Coronary heart disease in smokers: vitamin C restores coronary microcirculatory function.

BACKGROUND: Coronary endothelial function and vasomotion are impaired in smokers without coronary disease, and this is thought to be due to increased oxidative stress. METHODS AND RESULTS: We used positron emission tomography to measure the coronary flow reserve, an integrated measure of coronary flow, through both the large epicardial coronary arteries and the microcirculation in 11 smokers and 8 control subjects before and after administration of the antioxidant vitamin C. At baseline, coronary flow reserve was reduced by 21% in smokers compared with control subjects (P:<0.05) but was normalized after vitamin C, whereas the drug had no effect in control subjects. CONCLUSIONS: The present study is the first to demonstrate that the noxious prooxidant effects of smoking extend beyond the epicardial arteries to the coronary microcirculation and affect the regulation of myocardial blood flow. Vitamin C restores coronary microcirculatory responsiveness and impaired coronary flow reserve in smokers, which provides evidence that the damaging effect of smoking is at least in part accounted for by an increased oxidative stress.

Low density lipoprotein cholesterol and coronary microvascular dysfunction in hypercholesterolemia.

OBJECTIVES: The present study evaluates the impact of total cholesterol (TC) and its subfractions on coronary flow reserve (CFR), an index of the integrated function of the coronary circulation, in asymptomatic subjects. BACKGROUND: Endothelial dysfunction of the coronary microcirculation has been reported in asymptomatic subjects with hypercholesterolemia. METHODS: Using oxygen-15-labeled water and positron emission tomography, myocardial blood flow (MBF, in ml/min per g) was measured at rest and during intravenous adenosine (140 microg/kg body weight per min) in 80 asymptomatic nonsmoking men: group 1 (n = 61; age 45 +/- 7 years) had normal TC (< or =6.5 mmol/liter or < or =250 mg/dl) and group 2 (n = 19; age 48 +/- 10 years) had elevated TC. RESULTS: Total cholesterol were 5.1 +/- 0.8 and 7.2 +/- 0.7 mmol/liter in groups 1 and 2 (p < 0.0005), respectively; low density lipoprotein (LDL) cholesterol levels were 3.2 +/- 0.8 and 4.9 +/- 0.7 mmol/liter (p < 0.0005); high density lipoprotein (HDL) cholesterol levels were 1.1 +/- 0.3 and 1.0 +/- 0.4 mmol/liter (p = NS); and triglyceride levels were 1.8 +/- 1.3 and 3.0 +/- 1.8 mmol/liter (p < 0.005). Groups 1 and 2 did not differ with regard to MBF at rest (0.87 +/- 0.14 vs. 0.84 +/- 0.14), MBF during adenosine (3.63 +/- 1.02 vs. 3.30 +/- 0.86) or CFR (4.23 +/-1.29 vs. 3.95 +/- 0.93). A significant but weak correlation was found between CFR and HDL in group 1 (r = 0.29, p < 0.05), but not in group 2. In contrast, a significant inverse correlation between LDL and CFR was found in group 2 (r = -0.61, p < 0.05), but not in group 1. CONCLUSIONS: Low density lipoprotein cholesterol but not TC correlated inversely with CFR in hypercholesterolemic subjects. Thus, LDL-induced coronary microvascular dysfunction could play an important role in the pathogenesis of coronary artery disease and its complications.

Insulin resistance in patients with cardiac hypertrophy.

OBJECTIVE: Animal studies suggest that left ventricular hypertrophy might be associated with insulin resistance and alterations in glucose transporters. We have previously demonstrated myocardial insulin resistance in patients with post-ischemic heart failure. The aim was to investigate whether myocardial insulin resistance could be demonstrated in human cardiac hypertrophy in the absence of hypertension, diabetes and coronary artery disease. METHODS: Eleven normotensive nondiabetic patients with cardiac hypertrophy due to aortic stenosis and angiographically normal coronary arteries were compared to 11 normal volunteers. Myocardial glucose uptake (MGU) was measured with positron emission tomography and [18F]2-fluoro-2-deoxy-D-glucose during fasting (low insulinemia) or during euglycemic-hyperinsulinemic clamp (physiologic hyperinsulinemia). Myocardial biopsies were obtained in order to investigate changes in insulin-independent (GLUT-1) and insulin-dependent (GLUT-4) glucose transporters. RESULTS: During fasting, plasma insulin (7 +/- 1 vs. 6 +/- 1 mU/l) and MGU (0.12 +/- 0.05 vs. 0.11 +/- 0.04 mumol/min/g) were comparable in patients and controls. By contrast, during clamp, MGU was markedly reduced in patients (0.48 +/- 0.02 vs. 0.70 +/- 0.03 mumol/min/g, p < 0.01) despite similar plasma insulin levels (95 +/- 6 vs. 79 +/- 6 mU/l). A decreased GLUT-4/GLUT-1 ratio was shown by Western blot analysis in patients. CONCLUSIONS: Insulin resistance seems to be a feature of the hypertrophied heart even in the absence of hypertension, coronary artery disease and diabetes and may be explained, at least in part, by abnormalities in glucose transporters.

Effects of propranolol on the impulse activity of cardiovascular sympathetic afferent fibers.

The influence of beta-adrenergic receptor blockade on the impulse activity of 21 cardiovascular sympathetic afferent nerve fibers (11 from the thoracic aorta, 10 from the pulmonary veins), isolated from the left sympathetic rami communicantes T-3 and T-4 was studied in anesthetized, vagotomized cats. Aortic pressure, heart rate, and neural discharge were recorded during control conditions and during brief aortic occlusions of comparable amplitude and duration. Administration of dl-propranolol (0.2-0-4 mg/kg) did not modify aortic pressure or neural discharge of the fibers during control conditions, although, as expected, heart rate was diminished. dl-Propranolol administration did change the response of cardiovascular sympathetic afferents to similar aortic pressure increases. Before drug administration, aortic occlusion caused a significant increase in neural discharge of both aortic and pulmonary vein sympathetic afferent fibers, from 0.52 +/- 0.12 to 1.64 +/- 0.31 and from 0.67 +/- 0.10 to 2.08 +/- 0.25 impulses/sec, respectively (p less than 0.05). After dl-propranolol administration, comparable increases in aortic pressure resulted in slight but not significant increases in neural discharge of aortic and pulmonary vein fibers. Administration of d-propranolol (0.4-0.6 mg/kg), which possesses only membrane-stabilizing properties, did not modify the firing rate of four pulmonary sympathetic afferents, which subsequently decreased their response to pressure rises after administration of dl-propranolol. These results indicate that beta-adrenergic receptor blockade reduces the responsiveness to hemodynamic stimuli of sympathetic cardiovascular afferent fibers that are capable of mediating excitatory pressor reflexes.

Effect of naratriptan on myocardial blood flow and coronary vasodilator reserve in migraineurs.

BACKGROUND: Migraine drugs can produce adverse cardiac effects. The authors have demonstrated previously that ergotamine can lead to a significant reduction of hyperemic myocardial blood flow, but little is known about the effect of the newer serotonin analogues. Coronary artery constriction caused by serotonin or its analogues is mediated mainly by 5HT2 receptors. The selective 5HT1B/1D agonist naratriptan has no significant activity at 5HT2 receptors; however, like all 5HT1B/1D agonists developed for the acute treatment of migraine, naratriptan could potentially constrict coronary arteries by activation of 5HT1B receptors. METHODS: The effects on myocardial blood flow of subcutaneous naratriptan 1.5 mg compared with placebo were assessed under resting and hyperemic conditions with PET using oxygen-15 labeled water during two separate visits. This study was a randomized, double-blind, placebo-controlled crossover trial in 34 migraine subjects with no evidence of ischemic heart disease, studied outside a migraine attack. RESULTS: Naratriptan did not differ significantly from placebo in its effects on resting myocardial blood flow, but did evoke a small, significant fall in hyperemic myocardial blood flow (-13% versus placebo) and an increase in hyperemic coronary resistance (+19% versus placebo) without any signs or symptoms suggestive of myocardial ischemia. Naratriptan did not significantly affect the coronary vasodilator reserve (hyperemic/resting blood flow) compared with placebo. CONCLUSIONS: These results show that at therapeutic doses, naratriptan exerts only a minor effect on myocardial blood flow, coronary vasodilator reserve, or coronary resistance among subjects with no evidence of ischemic heart disease. These results should not be extrapolated to patients with coronary artery disease, in whom all 5HT1 agonists for migraine are contraindicated.

Assessment of the reproducibility of baseline and hyperemic myocardial blood flow measurements with 15O-labeled water and PET.

UNLABELLED: PET with 15O-labeled water allows noninvasive quantification of myocardial blood flow (MBF) at baseline and during pharmacologically induced hyperemia to assess the coronary vasodilator reserve (CVR = hyperemic/baseline MBF). Despite widespread use of PET, its reproducibility during one study session has not been tested. Intravenous adenosine (Ado), a powerful coronary vasodilator with a very short decay time, is commonly used for the induction of hyperemia. However, it is not known whether Ado can induce tachyphylaxis after short-term repetitive administration. In this study, we aimed to test the reproducibility of PET assessment of CVR during Ado-induced hyperemia. METHODS: In 21 healthy volunteer men, baseline and Ado MBF were measured twice using PET with 15O-labeled water to obtain two CVR assessments within 1 h. RESULTS: There was no significant difference between the two baselines (0.89 +/- 0.14 versus 0.99 +/- 0.15 mL/min/g, mean difference 13% +/- 11%) or between the two hyperemic MBFs (3.51 +/- 0.45 versus 3.83 +/- 0.49 mL/min/g, mean difference 10% +/- 14%), resulting in comparable values of CVR (4.05 +/- 0.75 versus 3.93 +/- 0.72, mean difference 2% +/- 15%). The repeatability coefficient for MBF was 0.17 mL/min/g at baseline and 0.94 mL/min/g during hyperemia. The repeatability coefficient of the rate pressure product (RPP) was lower at baseline (1,304 mm Hg x beat/min) than during hyperemia (3,448 mm Hg x beat/min). CONCLUSION: Repeated measurements of MBF and CVR during the same study session were not significantly different, demonstrating the validity of the technique. The larger variability of hyperemic flow, as indicated by the larger repeatability coefficient, was paralleled by a greater variability of the RPP. This could mean that the greater variability of MBF during stress is more likely due to a variable response to Ado rather than to a measurement error.

Effects of ergotamine on myocardial blood flow in migraineurs without evidence of atherosclerotic coronary artery disease.

The effects of intravenous ergotamine (0.25 mg) on basal and hyperemic (dipyridamole) myocardial blood flow (MBF), measured with positron emission tomography and H2(15)O, were assessed in 15 migraineurs in a double-blind, randomized, placebo controlled, crossover study. Ergotamine produced a 27% reduction in hyperemic MBF (2.62 +/- 0.11 vs 3.72 +/- 1.05 ml x min(-1) x g(-1); p <0.05), a 31% reduction in the coronary vasodilator reserve (1.81 +/- 0.50 vs 2.71 +/- 1.15; p <0.01), and a 55% increase in minimal coronary resistance (42.2 +/- 15 vs 26.7 +/- 8 mm Hg x min x ml(-1) x g(-1); p <0.001), suggesting vasoconstriction of the coronary microcirculation.

Sleeping hours: a relatively protected period for impending myocardial infarction.

We have retrospectively investigated the time of the onset of acute myocardial infarction in 2046 patients admitted to six coronary care units in a two-year period. A significantly reduced number of patients (P less than 0.01) showed the beginning of acute myocardial infarction during the 0 to 6 a.m. period, while, during the remaining periods, no difference in frequency distribution was observed. Our results suggest that an impending myocardial infarction is more likely to occur at certain times of the day than others, suggesting a period of relative protection from onset.

Lack of association between prodromes nausea and vomiting, and specific electrocardiographic patterns of acute myocardial infarction.

We conducted an observational study on 164 patients consecutively admitted to our coronary care unit in order to evaluate the predictive role of cardiac prodromes nausea and vomiting, in distinguishing a particular electrocardiographic pattern (Q wave versus non-Q wave and localisation) of an acute myocardial infarction. Patients with the prodromes made up 47.0% of all Q wave myocardial infarction and 59.4% in those without Q wave myocardial infarction. Furthermore, patients had nausea and vomiting in 25.0% of all Q wave myocardial infarction and in 31.2% of all non-Q wave infarction. No significant differences were found in the patients who experienced nausea and vomiting in the localisation (anterior versus inferior) of myocardial infarction. Our findings indicate that the cardiac prodromes of nausea and vomiting do not play any particular role in predicting a specific electrocardiographic pattern of acute myocardial infarction.

Meteorological influences on myocardial infarction in the metropolitan area of Milan.

We attempted to relate admission rate for acute myocardial infarction with some meteorological variables in a region having a temperate climate. We used 2830 consecutive episodes collected over a 2-year (1979-1980) period. The temperatures, atmospheric pressure, relative humidity, front passage, rain and snow and foehn wind have been associated in the past with acute myocardial infarction. No significant association with any of them was found in our study, nor any correlation over the time between admission rates in six different Coronary Care Units (at the time the only ones active in the area) which participated in the study.

Sympathetic rhythms and cardiovascular oscillations.

Spectral analysis of heart rate and arterial pressure variabilities is a powerful noninvasive tool, which is increasingly used to infer alterations of cardiovascular autonomic regulation in a variety of physiological and pathophysiological conditions, such as hypertension, myocardial infarction and congestive heart failure. A most important methodological issue to properly interpret the results obtained by the spectral analysis of cardiovascular variability signals is represented by the attribution of neurophysiological correlates to these spectral components. In this regard, recent applications of spectral techniques to the evaluation of the oscillatory properties of sympathetic efferent activity in animals, as well as in humans, offer a new approach to a better understanding of the relationship between cardiovascular oscillations and autonomic regulation.

Non-linear dynamics in the beat-to-beat variability of sympathetic activity in decerebrate cats.

Non-linear interactions between low-frequency rhythms (0.1 Hz) of beat-to-beat variability series of sympathetic discharge and respiratory rhythm (0.3 Hz) are observed in decerebrate artificially ventilated cats. Simple graphical tools as Poincaré and recurrence maps are used to detect, in a qualitative way, phase-locking phenomena. Non-parametric bispectral analysis is also carried out to quantify the degree of second-order coupling between oscillations at different frequencies.

Restraining effect of captopril on cardiovascular sympathetic efferent neural activity.

In 13 decerebrate cats we studied the effects of captopril (10 mg/kg, intravenous bolus) on the background cardiac preganglionic sympathetic discharge and on its responsiveness to brief baroreceptor deactivations induced by premature ventricular contractions. Captopril caused a significant reduction of 57 +/- 7% (from 2.4 +/- 0.4 impulses/0.1s) in sympathetic discharge, with a mean latency of 35 +/- 3 min from the time of drug administration. In addition, the increase in cardiac sympathetic firing during premature ventricular contractions was markedly reduced, from 257 +/- 30% to 70 +/- 17%, before and after administration of captopril. These data indicate that captopril is not only likely to inhibit sympathetic discharge to the heart, but is also likely to restrain the excitatory sympathetic responses to baroreceptor deactivation.

Temporal asymmetries of short-term heart period variability are linked to autonomic regulation.

We exploit time reversibility analysis, checking the invariance of statistical features of a series after time reversal, to detect temporal asymmetries of short-term heart period variability series. Reversibility indexes were extracted from 22 healthy fetuses between 16th to 40th wk of gestation and from 17 healthy humans (aged 21 to 54, median=28) during graded head-up tilt with table inclination angles randomly selected inside the set {15, 30, 45, 60, 75, 90}. Irreversibility analysis showed that nonlinear dynamics observed in short-term heart period variability are mostly due to asymmetric patterns characterized by bradycardic runs shorter than tachycardic ones. These temporal asymmetries were 1) more likely over short temporal scales than over longer, dominant ones; 2) more frequent during the late period of pregnancy (from 25th to 40th week of gestation); 3) significantly present in healthy humans at rest in supine position; 4) more numerous during 75 and 90 degrees head-up tilt. Results suggest that asymmetric patterns observable in short-term heart period variability might be the result of a fully developed autonomic regulation and that an important shift of the sympathovagal balance toward sympathetic predominance (and vagal withdrawal) can increase their presence.

A circadian perspective on myocardial ischaemia.

The non-uniform occurrence of myocardial ischaemia, with a trough at night and a peak in the morning, is at the base of the concept of a circadian distribution of coronary events. Cardiovascular variables known to influence the occurrence of ischaemia have similar rhythms, and a likely culprit could be hidden among them. Nevertheless, in many cases an identifiable trigger is lacking and the prediction of ischaemia is still elusive.

Effect of captopril on sympathetic preganglionic efferent activity in cats.

In 13 decerebrate cats, we studied the effects of captopril (10 mg/kg iv bolus) on the background discharge of thoracic preganglionic sympathetic fibers. After drug administration there was an initial reduction in systolic arterial pressure (SAP), which was followed by a later inhibition of sympathetic discharge (from 2.7 +/- 0.5 to 0.79 +/- 0.1 imp/0.1 s; P < 0.01). Captopril significantly reduced the excitatory response of sympathetic fibers to premature ventricular contraction (70 +/- 17 vs. 257 +/- 30%), inferior vena cava obstruction (176 +/- 56 vs. 315 +/- 85%) and asphyxia (143 +/- 20 vs. 245 +/- 51%). Vice versa the sympathetic response to aortic occlusion was unaffected (-58 +/- 8 vs. -62 +/- 6%). A similar reduction in sympathetic discharge was observed after captopril administration in anesthetized cats (n = 3). On the contrary, no changes in background neural discharge were noticed in decerebrate-spinalized cats (n = 5), despite comparable hemodynamic effects. These data indicate that captopril reduces sympathetic efferent activity and its responsiveness to excitatory stimuli. The lack of neural effects in decerebrate-spinalized cats is consistent with a brain stem site of action of captopril.

[Role of low-frequency neuronal activity in the medulla in the regulation of the cardiovascular system]. / Evidenza di un ritmo a bassa frequenza nella scarica di singoli neuroni del tronco encefalico coinvolti nella regolazione del sistema cardiovascolare.

We recorded discharge activity of 45 single neurons located in the rostral ventrolateral medulla (n = 21), lateral tegmental field (n = 10) and caudal raphe (n = 14) nuclei in baroreceptor-denervated decerebrate cats (n = 27). Autoregressive spectral analysis was performed on neuronal activity and systolic arterial pressure (SAP). The discharges of the recorded neurons were correlated to 2- to 6 Hz oscillations or 10 Hz rhythm present in sympathetic neural discharge. A low frequency (LF) oscillation (0.12 +/- 0.02 Hz) was observed in 25 (55%) units. The same rhythmicity was found in SAP variability in 25 of 45 (55%) recordings. In 21 of these cases the LF in SAP variability was highly correlated to LF in neural activity. Moreover, 32 out of 45 (71%) neurons showed a higher rhythm (HF; 0.34 +/- 0.06 Hz) related to the ventilation rate. These data demonstrate the presence of an LF oscillation in the discharge of single medullary neurons, involved in the regulation of cardiovascular system. This LF component was similar to that detectable in the spectral analysis of SAP variability, thus supporting the hypothesis of a central origin of this rhythm, largely independent of baroreceptor input.

Adenosine activates cardiac sympathetic afferent fibers and potentiates the excitation induced by coronary occlusion.

Adenosine is a possible mediator of cardiac pain during myocardial ischemia; however, little is known about the influence of adenosine on cardiac sympathetic afferent activity and thereby on its algogenic mechanism. In 20 anaesthetized, decerebrated, curarized and artificially ventilated cats, we studied the impulse activity of 20 single afferent sympathetic fibers with a left ventricular receptive field in relation to epicardial applications of adenosine, coronary artery occlusions and arterial pressure rises. All fibers increased their impulse activity (from 1.2 +/- 0.2 to 2.6 +/- 0.5 imp/s; P < 0.001) during slight (20 +/- 8%) rises in aortic pressure, thus exhibiting low-threshold receptor characteristics. In 10 cats, epicardial applications of three different doses of adenosine (0.1, 1 and 10 mg/ml) caused a brief increase in neural activity with dose-related responses. This response was abolished by aminophylline, a P1 purinergic inhibitor. In the other group of 10 cats, four subsequent 30-s occlusions of the coronary arterial vessel supplying the receptive fields of the fibers were performed, in control conditions and 30 s, 3 and 7 min, respectively, after the end of excitation induced by adenosine (1 mg/ml) application. During the control coronary occlusion the impulse activity increased from 1.1 +/- 0.1 to 5.5 +/- 0.7 imp/s (P < 0.0001). A similar activation was present during the second occlusion initiated 30 s after the end of adenosine-induced activation. In contrast, a significant potentiation of the response was observed (8.8 +/- 1.2 vs. 5.3 +/- 0.9 imp/s; P < 0.001) during the occlusion initiated 3 min after the end of excitation by adenosine. This effect was no longer present during the last occlusion performed after 7 min. When the protocol was repeated substituting adenosine with saline (n = 5) or after i.v. administration of aminophylline (n = 5), no potentiation was observed, even though the excitatory response to coronary occlusion was preserved. These data show that adenosine can activate cardiac sympathetic afferent fibers in a dose-related manner, and potentiate their responses to coronary occlusion, while leaving unaffected the responsiveness to a hemodynamic stimulus. The excitatory effects are likely to involve the P1 purinergic receptors. The potentiation phenomenon might play a role in the genesis of an algogenic code.

Presence of vasomotor and respiratory rhythms in the discharge of single medullary neurons involved in the regulation of cardiovascular system.

We analyzed the discharges of 77 single neurons located in the rostral ventrolateral medulla (RVLM, n = 25), caudal ventrolateral medulla (CVLM, n = 18), lateral tegmental field (LTF, n = 19) and caudal raphe nuclei (n = 15). These recordings were made from 36 vagotomized and sinoaortic denervated cats that were either decerebrate (n = 27) or anesthetized with urethane (n = 9) and from 3 decerebrate cats with intact sinoartic and vagal nerves. These neurons were classified as sympathetic-related (n = 61) if spike triggered averaging showed that their naturally occurring discharges were correlated to either the cardiac related (2-6 Hz) or a faster (10 Hz) oscillation in inferior cardiac sympathetic nerve discharge. Neurons were classified as sympathetic-unrelated (n = 16) if they lacked these characteristics. We used autoregressive spectral techniques to detect additional slower oscillations hidden in the variability of neuronal discharge and possibly correlated to the oscillations of systolic arterial pressure (SAP). This analysis revealed the existence of a low frequency (LF) oscillation (0.12 +/- 0.02 Hz) in the discharges of 36 sympathetic-related and 9 sympathetic-unrelated neurons. In relation to 35 neurons in 21 animals there was also an LF component in SAP variability. In 29 instances the LF neuronal discharges and SAP variabilities were significantly correlated. In addition, there was a high frequency (HF) oscillation (0.34 +/- 0.06 Hz) in the discharges of 59 medullary neurons. In 56 cases the HF in neuronal discharge variability cohered to that in SAP variability. These data are the first to demonstrate the existence of an LF component in the discharges of individual medullary neurons, at least some of which were likely to be involved in the regulation of the cardiovascular system. Since these oscillations were evident in cats with section of sinoaortic and vagal nerves, they likely reflect central rhythmogenic properties.

Morning and Monday: critical periods for the onset of acute myocardial infarction. The GISSI 2 Study experience.

The onset of acute myocardial infarction (AMI) is unevenly distributed over the 24 h and the week. While presence of a morning peak is generally agreed upon, contrasting results had been obtained regarding other periods of the day, probably due to differences of origin, size and composition of the populations. The 24 h and weekly distributions were studied within 6 h from the beginning of the symptoms in a population following a Latin life-style, who were enrolled in the GISSI 2 Study (n = 11472). Subgroups (smokers, the elderly (> 65 years), diabetics, hypertensives) were also considered. Six hour periods starting at midnight were tested for uniformity. Circadian non-uniformity was found. Events increased in the morning hours and reduced during the night regardless of the day of the week. The night and day difference was attenuated in smokers and diabetics. Non-uniformity of the events was also found among the days of the week. AMI significantly increased in non-smokers on Monday. We suggest that there is a night-day gradient (characterized by the short time interval between the two frequency extremes) in the time of onset of AMI. The different distribution in smokers stresses the possible unfavourable and masking effect of a heightened sympathetic tone during the day while the general protective role of the night hours is preserved. Moreover, the increased incidence of events on Monday may suggest the importance of the shift from a period of non-scheduled to scheduled activity.