Short-term effects of atrial versus atrio-ventricular pacing on myocardial ischaemia in coronary artery disease patients

This investigation was undertaken to evaluate the effects ofshort-term atrial vs atrio-ventricular pacing on myocardialischaemia. The study was in two parts. In part one, 12 coronary arterydisease patients were studied to investigate the effects ofthe two pacing modes on angina pectoris, coronary sinus O₂ saturationand lactate. The two pacing modes were each applied for 5 minat 25 beats. min^–1 more than the maximum heart rate ofthe exercise test. Coronary sinus O₂ saturation and lactatewere estimated before and after pacing. In part two, 13 patientswith left anterior descending coronary artery disease were studiedto investigate the effects of the two pacing modes on coronaryflow reserve, using a Doppler catheter in the above mentionedbranch after the administration of 10 mg intracoronary papaverine.The pacing rate was 15 beats . min^–1 greater than theresting heart rate. Coronary sinus lactate and O₂ saturation changes were the sameand angina pectoris developed at about the same time from thebeginning of pacing under both modes. Coronary flow reservewas 2.1±0.7 during atrial pacing and 2.1±1.1 duringatrio-ventricular pacing (ns). It is concluded that short-term atrial and atrio-ventricularpacing have the same effects on myocardial ischaemia in coronaryartery disease patients.     

Felodipine in ventricular dysfunction

The systemic and coronary haemodynamic effects of felodipinewere evaluated at rest and during stress induced atrial pacingin fourteen patients with chronic cardiac failure, secondaryto coronary heart disease. Felodipine was an effective arteriolarvasodilator producing increases in cardiac index from 2.6 ±0.l to 3.5 ± 0.2 l min^–1 m^–2 (P<0.001)and stroke volume 35.3 ± 2.7 to 41.4 ± 2.4 mlbeat^–1 m^–2 (P<0.002). Coronary venous flow also increased significantly (126 ±8 to 168 ± 13 ml min^–1) (P<0.005) and this didnot appear to be accompanied by an increase in myocardial oxygenusage, as myocardial oxygen consumption was essentially unchanged.When the myocardium was stressed by atrial pacing the increasein cardiac output and stroke volume was maintained—25%and 23%, respectively (P<0.01). These results suggest thatfelodipine may well have a significant role in the managementof patients with congestive cardiac failure.     

The effects of intracoronary substance P and acetylcholine on coronary blood flow in patients with idiopathic dilated cardiomyopathy

Attenuation of the increase in blood flow caused by acetylcholinein the peripheral vasculature and coronary circulation of patientswith heart failure has been interpreted as an impairment ofendothelium-dependent vasodilation. The aim of this study wasto compare in man the effects of acetylcholine, which also hasendothelium-independent actions, with substance P, which appearsto be a pure endothelium-dependent vasodilator, on epicardialand resistance coronary arteries in patients with idiopathicdilated cardiomyopathy. The effects of intracoronary acetylcholine (10^–1M and10^–6M) and substance P (5, 10 and 25 pmol. min^–1)on epicardial coronary artery diameter and coronary blood flowvelocity were measured with an intracoronary Doppler flow probeand quantitative coronary angiography in 11 patients with idiopathicdilated cardiomyopathy and 10 control subjects. Epicardial coronary artery diameter did not change with acetylcholinebut increased significantly with substance P in both groups(cardiomyopathy patients: 3.3 ± 0.2 mm (mean ±SEM) at baseline vs 3.9 ± 0.2 mm with substance P 25pmol. min^–1, P<0.01, controls: 3.1± 0.2 mm atbaseline vs 3.9 ± 0.3 mm with substance P 25 pmol. min^–1,P<0.05). Coronary flow ratios with acetylcholine were lowerin cardiomyopathy patients (10^–7m: 1.4± 0.1 vs2.3 ± 0.4, P=0.05; 10^–6M: 1.8 ± 0.2 vs 3.2± 0.5, P=0.05 vs controls). Coronary flow ratios withsubstance P 5, 10 and 25 pmol. min^–1 were 1.5 ±0.1 vs 1.5± 0.1, l.8 ± 0.2 vs 2.2 ± 0.2and 2.1 ±0.2 vs2.8 ± 0.3 (P=NS, cardiomyopathypatients vs controls respectively). Whereas epicardial coronary artery responses to acetylcholineand substance P are similar in patients with dilated cardiomyopathyand control subjects, the actions of acetylcholine and substanceP on coronary resistance vessels differ. The impairment withacetylcholine has several components, related either to muscarinicreceptorltransduction mechanisms or the production of othervasoactive compounds, rather than a simple inability of thevascular endothelium to cause vasodilation.     

The protective effect of L-arginine on myocardial injury and endothelial function following ischaemia and reperfusion in the pig

The protective effect of the nitric oxide (NO) substrate L-arginineon myocardial ischaemialreperfusion injury was studied in pigs.Four groups were subjected to 45 min ischaemia and 4 h reperfusion.One control group received coronary venous retroinfusion ofsaline, the second retroinfusion of L-arginine (1 mg. kg^–1.min^–1), the third retroinfusion of L-arginine plus theNO synthase inhibitor N-nitro-L-arginine (L-NNA), and the fourthsystemic i.v. infusion of L-arginine (1 mg. kg^–1. min^–1).The infarct size in the L-arginine retroinfusion group was 35± 5% of the myocardial area at risk compared to 76 ±5% in saline treated controls (P<0.001). In pigs receivingthe combination of retroinfused L-arginine and L-NNA the infarctsize was similar to that of controls (79 ± 4%). Systemici.v. infusion of L-arginine did not influence the infarct size.Administration of L-NNA + L-arginine slightly increased arterialblood pressure during ischaemia but the groups did not differin blood pressure, heart rate, rate-pressure product, left ventriculardP/dt or coronary blood flow during the reperfusion period.Coronary vasodilatation by acetylcholine was significantly compromisedin the saline retroinfusion group, but not in the L-arginineretroinfusion group as compared to pigs not subjected to myocardialischaemia. The results show that coronary venous retroinfusionof L-arginine reduces myocardial infarct size and preservesendothelial function via a local action which seems to be relatedto maintained nitric oxide formation.     

The link between acute haemodynamic adrenergic beta-blockade and long-term effects in patients with heart failure: A study on diastolic function, heart rate and myocardial metabolism following intravenous metoprolol

The present study was performed to find possible mechanismslinking the early effects of beta-blockade with the observedlong-term effects in patients with heart failure. In 57 patients with heart failure, 13±3.1 mg of metoprololwas given intravenously. The patients were investigated by invasivehaemodynamics (n = 34), including collection of myocardial metabolicdata during atrial pacing stress (n = 16), by radionuclide angiographyduring physiological atrial pacing (n = 13), and by a bedsideevaluation (n = 10). Diastolic function, measured by early peak filling rate, followedchanges in heart rate, but was similar when heart rate was heldconstant by atrial pacing before and after beta-blockade. Followingbeta-blockade and slower heart rates, diastolic filling volumeswere redistributed to late diastole. Metoprolol induced a paralleldecrease in coronary sinus flow and myocardial oxygen consumption.Myocardial oxygen consumption following beta-blockade decreasedboth during spontaneous rhythm (25±15 to 16±8.8ml. min^–1; P = 0.006), and during atrial pacing stress(30±13 to 23±11 ml.min^–1; P = 0.004). Cardiacindex decreased owing to reduction of heart rate (2.3±1.0to 1.9±0.64 l.min^–1.m²; P = 0.0003), while leftventricular filling pressure was unchanged. Ejection fractionand ventricular volumes were unaltered following atrial pacingor beta-blockade. There was a reflex increase in noradenalineconcentration after beta-blockade injection (0.96±0.66to 1.20±0.91 nmol.l^–1; P = 0.002), whereas myocardialnoradrenaline overflow was unchanged. There was a trend towardsan increase in myocardial lactate consumption after beta-blockadeadministration during atrial pacing stress. It is suggested that the surprisingly good tolerability seenafter acute administration of beta-blockers to patients withsevere heart failure may be explained by prolongation of thediastolic filling phase, which outweighs the negative ino tropiceffects. The reduced myocardial metabolic demand may allow thefailing myocardium to recover and explain the excellent long-termeffect on heart function following beta-blockade treatment.     

Haemodynamic and cardiac metabolic effects of the new {beta}1 agonist prenalterol in patients with cardiac failure

Prenalterol, a ß₁ selective agonist, exerts a positiveinotropic action in animal studies as well as in human volunteersand is effective when administered orally. To assess its immediatehaemodynamic and myocardial metabolic effects, we studied theresponse to prenalterol (50 and 100 µg kg^–1 givenintravenously by cardiac catheterization) in 15 patients withcongestive heart failure secondary to coronary artery diseaseor non-ischaemic cardiomyopathy. At peak effect, cardiac indexincreased from 2.6 ± 0.5 to 3.2 ± 0.81 min^–1m² (mean ± S.D.) (P <0.001); peak rate of left ventricularpressure development rose from 963 ± 242 to 1335 ±411 mmHg s^–1 (P < 0.001); left ventriuclar end-diastolicpressure fell from 25 ± 6 to 17 ± 7 mgHg (P <0.001);coronary sinus blood flow increased from 113 ± 39 to148 ± 55 ml min^–1 (P <0.01); myocardial oxygenconsumption was augmented from 12.7 ± 3.9 to 16.4 ±5.8 ml min^–1 (P < 0.001); and heart rate increasedslightly (from 76 ± 12 to 86 ± 14 beats min^–1;(P <0.05)). No significant changes occurred in left ventricularsystolic pressure, stroke volume index, myocardial lactate extractionrate and myocardial arteriovenous oxygen difference, and nopatients developed angina, ECG changes or ventricular arrhythmias.Infusion of prenalterol effectively improved haemodynamic functionand cardiac metabolism in cardiomyopathy. Therefore this agentdeserves further investigation to evaluate its possible rolefor the long-term therapy of patients with chronic heart failure.     

Influence of nifedipine on coronary haemodynamics and myocardial metabolism in coronary artery disease

The effect of 30 mg sublingual nifedipine on cardiac metabolismand haemodynamics was studied during two identical periods ofpacing in 11 patients with chronic coronary artery disease.The pace time to angina pectoris improved after nifedipine in6 patients, deteriorated in 2 and was unchanged in 3. Nifedipinedecreased blood pressure (12%), rate pressure product (10%)and coronary vascular resistance (17%) during pacing. Aorto-coronarysinus (A-Cs) oxygen difference decreased at rest (9%) and postpacing(10%) after nifedipine, although an opposite tendency in coronarysinus blood flow resulted in unchanged myocardial oxygen uptakethroughout the study. Although mean myocardial lactate extractionafter nifedipine was unchanged during pacing in the whole groupof patients, it increased in 9 patients who showed a net lactaterelease at control pacing (from –50.9±33.5% to–35.9±30.2%, P>0.05). Nifedipine increased freefatty acid (FFA) extraction during pacing (from 1.5±12.9%to 17.4±13.1%, P<0.02) and uptake (from 1.8±8.5to 11.1±10.6 µmol min^–1, P<0.05). Nifedipineinfluenced only glucose exchange significantly (46% decreasedextraction) at 5 min postpacing. The A–Cs citrate gradientlessened 30–40% postpacing after nifedipine administration. Since the unloading effects of nifedipine did not alter myocardialoxygen uptake, the most important net haemodynamicfinding wasthe decrease in coronary vascular resistance. Although no significantantianginal effect of a fixed dose of nifedipine was found,the increased uptake of FFA may reflect improved myocardialoxidative metabolism after nifedipine     

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.     

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.     

Comparative study on the effects of intracoronary nicorandil and nitroglycerin in ischaemic, reperfused porcine hearts

The direct cardioprotective properties of nitroglycerin andnicorandil were compared in regionally ischaemic (45 min), reperfused(24 h) porcine hearts. Intracoronary treatments, which werestarted 15 min prior to occlusion of the distal left anteriordescending coronary artery (LAD), were continuously administeredfor 105min. The following equi-hypotensive drug dosages wereused in nine pigs each; nitroglycerin 6 fig. kg^–1 x minbefore ischaemia and during 45 min of reperfusion, 0.6 µg.kg^–1x min during ischaemia; nicorandil 5 fig. kg^–1x min before ischaemia and during 45 min of reperfusion, and0.5 fig. kg^–1 x min during ischaemia. Nine control animalswere treated with isotonic sodium hydrochloride solution (1ml. min^–1). Despite comparable effects on blood pressure, intracoronarynicorandil, in contrast to intracoronary nitroglycerin, didnot increase heart rate. Although neither drug affected coronaryblood flow significantly, nicorandil substantially reduced regionalmyocardial oxygen consumption before coronary artery occlusion( – 37±22%, P=0003 vs control group, P=0.01 vsnitroglycerin treatment). Infarct sizes (tetrazolium method)after 45 min of ischaemia and 24 h of reperfusion were significantlydecreased by nicorandil (control group 76.9 ± 19%, nicorandilgroup 49.3 ± 24%, P=0.012)whereas nitroglycerin exhibiteda borderline effect (62.5 ± 15%, P=0.054). Both treatmentsresulted in improved regional systolic shortening of the reperfusedsegment at the end of the experiments but this was not significant.At these drug dosages the direct cardioprotective action ofnicorandil is slightly superior to nitroglycerin. This may beascribed to its K-channel opening property associated with reducedregional myocardial oxygen consumption before the onset of ischaemia.     

Coronary artery thrombosis and thrombolysis in baboons: the effect of atenolol treatment on myocardial infarct size

The effect of the beta-blocker atenolol on experimental infarctsize was studied in a non-human primate model. In 12 baboonsthrombosis of the left anterior descending coronary artery (LAD)was induced and atenolol (0·1 to 0·2 mg . kg^–1intravenously, sufficient to lower the heart rate by 20%) wasadministered 10 mm after the onset of ischaemia in six animals,whereas the others received placebo. Thrombolysis was induced60 mm after the onset of ischaemia by intravenous injectionof rt PA (12 µg. kg^–1. min^–1) in all animals. Heart rate dropped signficantly after atenolol injection (128±9beats . min^–1 versus 163±15 beats . min^–1,P<0001) and was also lower than in the control group (128±9beats. min^–1 versus 158±22 beats.min^–1, p<0·05).Blood pressure remained unchanged after atenolol treatment.As compared to the control group, atenolol limited infarct size,expressed as a percentage of left ventricular mass (4·6±1·9%versus 7·9±1·3%, P<0·05 or asa percentage of the perfusion area (26±8% versus 43%8%,P<0·05).     

Functional characteristics of myocardial bridging: A combined angiographic and intracoronary Doppler flow study

AIMS: Combined quantitative coronary angiography and intracoronaryDoppler flow velocity measurements were performed to study theunderlying haemodynamic mechanisms leading to myocardial ischaemiain patients with myocardial bridging in the absence of coronaryartery disease. METHODS AND RESULTS: In 42 symptomatic patients with myocardial bridging of the leftanterior descending coronary artery, quantitative coronary angiographywas used to measure absolute and relative vessel diameters duringsystole and diastole. In 14 patients, serial frame-by-framediameter quantification during a complete cardiac cycle wasperformed. Intracoronary blood flow velocities were determinedusing a 0·014 inch Doppler flow guide wire proximal,within, and distal to myocardial bridges, and coronary flowreserve was calculated. Quantitative coronary angiography revealeda maximal systolic lumen diameter reduction of 71 ± 16%with a persistent diameter reduction of 35 ± 13% duringmid-diastole. Flow velocities revealed increased average diastolicpeak flow velocities within myocardial bridges of 38·6± 19 cm. s^–1 vs 22·4 ± 7·7cm. s^–1 proximal and 18·6±4·6cm.s^–1 distal (P<0·001), which increased duringrapid pacing (64·7 ± 25 cm. s^–1, P<0·001vs baseline). Coronary flow reserve distal to myocardial bridgeswas 2·3 ± 0·9 (vs 2·9 ± 0·9proximal, P<0·05). There was a characteristic Dopplerflow profile within myocardial bridges with an early diastolicovershoot, which was further augmented during rapid pacing. CONCLUSION: Myocardial bridging is characterized by a delay in diastoliclumen gain and a concomitant increase in diastolic intracoronaryDoppler flow velocities, which are enhanced by rapid pacing.In combination with a reduced coronary flow reserve and anginalsymptoms these findings support the concept of a haemodynamicallysignificant obstruction to coronary flow due to myocardial bridgingin a selected subset of patients.     

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.     

Does sublingual 17{beta}-oestradiol have any effects on exercise capacity and myocardial ischaemia in post-menopausal women with stable coronary artery disease?

Background A variety of vascular effects have been ascribed to 17ß-oestradiol.These effects may partially explain the reduced incidence ofcardiovascular disease found in post-menopausal women on oestrogenreplacement therapy. Objectives To evaluate the effects of 2mg sublingual 17ß-oestradiolon exercise capacity, exercise-induced myocardial ischaemiaand circulating levels of endothelin-1 in post-menopausal womenwith stable coronary artery disease. Methods Twelve post-menopausal women, mean age 61 (range 52–72)years, with angiographically verified significant coronary arterydisease, were randomly assigned to 2mg of sublingual 17ß-oestradiol,2·5mg of buccal nitroglycerine and to placebo in a double-blindcross-over study design with at least 2 days between each ofthe study arms. Antianginal medications, with the exceptionof beta-blockers, were discontinued before investigation. Allstudy patients underwent a maximal bicycle exercise test 30minafter drug intake. Blood was withdrawn immediately before andup to 8h after medication for analyses of circulating levelsof oestradiol and endothelin-1. Results The mean serum levels of oestradiol increased from a controllevel of 72±28pmol.l^–1to 3557± 1631pmol.l^–1after30min and to 5028±3971pmol.l^–1after 60min witha gradual decline thereafter. Sublingual 17ß-oestradioldid not induce any improvement in exercise duration when comparedwith nitroglycerin and placebo (500±112s, 505±107s,498±157s), and did not influence time to onset of ST-segmentdepression (358±89s, 436±93s, 384±116s).The plasma levels of endothelin-1 did not change after administrationof 17ß-oestradiol, nitroglycerin or placebo. Conclusions No effects on exercise capacity, exercise-induced acute ischaemia,or plasma levels of endothelin-1 were found after a single doseof 2mg 17ß-oestradiol in post-menopausal women withdocumented coronary artery disease.     

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.     

Skeletal muscle lactate accumulation and creatine phosphate depletion during heavy exercise in congestive heart failure: Cause of limited exercise capacity?

OBJECTIVE: To study the mechanisms of limited exercise capacity and skeletalmuscle energy production in male patients with congestive heartfailure. DESIGN: Muscle biopsy study. PATIENTS: Skeletal muscle metabolic response to maximal bicycle exercisewas studied in 10 patients with chronic congestive heart failure(ejection fraction 0·22±0·05; peak oxygenconsumption, Vo₂ 15·1±4·9 ml. min^–1.kg^–1) and in nine healthy subjects (peak Vo₂ 33·5±6·7ml. min^–1. kg^–1). Activities of skeletal muscleenzymes were measured from the vastus lateralis muscle of 48patients (ejection fraction 0·24±0·06,peak Vo₂ 17·4±5·4 ml. min^–1. kg^–1)and 36 healthy subjects (peak Vo₂ 38·3±8·4ml. min^–1. kg^–1). RESULTS: Although blood lactate levels were lower in patients than inhealthy subjects (2·2±0·3 vs 5·2±0·6mmol. 1^–1; P<0·001) at peak exercise (96±11W for patients and 273±14 W for controls), skeletal musclelactate was similarly elevated (25·6±3·2vs 22·7±2·7 mmol.kg^–1) and creatinephosphate was equally depressed (P<0·02) to low levels(7·0±1·9 vs 6·7±0·9mmol.kg^–1). The muscle ATP decreased by 21% (P<0·05)and 8% (P<0·01) in the patients and controls, respectively.Activities of rate limiting enzymes of the citric acid cycle(alpha-ketoglutarate dehydrogenase) and oxidation of free fattyacids (carnitine palmitoyltransferase II) were 48% and 21% lowerthan in controls, but the mean phosphofructokinase activitywas unchanged in congestive heart failure. CONCLUSIONS: It seems that the main limiting factor of exercise performanceduring heavy exercise is the same in congestive heart failureand healthy subjects, a high rate of skeletal muscle lactateaccumulation and high-energy phosphate depletion. In congestiveheart failure, the low activity of aerobic enzymes is likelyto impair energy production and lead to lactate acidosis atlow workloads.     

Acute antiischaemic properties of high dosages of intravenous diltiazem in humans in relation to its coronary and systemic haemodynamic effects

The antiischaemic properties of intravenous diltiazem in recommendedtherapeutic doses are disputed. In 17 patients with coronaryartery disease the systemic and coronary haemodynamic effectsof diltiazem were assessed during a high-dose infusion (0.4mg kg^-1 per 5 min. followed by 0.4 mg kg^-1 per 10 min). In addition,its potential antiischaemic properties were investigated duringidentical pacing stress tests. 30 minutes before (P₁) and immediatelyafter diltiazem administration (P₂). Diltiazem reduced leftventricular systolic pressure from 133±5 to 116±5mmHg (P<0.005, ±SEM). persisting until after P₂. Itdecreased systemic and coronary resistance by 32% (P<0.001)and 29% (P<0.005), respectively, with a sustained increasein cardiac output from 5.9±0.4 to 7.3±0.61 min^-1(P<0.01), but a brief 20% rise in coronary flow (P<0.05),after the bolus infusion only. Heart rate, contractility, leftventricular filling pressure and myocardial O₂ consumption remainedunchanged. Despite high plasma levels (673±81 µgl^–1)diltiazem was well tolerated. During identical maximal pacingrates diltiazem considerably reduced myocardial O₂ demand (doubleproduct: 16.3±0.8 (P₂) vs 21.1±1.1 (P₁), P<0.005),due to an 18% decrease in left ventricular systolic pressure,resulting in diminished coronary flow and myocardial O₂ consumptionduring P₂ (14% and 15%, respectively, P<0.05 vs P₁). Diltiazemalso significantly reduced pacing-induced ischaemia, indicatedby normalization of myocardial lactate extraction (1±8%(P₂) vs –41±12% (P₁), P<0.05), and left ventricularfilling pressure (13±2 (P₂ vs 27±3 mmHg (P₁),P<0.01). less ST-segment depression (0.12±0.01 (P₂)vs 0.24±0.02 mV (P₁), P<0.01) and improved contractility(V_max 59±5 (P₂) vs 48±3 s^-1 (P₁), P<0.05).Angina was absent or less in 15 patients during pacing afterdiltiazem. Thus, diltiazem, in high dosages, induces continuingsystemic but short lasting coronary vasodilation, improves pumpfunction without negative chronotropic and inotropic effectsand has pronounced antiischaemic properties, predominantly dueto diminished myocardial O₂ demand.     

Acute antiischaemic properties of high dosages of intravenous diltiazem in humans in relation to its coronary and systemic haemodynamic effects

The antiischaemic properties of intravenous diltiazem in recommendedtherapeutic doses are disputed. In 17 patients with coronaryartery disease the systemic and coronary haemodynamic effectsof diltiazem were assessed during a high-dose infusion (0.4mg kg^-1 per 5 min. followed by 0.4 mg kg^-1 per 10 min). In addition,its potential antiischaemic properties were investigated duringidentical pacing stress tests. 30 minutes before (P₁) and immediatelyafter diltiazem administration (P₂). Diltiazem reduced leftventricular systolic pressure from 133±5 to 116±5mmHg (P<0.005, ±SEM). persisting until after P₂. Itdecreased systemic and coronary resistance by 32% (P<0.001)and 29% (P<0.005), respectively, with a sustained increasein cardiac output from 5.9±0.4 to 7.3±0.61 min^-1(P<0.01), but a brief 20% rise in coronary flow (P<0.05),after the bolus infusion only. Heart rate, contractility, leftventricular filling pressure and myocardial O₂ consumption remainedunchanged. Despite high plasma levels (673±81 µgl^–1)diltiazem was well tolerated. During identical maximal pacingrates diltiazem considerably reduced myocardial O₂ demand (doubleproduct: 16.3±0.8 (P₂) vs 21.1±1.1 (P₁), P<0.005),due to an 18% decrease in left ventricular systolic pressure,resulting in diminished coronary flow and myocardial O₂ consumptionduring P₂ (14% and 15%, respectively, P<0.05 vs P₁). Diltiazemalso significantly reduced pacing-induced ischaemia, indicatedby normalization of myocardial lactate extraction (1±8%(P₂) vs –41±12% (P₁), P<0.05), and left ventricularfilling pressure (13±2 (P₂ vs 27±3 mmHg (P₁),P<0.01). less ST-segment depression (0.12±0.01 (P₂)vs 0.24±0.02 mV (P₁), P<0.01) and improved contractility(V_max 59±5 (P₂) vs 48±3 s^-1 (P₁), P<0.05).Angina was absent or less in 15 patients during pacing afterdiltiazem. Thus, diltiazem, in high dosages, induces continuingsystemic but short lasting coronary vasodilation, improves pumpfunction without negative chronotropic and inotropic effectsand has pronounced antiischaemic properties, predominantly dueto diminished myocardial O₂ demand.     

Antihypertensive treatment with felodipine but not with a diuretic reduces episodes of myocardial ischaemia in elderly patients with hypertension

Episodes of transient myocardial ischaemia can frequently beobserved in hypertensive patients. To assess the effects ofantihypertensive treatment with the calcium antagonist felodipineor the diuretic combination hydrochlorothiazidel triamtereneon episodes of ischaemic-type ST-segment depression (ST-D),simultaneous ambulatory electrocardio-graphic and blood pressure(BP) monitoring was performed in 42 elderly hypertensives withoutmanifest coronary artery disease. All patients (mean age 79± 6 years, office BP 160/95 mmHg) were evaluated offany antihypertensive or anti-ischaemic therapy and after 3 monthstreatment with either felodipine or the diuretic (randomized,double-blind study) for episodes of significant ST-D (0.1 mV,duration 1 min, interval 1 min). The reduction in office BPand daytime ambulatory BP was similar for both agents, as wasa significant reduction in the heart rate x systolic BP product(DP) over 24 h (felodipine: 12 441 ±2076 vs 11 643 ±1953 mmHg. min^–1; P=0.048; diuretic: 12 366 ± 2782vs 11 062 ± 2012 mmHg. min^–1; P=0.003). While felodipinesignificantly decreased the total number of ST-D (from 40 tosix episodes; P=0.03), the total number of ST-D remained unchangedwith the diuretic (non-significant increase from 31 to 45 episodes;P=0.24). The same trend was observed for the number of patientswith ST-D. The ischaemic threshold, defined as DP at the onsetof the episodes of ST-D, increased with felodipine (12 171 ±340vs 13 770 ± 138 mmHg. min^–1) and decreased withthe diuretic (16 210 ±312 vs 14 092 ± 319 mmHg.min^–1). In conclusion, antihypertensive treatment withfelodipine reduces blood pressure and episodes of transientmyocardial ischaemia in elderly hypertensive patients, whilehydrochlorothiazidel triamterene increases these episodes despitea similar BP reduction. Felodipine may influence structuraland functional factors at the coronary micro circulation level.These mechanisms improve coronary blood flow and increase theischaemic threshold.     

Balloon occlusion during coronary angioplasty as a model of myocardial ischaemia: reproducibility of sequential inflations

In order to evaluate the potential of balloon occlusion duringcoronary angioplasty as a model of myocardial ischaemia in manwe have measured coronary sinus blood flow (CSBF), myocardialoxygen consumption (MVO₂), lactate extraction (LER) and electrocardiographicchanges in 11 patients undergoing left anterior descending artery(LAD) angioplasty. Baseline measurements were made before ballooncrossing and between inflations. Four consecutive inflationseach of 60 s duration were made; 5 min return to baseline wasallowed between inflations. There was a significant reduction in CSBF and MVO₂ (ml min^–1)during inflations 2, 3 and 4 (CSBF: 121±6694±53,113±4999±42, 124±66102±41, P<0.02;MVO₂:11.3±6.6–9.1±3.9, 10.4±3.7–8.7±2.4,12.2±4.49.4±2.8, P<0.05). However during thefirst period of balloon occlusion there were inconsistent changesin coronary flow with an overall rise in mean flow (97±35128±80ml min^–1, P = NS) and an overall rise in mean myocardialoxygen consumption (9.6 ± 3.812.5 ± 7.5 ml min^–1,P = NS). There was lactate production during all four inflationsbut the changes during the first one did not achieve statisticalsignificance. These inconsistent changes during the first inflation were thoughtto be due to partial obstruction of the stenosis by the deflatedballoon before primary dilatation. The changes due to crossingand during the first two inflations were further investigatedin another group of 12 patients undergoing LAD angioplasty.Great cardiac vein flow (GCVF), CSBF, MVO₂ and LER were recordedat baseline, during crossing and during the first two inflations.With the deflated balloon across the stenosis there were nochanges in CSBF or MVO₂ but there was a fall in GCVF (103±2877±50,P = NS) and a significant fall in LER (77±5716±37,P<0.01). Although there was a fall during the first inflationin CSBF, GCVF, MVO₂ and lactate extraction none of these changeswere significant. During the second inflation these changeswere of greater magnitude and achieved statistical significance. While balloon occlusion during coronary angioplasty has thepotential of providing a model of ischaemia in man we have foundthe first inflation period unreliable, due to the variable degreeof occlusion by the deflated balloon. We suggest that only subsequentinflations after the primary dilatation are used for observations.These findings are of significance when evaluating the effectsof therapeutic interventions during PTCA. Various refinementsin measurements of the effects of ischaemia will improve thespecificity of the model.