIMI 2–3 groups). After myocardial infarction, thrombolysis is followed by activeand persistent fibrin degradation more marked and lasting afterstreptokinase than after urokinase. When occurring sooner, itis a consequence of plasmin activation induced by thrombolyticagents; later it seems to be related to intracoronary substrate,as suggested by the relation ship of plasma elevation of D-dimerwith the presence of occluded or subocciuded infarction-relatedvessels.     

Cardiac anatomy, function and metabolism in elite cyclists assessed by magnetic resonance imaging and spectroscopy

We investigated whether left ventricular hypertrophy in elitecyclists is associated with functional changes or abnormal energymetabolism. Left ventricular hypertrophy is a powerful risk factor for suddencardiac death with different prognostic significance among thevarious geometric forms. Cyclists may have a combination ofmixed eccentric and concentric hypertrophy. Magnetic resonance imaging was used to define left ventricularmass, geometry and function. Thirteen highly trained male cyclistsand 12 healthy controls were investigated. Proton-decoupledphosphorus-31 cardiac spectroscopy was performed to assess parametersof myocardial high-energy phosphate metabolism. Left ventricularmass and end-diastolic volumes normalized for body surface areawere significantly higher in cyclists (124·1 ±9·4 g. m^–2 and 106·2 ± 11·4ml. m^–2, respectively) than in controls (85·9 ±9·3 g. m^–2 and 79·1 ± 11·6ml. m^–2, respectively), (both P<0·0001). Theleft ventricular mass to end-diastolic volume ratio, as a parameterof left ventricular geometry, was not significantly increasedin cyclists compared to controls. Resting left ventricular ejectionfraction, cardiac index, and systolic wall stress in cyclistsdid not differ significantly from those of controls. The phosphocreatineto adenosine triphosphate ratio was not significantly differentbetween cyclists and controls (2·2 ± 0·34vs 2·2 ± 0·17, ns). Cyclists show prominent left ventricular hypertrophy with normalgeometry. The finding that the hypertrophic hearts of the cyclistshad normal left ventricular function and a normal phosphocreatineto adenosine triphosphate ratio suggests that sport-inducedleft ventricular hypertrophy is a physiological adaptation ratherthan a pathophysiological response.     

Short-term cardiac adaptation to severe haemodilution: an echocardiographic study in normal and hypertensive subjects

In order to avoid transfusion risks and optimize blood bankresources, in recent years many blood sparing techniques havebeen proposed, including severe haemodilution. The aim of thisstudy is to assess the pattern of normal haemodynamic and cardiacadaptation to severe haemodilution in patients undergoing majororthopaedic surgery and refusing blood transfusions for religiousreasons (the patients were Jehovah's Witnesses). Two-dimensionally guided M-mode echocardiograms were performedat baseline and 4 days after major orthopaedic surgery in 26Jehovah's Witnesses (age 61±11 years), with normal regionaland global baseline left ventricular function and no valvulardisease. Left ventricular (LV) volumes were estimated by usingthe Teichholz formula. From the latter, we calculated ejectionfraction and stroke volume, cardiac output (stroke volumex heartrate), and total peripheral resistance estimated as mean arterialpressure by cuff sphygmomanometer x 80/cardiac output. On thebasis of LV mass (ASE-cube corrected by Devereux), two groupswere identified: non-hypertrophic (LV mass index <110 g.m^–2 in women and <130g. m^–2 in males) and hypertrophic. In the 19 patients without LV hypertrophy, haemoglobin decreasedfrom 13.5±1.6 (mean ± standard deviation) g. dl^–1(at baseline) to 8.7 ± 1.3 post-operation (P<0.01),and peripheral vascular resistances fell from 2131 ±450 to 1278±310 (dyne. s. cm^–5) (P<0.01). Therewas an increase in heart rate (from 68±9 to 87±9beats. min^–1, P<0.01) and cardiac output (from 3.8±0.7 to 6.7 ±1.41 min^–1, P<0.01), witha rise in ejection fraction (from 62 ± 5 to 66 ±6%, P<0.01) and a decrease in relative wall thickness (from0.42 ± 0.03 to 0.35 ± 0.04, P<0.01). In theseven hypertensive hypertrophic patients, haemoglobin went from12.4 ± 1 (at baseline) to 8.4 ± 1.5 post-operation(P<0.01) and peripheral vascular resistances fell from 2551± 845 to 1363 ± 413 (P<0.01). There was anincrease in heart rate (+38%) and cardiac output (+46%) comparableto that found in non-hypertrophic patients, but with no significantvariation in LV relative wall thickness (from 0.50 ±0.08 to 0.48 ± 0.05, P=ns) and no increase in ejectionfraction (from 62 ±8 to 62.3 ±9%, P=ns). Therewas an inverse correlation between haemoglobin levels and LVcardiac output in both the normal (r= - 0.74; P<0.01) andthe hypertrophic (r= -0.63, P<0.05) group. In conclusion, severe haemodilution induces a high output statewith a fall in peripheral vascular resistance. This haemodynamicadaptation is accompanied by an eccentric remodelling in normal,but not in hypertrophic, hearts. In normal patients, but muchless so in the hypertrophic ones, LV geometry is a dynamic variablewhich can be profoundly modified by a few days of severe haemodilutionand can thus significantly contribute to the overall adaptationto altered haemodynamics.     

Effect of altered loading conditions during haemodialysis on left ventricular filling pattern

Changes in the circulating volume associated with haemodialysisresult in modification of left ventricular loading conditions.To determine the influence of haemodialysis on Doppler indicesof left ventricular filling, 12 patients (mean age 40.8 ±2.7(SEM) years) with renal insufficiency but without overt heartdisease were studied by Doppler-echocardiography immediatelybefore and after haemodialysis. Haemodialysis resulted in adecrease in body weight from 68.0±3.8 kg to 65.0 ±3.7kg (P< 0.01). Heart rate and blood pressure did not changesignificantly during haemodialysis. Left ventricular diastolicdimension (M-mode) decreased from 53.5±1.1 mm to 49.5±1.9mm (P < 0.05), whereas the shortening fraction did not change.Haemodialysis elicited marked changes in the early diastolicrapid filling wave (E wave) recorded by pulsed Doppler at thelevel of the mitral annulus. Peak velocity of the early rapidfilling phase (peak E) decreased significantly from 95.3 ±8.2 cm .s^–1 to 63.0 ±5.7cm .s^–1 (P< 0.001)and mid-diastolic deceleration of transmitral velocity decreasedfrom 437.3 ±54.2 cm . s^–2 to 239.7 ±54.4cm . s^–2 (P<0.01). The peak filling velocity duringatrial contraction (peak A) did not change (79.7 ±6.3cm .s^–1 vs 74.1±4.7 cm.s^–1;P=NS). The ratiopeak E/peak A decreasedfrom 1.19±0.06 to 0.85 ±0.04 (P < 0.01) during haemodialysis. The results providefurther evidence for the pronounced preload-dependence of Dopplerindices of left ventricular diastolic function.     

Effects of clopidogrel, aspirin and combined therapy in a porcine ex vivo model of high-shear induced stent thrombosis

Aims Use of ticlopidine in coronary stenting is limited by delayedonset of action. We studied the effects of clopidogrel, a rapidlyacting analog of ticlopidine alone, and in combination withaspirin, in inhibiting stent thrombosis.|P[s8|P]Methods Unpolished nitinol stents were deployed in a porcine ex vivoarteriovenous shunt and exposed to flowing arterial blood ata shear rate of approximately 1500.s^–1. Stent thrombus,platelet aggregation and bleeding times were measured at baselineand after treatment.|P[s8|P]Results Intravenous clopidogrel produced a rapid (within 30min) anddose-dependent inhibition of stent thrombosis, with 87% reductionat a dose of 10mg.kg^–1(P<0·001). Aspirin alone(10mg.kg^–1) was minimally effective (20% inhibitionP>0·05)in inhibiting stent thrombosis. Combined treatment with clopidogreland aspirin produced 95–98% inhibition of stent thrombosis,even at low doses of clopidogrel (2·5–5·0mg.kg^–1)(P<0·0001). At effective doses both clopidogrel andcombined therapy produced significant prolongation of bleedingtime (P<0·05) and inhibition of platelet aggregation(P<0·05). Conclusion Clopidogrel, either alone or combined with aspirin,may have a potential role in preventing stent thrombosis inhigh-risk clinical situations.