Jacek Nowak

Chaos-related deterministic regulation of heart rate variability in time- and frequency domains: effects of autonomic blockade and exercise

OBJECTIVESnTo study non-linear complexity or chaotic behaviour of heart rate in short time series and its dependence on autonomic tone.nnnMETHODSnTen healthy individuals (5 men, mean age 44 years) were investigated at rest, after intravenous injections of propranolol (0.15 mg/kg), followed by atropine (0.03 mg/kg). On another occasion, investigation was made during exercise on a bicycle ergometer at 40% and at 70% of maximal working capacity. Heart rate variability was assessed by: local sensitive dependence on initial conditions as quantitated by the dominant Lyapunov exponent, coefficient of variation of heart rate, power spectral analysis of high- and low-frequency bands and the 1/f-slope of the very-low-frequency band and time domain analysis.nnnRESULTSnThe approximate dominant Lyapunov exponent was positive at rest and remained positive during autonomic blockade and during exercise. The exponent decreased significantly with propranolol+atropine and even more so during exercise but did not attain zero. At baseline approximate predictability was lost after about 30 s whereas after autonomic blockade or exercise it was lost after about 60 s. The 1/f-slope remained unaltered around -1. As expected, power in high- and low-frequency bands as well as time domain index decreased significantly with autonomic blockade. The low-frequency band and time domain index were affected by exercise.nnnCONCLUSIONSnHeart rate variability of sinus rhythm in healthy individuals has characteristics suggestive of low-dimensional chaos-like determinism which is modulated but not eliminated by inhibition of autonomic tone or by exercise. The dominant Lyapunov exponent characterises heart rate variability independent or the other investigated measures.

Potential of Carotid Ultrasonography in the Diagnosis of Coronary Artery Disease A Comparison With Exercise Test and Variance ECG

BACKGROUND AND PURPOSEnCarotid artery atherosclerosis has been shown to correlate with coronary artery disease (CAD). This study evaluates the capacity of duplex ultrasonography of the carotid arteries as a tool in the diagnosis of CAD in comparison with exercise stress test and variance ECG.nnnMETHODSnCarotid ultrasonography, exercise stress test, and variance ECG were performed in 184 symptomatic patients evaluated with coronary angiography. The diagnostic capacity of the studied noninvasive methods was assessed by use of receiver operating characteristic (ROC) curves constructed by successive consideration of several cut points, such as (1) the presence of unilateral/bilateral plaques and (2) cross-sectional common carotid artery (CCA) intima-media (IM) area from 10 to 30 mm2 for ultrasonography; (1) ST depression > or =0.1 mV and > or =0.2 mV with and (2) without chest pain for exercise test; and electrical variability index from 50 to 100 for variance ECG.nnnRESULTSnCoronary angiography revealed the presence of CAD (> or =50% luminal stenosis in 1 or more major epicardial arteries) in 147 patients (80%). Identification of carotid plaques on one or both sides and calculation of the left-sided (but not right-sided) CCA IM area provided a significant discrimination (P<.001 and P<.01, respectively) of patients with CAD. The discriminating capacity of the ultrasound procedures was equal to that of variance ECG and exercise test with ST depression criterion only but somewhat lower than that of exercise test with the combined chest pain and ST depression criterion (P<.05). However, at the chosen cut points, carotid plaque identification offered higher sensitivity than exercise test with either criterion (P<.01 and P<.001, respectively).nnnCONCLUSIONSnCarotid ultrasonography is a useful diagnostic method that is comparable to exercise test and variance ECG for detection of CAD in a high-prevalence population.

Prostaglandins contribute to the vasodilation induced by nicotinic acid

The significance of endogenously formed prostaglandins in the vasodilation induced by nicotinic acid (NIC) was investigated. The forearm venous plasma level of radioimmunoassayed PGE (R-PGE) and the forearm blood flow (FBF) were measured in 13 healthy male volunteers at rest and during infusion of NIC. Each subject was subsequently re-studied after pretreatment with the PG synthesis inhibitor, naproxen. In the absence of naproxen, NIC infusion resulted in an almost four-fold rise in the release of R-PGE and a 60% increase in FBF. Pretreatment with naproxen did not affect the basal release of R-PGE or the basal FBF but inhibited both the release of R-PGE and the increase in FBF following NIC. The data support the hypothesis that the vasodilating effect of NIC is largely dependent upon an increased vascular formation of PG.

Cardiac synthesis of prostaglandins from arachidonic acid in man

The bioformation of PGs in the human heart was studied in 7 male volunteers by constant rate infusion of 14C-labelled arachidonic acid (AA) into the aortic root and simultaneous blood sampling from the coronary sinus. After conventional extraction of lipids from the plasma samples, the various 14C-PGs formed were separated and quantified by means of thin layer chromatography and fractionated liquid scintillation spectrometry. The infused arachidonic acid was metabolized and well defined chromatographic peaks of 14C-PGs were obtained. Apart from a chromatographic peak corresponding to 14C-PG metabolites, 6-keto-PGF1 alpha constituted the main 14C-PG formed (23 +/- 8%) reflecting a considerable synthesis of prostacyclin in the heart. 14C-PGs of the D, E and F series were formed in roughly equal amounts (14--19%). In a 54-year-old subject, 6-keto-PGF1 alpha constituted a greater proportion of 14C-PGs (60%) than in the other subjects. This can reflect a general effect of ageing or it can indicate the presence of ischemic heart disease in this subject.

Release of prostacyclin from the human pulmonary vascular bed in response to cholinergic stimulation

SummaryThe ability of the human pulmonary vascular bed to synthesize prostaglandins (PGs) in response to cholinergic stimulation was investigated in healthy male volunteers. In all of them, except controls, carbaminoylcholine (CCh) was injected subcutaneously at a dose of 5 μg/kg. In 3 subjects [1-14C]-labelled arachidonate was then infused at a constant rate into the right atrium between 10 and 15 min after the administration of the drug and the blood from the subclavian artery was sampled simultaneously. The arterial content of [14C]-labelled metabolites was extracted, separated by thinlayer chromatography and quantified using liquid scintillation spectrometry. In 8 other subjects PGI2-like activity after the administration of CCh was assayed in the arterial blood and in 1 subject in the venous blood, using a technique for continuous measurement of platelet aggregation on blood-superfused collagen strip.The major portion of [14C]-activity in the radiochromatograms migrated in parallel with the 6-keto-PGF1α standard. No early defined peaks corresponding to any of the unlabelled PGs D2, E2, or F2α, appeared, but in one chromatogram a minor radiopeak corresponding to authentic thromboxane B2 was observed. Also in the platelet aggregation experiments, 5–15 min after the administration of CCh, a significant increase in the PGI2-like activity was observed in the arterial as well as in the peripheral venous blood, which effect of the drug was abolished by pretreatment with atropine and acetylsalicylic acid.The results demonstrate that the human pulmonary vasculature has a considerable ability to synthesize prostacyclin and that cholinergic stimulation causes a liberation of significant amounts of this prostaglandin from the lungs into the systemic circulation.

Beat-to-beat QRS amplitude variability during dobutamine infusion in patients with coronary artery disease

The aim of this study was to investigate if provoked myocardial ischemia induces increased beat-to-beat QRS amplitude variability in patients with angiographically verified coronary artery disease. 15 patients (median age 62 years, range 46-73 years) and 10 healthy controls (median age 25 years, range 22-42 years) were studied. Dobutamine was infused intravenously at a low and at a high dose. The mean low dose of the drug was 10.0 micrograms/kg/min for both patients and controls, whereas the mean maximum dose was 31 +/- 2 for patients and 38 +/- 1 microgram/kg/min for controls. The total QRS amplitude beat-to-beat variance from 12 leads as well as individual variance scores in each single lead were evaluated. Before infusion, the total QRS variance did not differ between patients and controls, nor did the individual variance in 9 of the 12 ECG leads. Dobutamine elicited an increase (p < 0.01) in the total QRS variance, with significantly higher (p < 0.001) total variance in patients than in controls. At the high dose of the drug, the patients displayed significantly higher individual variance values in each ECG lead as well. During dobutamine infusion, 7 of 15 patients developed ST depressions (> or = 0.1 mV in > or = 2 leads) in 12-lead ECG readings. Eleven of 15 patients developed chest pain (grade > or = 3 at the Borgs CR-10 scale). In conclusion, in patients with ischemic heart disease, dobutamine-provoked stress gives rise to increased QRS amplitude beat-to-beat variability, as a sign of electrical instability of the myocardium.

Beat-to-beat QRS amplitude variability after acute myocardial infarction and coronary artery bypass grafting.

Ischemic myocardial injury has been demonstrated to be associated with increased beat-to-beat electrical variability of the depolarization phase. This can be quantified by electrocardiographic (ECG) signal variance analysis, a technique that has proven its diagnostic value in the detection of coronary artery disease (CAD). This study evaluates QRS amplitude variability during a 6-month follow-up period in 73 patients with acute myocardial infarction (AMI) and in 56 patients subjected to coronary artery bypass grafting (CABG). The beat-to-beat QRS amplitude variability was quantified with variance electrocardiography. The equipment allows computerized time domain analysis of high-fidelity ECG signals from 24 leads, and the detected electrical heterogeneity is then expressed as a nondimensional index ranging from 0 to 150, with values >90 being indicative of ischemic myocardial involvement. One week after AMI 55% of the patients presented with an abnormal QRS variability index >90. A significant (p <0.01) increase in the index values occurred during the follow-up period, but only in the patients with an initial index <70. In the CABG group 44% of the patients had a preoperative QRS variability index >90. The values increased (p <0.05) in all patients after surgery; the increase was transient in patients with an initial index <70 (p <0.01). The results demonstrate that the myocardial injury in patients with CAD is often associated with increased electrical variability of myocardial depolarization. The QRS amplitude variability index can be used as a marker of such an injury, and analysis of its changes in the course of ischemic cardiac events may provide new insights into the dynamics of ischemic heart disease and the myocardial healing process.

Biosynthesis of prostaglandins in microsomes of human skeletal muscle and kidney

The capacity of human skeletal muscle, renal cortical and renal medullary microsomes to synthesize prostaglandins (PGs) from exogenous precursor was investigated. The microsomal fractions were incubated with [1-14C]-labelled arachidonate ([14C]-AA) in the absence and in the presence of reduced glutathione (GSH). [14C]-PGs formed in the incubates were extracted, separated by thin-layer chromatography and quantified using liquid scintillation spectrometry. [14C]-labelled PGE2, PGF2 alpha and 6-keto-PGF1 alpha were found to be the principal products of microsomal PG formation and appeared in similar relative quantities in the incubates of all three tissues studied. In some incubates of renal cortical and renal medullary microsomes formation of smaller relative amounts of [14C]-PGD2 and thromboxane B2 was also noted. In addition, formation of substantial amounts of a polar, not yet identified compound was frequently observed in all incubates. In the absence of GSH, [14C]-6-keto-PGF1 alpha was the main PG formed by microsomes of all of the three tissues. At the expense of 6-keto-PGF, the addition of GSH resulted in an almost 2-fold stimulation of [14C]-PGF2 alpha formation in the skeletal muscle and renal cortical incubates, whereas in the renal medullary incubates an increase in the relative amounts of [14C]-PGE2 was observed. The PG synthetic capacity was highest in the skeletal muscle and lowest in the renal cortical microsomes. The results demonstrate a considerable capacity of human skeletal muscle and of the renal cortex and renal medulla to synthesize prostacyclin. Furthermore, the data reveal GSH-dependent differences in the expression of PG biosynthesis in these tissues. The GSH-dependent differentiation of PG synthesis may reflect a mechanism of adaptation of local PG production to the physiological processes.

Effect of nicotine on prostacyclin formation in human endocardium in vitro

The effect of nicotine on the formation of prostacyclin by human endocardium was studied in vitro. Slices of cardiac valve cusps were incubated in a saline medium and the prostacyclin-like activity generated spontaneously by the tissue specimens was assessed in terms of its capacity to inhibit ex vivo platelet aggregation. In separate experiments supernatants of valvular tissue homogenates were incubated with [14C]arachidonate. This resulted in the appearance of labelled 6-keto-prostaglandin F1 alpha in the radiochromatograms, indicating the formation of prostacyclin in the homogenates. Nicotine inhibited dose-dependently the spontaneous generation of prostacyclin-like activity (I50 approximately equal to 2 X 10(-4) M), as well as the formation of 6-keto-prostaglandin F1 alpha (I50 approximately equal to 2 X 10(-5) M), indicating an inhibitory effect of the drug on endocardial prostacyclin production.

Effect of propranolol, practolol and atenolol on human platelet thromboxane formation and plasma levels of prostaglandins 6-KETO-F 1lα and E2

The effects of three different beta-adrenergic blocking drugs, propranolol, practolol and atenolol on platelet thromboxane production and the release of prostacyclin and prostaglandin E2 into the circulation were investigated in healthy volunteers. The beta-adrenergic antagonists were administered intravenously at equipotent doses. The serum TxB2 levels after whole blood clotting and the arterial and venous plasma concentrations of 6-keto-PGF1 alpha and PGE2 were measured before and during a 60 min period after the administration of the drugs, using radioimmunoassay. Practolol and atenolol elicited a significant decrease in platelet thromboxane formation but remained without effect on plasma 6-keto-PGF1 alpha and PGE2 levels. In contrast, propranolol did not influence serum TxB2 concentrations but induced a significant increase in plasma content of 6-keto-PGF1 alpha and PGE2. The results indicate that beta-adrenergic antagonists alter the balance between the proaggregatory, vasoconstricting and antiaggregatory, vasodilating prostanoids in the human cardiovascular system. Although the direction of the action of these drugs seems to differ depending on the selectivity of the beta-adrenoceptor blocking properties the net effect of this action should be beneficial.