Patterns of inflammatory activation associated with precipitants of acute coronary syndromes: a case-crossover study.

AIMS: We sought to assess a broad array of possible precipitants of acute coronary syndromes (ACS) and evaluate their association with detectable inflammatory activation. METHODS AND RESULTS: Within a case-crossover design, using a standardised questionnaire, interviews among 348 ST-elevation myocardial infarction (44%) or high-risk non-ST-elevation ACS patients (56%), explored potential precipitants, including: infection (INF)-temperature >38°C and/or respiratory tract, urinary or skin infection; inflammation (INFL)-exacerbation of inflammatory conditions; exercise (EX)-moderate to heavy exercise; fast food (FF)-consumption of a meal purchased from a fast food company. Risk and control periods were: weekly over 8 weeks for INF and INFL; 24 hourly over 4 days for FF and 4 hourly over 48 h for EX. C-reactive protein (CRP) levels were assessed at admission. These precipitants were identified in 203/348 (58.3%) patients. An increased temporal risk was observed for: INF (0-7 days vs 7-8 weeks odds ratio (OR): 7.5, confidence interval (CI): 1.7-67.6, P = 0.002); INFL (0-7 days vs 7-8 weeks OR: 14.0, CI: 2.13-591.9, P = 0.001); EX (0-4 h vs 24-28 h OR: 2.2, CI: 1.3-3.5, P = 0.001) and FF (0-24 h vs 72-96 h OR: 5.67, CI: 1.6-30.2, P = 0.003). CRP levels were significantly elevated among patients reporting infective and inflammatory potential precipitants, but not among those reporting fast food consumption and unaccustomed moderate-heavy exercise. CONCLUSION: Infection, inflammatory conditions, moderate-heavy exercise and potentially fast food consumption appear to precipitate high-risk ACS. Increased inflammation as measured by CRP was not consistently detected despite the identification of an ACS precipitant. Strategies that target improved overall health may also lead to fewer ACS events through a reduction in triggers.

Alcohol consumption alters insulin secretion and cardiac autonomic activity.

BACKGROUND: Alcohol may have a cardioprotective effect. One possible mechanism is by modifying insulin resistance/secretion. The aims of this study were: (i) to examine the effect of short-term alcohol consumption on the metabolic control of glucose tolerance; (ii) to study the influence of short-term alcohol consumption on cardiac autonomic activity using spectral analysis of heart rate variability. METHODS: Twenty-one healthy subjects, in a randomized crossover design, either received three units of ethanol daily for 1 week or abstained from ethanol. The control of glucose tolerance was assessed using the intravenous glucose tolerance test with minimal modelling. RESULTS: There was no difference in fasting glucose, fasting insulin or insulin sensitivity between the two groups. Alcohol showed a lower insulin first phase insulin response (no alcohol 659.0 +/- 394.1 SD, alcohol 535.2 +/- 309.1) pmol L-1 min-1, P = 0.027). There was no difference in heart rate or blood pressure but a significant difference in the ratio of high to low frequency spectral power of heart rate variability; (no alcohol 4.55 +/- 3.78, alcohol 8.16 +/- 6.77, P = 0.033). This suggests decreased sympathetic and/or increased vagal modulation of heart rate in the alcohol group. CONCLUSION: The finding of no difference in insulin sensitivity between the two groups contrasts with, but does not entirely contradict, the results of previous epidemiological studies--perhaps suggesting that longer term changes such as liver enzyme induction may be important. The difference in insulin secretion questions the validity of previous studies of the influence of alcohol on insulin sensitivity, where insulin levels were used as a surrogate for insulin resistance.

Effects of angiotensin II (AT1) receptor blockade on cardiac vagal control in heart failure.

The objective of the present study was to determine the autonomic effects of angiotensin II (AT(1)) receptor blocker therapy in heart failure. In a randomized double-blind cross-over study, we compared the effects of candesartan and placebo on baroreflex sensitivity and on heart rate variability at rest, during stress and during 24 h monitoring. Acute effects were assessed 4 h after oral candesartan (8 mg) and chronic effects after 4 weeks of treatment (dose titrated to 16 mg daily). The study group comprised 21 patients with heart failure [mean (S.E.M.) ejection fraction 33% (1%)], in the absence of angiotensin-converting enzyme (ACE) inhibitor therapy. We found that acute candesartan was not different from placebo in its effects on blood pressure or mean RR interval. Chronic candesartan significantly reduced blood pressure [placebo, 137 (3)/82 (3) mmHg; candesartan, 121 (4)/75 (2) mmHg; P<0.001; values are mean (S.E.M.)], but had no effect on mean RR interval [placebo, 857 (25) ms; candesartan, 857 (21) ms]. Compared with placebo there were no significant effects of acute or chronic candesartan on heart rate variability in the time domain and no consistent effects in the frequency domain. Baroreflex sensitivity assessed by the phenylephrine bolus method was significantly increased after chronic candesartan [placebo, 3.5 (0.5) ms/mmHg; candesartan, 4.8 (0.7) ms/mmHg; P<0.05], although there were no changes in cross-spectral baroreflex sensitivity. Thus, in contrast with previous results with ACE inhibitors, angiotensin II receptor blockade in heart failure did not increase heart rate variability, and there was no consistent effect on baroreflex sensitivity.

Nitric oxide and cardiac autonomic control in humans.

Cardiac autonomic control is of prognostic significance in cardiac disease, yet the control mechanisms of this system remain poorly defined. Animal data suggest that nitric oxide (NO) modulates cardiac autonomic control. We investigated the influence of NO on the baroreflex control of heart rate in healthy human subjects. In 26 healthy male volunteers (mean age, 23+/-5 years), we measured heart rate variability and baroreflex sensitivity during inhibition of endogenous NO production with N(G)-monomethyl-L-arginine (L-NMMA) (3 mg/kg per hour) and during exogenous NO donation with sodium nitroprusside (1 to 3 mg/h). Increases from baseline (Delta) in high-frequency (HF) indexes of heart rate variability were smaller with L-NMMA in comparison to an equipressor dose of the control vasoconstrictor phenylephrine (12 to 42 microg/kg per hour): Deltaroot mean square of successive RR interval differences (DeltaRMSSD)=23+/-32 versus 51+/-48 ms (P<0.002); Deltapercentage of successive RR interval differences >50 ms (DeltapNN50)=5+/-15% versus 14+/-12% (P<0.05); and DeltaHF normalized power=-2+/-7 versus 9+/-8 normalized units (P<0.01), respectively. Relative preservation of these indexes was observed during unloading of the baroreflex with sodium nitroprusside compared with a matched fall in blood pressure produced by a control vasodilator, hydralazine (9 to 18 mg/h): DeltaRMSSD=-8+/-8 versus -24+/-15 ms (P<0.001); DeltapNN50=-6+/-11% versus -15+/-19% (P<0.01); DeltaHF normalized power=-7+/-13 versus -13+/-11 normalized units (P<0.05), respectively. The change in cross-spectral alpha-index calculated as the square root of the ratio of RR interval power to systolic spectral power in the HF band (although not alpha-index calculated in the same way for the low-frequency bands or baroreflex sensitivity assessed by the phenylephrine bolus method) was attenuated with L-NMMA compared with phenylephrine (Delta=4+/-8 versus 14+/-15 ms/mm Hg, respectively; P<0.02) and with sodium nitroprusside compared with hydralazine (Delta=-7+/-6 and -9+/-7 ms/mm Hg, respectively; P<0.05). In conclusion, these data demonstrate that NO augments cardiac vagal control in humans.

The effects of acute and chronic dihydropyridine calcium antagonist therapy on baroreflex sensitivity: a re-analysis using the sequence method.

The objective of this study was to examine the effects of dihydropyridine calcium antagonist therapy on 24-h baroreflex sensitivity. Twenty-three patients with moderate essential hypertension were studied before and during acute (10 patients) and chronic (21 patients) treatment with a dihydropyridine calcium antagonist (nifedipine, nicardipine or felodipine) as monotherapy in a dose titrated to produce a fall in mean cuff pressure of at least 10%. Twenty-four hour unrestricted ambulatory intra-arterial blood pressure (IABP) and heart rate (R-R interval) were monitored. Baroreflex sensitivity (BRS) was assessed throughout the 24-h period by off-line computer analysis of spontaneous variations in IABP and R-R interval. During acute first dose treatment with a calcium antagonist there was a significant fall in blood pressure (BP), increase in heart rate and reduction in BRS. With chronic therapy (6-16 weeks) there was a continued reduction in mean BP of 11% (P < 0.001), but heart rate had returned to control levels and BRS was significantly increased over the 24 h by 14% (P < 0.01). The increase in BRS was evident during both the waking and sleeping periods, but the greatest increase was during sleep (awake 12% P = 0. 02, asleep 28% P = 0.003). In conclusion, although dihydropyridine calcium antagonists acutely cause a reflex tachycardia associated with a reduced BRS, there is no such effect with chronic therapy. BRS was significantly increased after chronic treatment, with exaggeration of the diurnal pattern. Journal of Human Hypertension (2000) 14, 189-194.

Use of opposing reflex stimuli and heart rate variability to examine the effects of lipophilic and hydrophilic beta-blockers on human cardiac vagal control.

Evidence from animal studies suggests that beta-blockers can act within the central nervous system to increase cardiac vagal motoneuron activity. We have attempted to determine whether such an effect is evident in healthy humans, by examining the effects of lipophilic and hydrophilic agents on heart rate variability and cardiac vagal reflexes. A total of 20 healthy volunteers took part in the study. Autonomic studies were performed after 72 h of treatment with placebo, atenolol or metoprolol in a blinded cross-over design. ECG recordings were taken at rest and during mental and orthostatic stress. Heart rate variability was measured in the time and frequency domains. The effects on heart rate of two opposing cardiac vagal reflexes were examined. Trigeminal stimulation causing vagal stimulation, and isometric forearm muscle contraction ('muscle heart reflex') causing vagal inhibition, were performed alone and simultaneously. At rest, during mental stress and during trigeminal stimulation, beta-blocker therapy was associated with significantly increased high-frequency beat-to-beat heart rate variability when compared with placebo. There were no significant differences in effects on heart rate or heart rate variability between atenolol and metoprolol. Analysis of the muscle heart reflex, alone and with simultaneous trigeminal stimulation, showed that the magnitude of the R-R interval response was significantly greater after beta-blocker therapy compared with placebo, but the effects of atenolol and metoprolol were equivalent. beta-Blocker therapy increased cardiac vagal activity, as shown by measures of high-frequency heart rate variability and reflex studies. Lipophilic and hydrophilic beta-blockers appeared to be equally efficacious in increasing the cardiac vagal modulation of heart rate.

The autonomic control of heart rate and insulin resistance in young adults.

The pathophysiology of insulin resistance is unclear. A link between increased heart rate (HR) and insulin resistance suggests an association with sympathetic nervous system activity. To further evaluate this, we examined autonomic activity using spectral analysis of HR variability (HRV), which provides a measure of cardiac sympathovagal modulation, and related this to insulin sensitivity (Si) in 137 men and women (20 yr old). The HRV spectrum displays 2 major peaks: a high-frequency peak, reflecting vagal activity, and a low-frequency peak caused by vagal and sympathetic activity. The high-to-low ratio (HLratio) reflects sympathovagal balance. Si was measured, using the i.v. glucose tolerance test with minimal modeling, and HR data was derived from a 15-min supine electrocardiogram. Women were more insulin resistant than men (Si, 3.94 vs. 5.09 10(4) min(-1)/per pmol x L; P = 0.002), had higher HR (59 vs. 56 beats/min, P = 0.019), but had a higher HLratio (2.04 vs. 1.31, P = 0.001). In men (but not women), Si correlated with HR (r = -0.410, P = 0.001) and measures of HRV: HLratio (r = 0.291, P = 0.002) independently of body mass index. In conclusion, Si correlates with cardiac sympathovagal balance in men, but not women, suggesting gender differences in the autonomic modulation of insulin resistance.

Angiotensin II modulates cardiovascular autonomic control in the absence of baroreflex loading.

OBJECTIVE: To investigate the effects of angiotensin II in the absence of baroreflex activation. DESIGN: Ten healthy male volunteers were studied in a single blind, randomised, crossover study of heart rate variability during intravenous angiotensin II infusion (5-20 ng/kg/min) compared with a control pressor infusion of phenylephrine (0.7-2.8 micrograms/kg/min). Each infusion was titrated to increase mean blood pressure by 20 mm Hg; sodium nitroprusside was then infused simultaneously to restore blood pressure to baseline values. RESULTS: During concomitant angiotensin II (AII) and sodium nitroprusside (SNP) infusion, the mean (SD) RR interval (864 (117) ms) was significantly shorter than during phenylephrine (PE) and sodium nitroprusside infusion (1057 (163) ms), and was significantly shorter than at baseline (999 (164) ms), despite comparable levels of blood pressure. Values of high frequency heart rate variability measured in the time and frequency domains were significantly lower during AII/SNP infusion than during PE/SNP: percentage of successive RR interval differences exceeding 50 ms, 30(16)% v 57(21)%; root mean square of successive RR interval differences, 63 (39) v 90 (40) ms; high frequency power 0.48 (0.19) v 0.66 (0.26) nu. CONCLUSIONS: When the pressor response is controlled by sodium nitroprusside, angiotensin II infusion is associated with tachycardia. Analysis of heart rate variability suggests that this reflects inhibition of cardiac vagal activity.

A central gamma-aminobutyric acid mechanism in cardiac vagal control in man revealed by studies with intravenous midazolam.

1. Animal studies show that cardiac vagal tone can be modified by gamma-aminobutyric acid neurons acting at several sites in the central nervous system. The present study has attempted to determine whether similar control exists in humans by using midazolam, a benzodiazepine. Benzodiazepines exert their main actions on the central nervous system by interacting co-operatively at the gamma-aminobutyric acid receptor. 2. Twenty patients took part in the study before undergoing cardiac catheterization. After resting for 20 min in a semi-supine position on a couch, ECG, blood pressure and respiration were recorded for 5-min periods with either controlled (fixed) or free respiration. During this time a baroreceptor sensitivity test was conducted. 3. Doses of 1 mg and 5 mg of midazolam were administered intravenously. 4. Five-minute segments of data, before and after midazolam, were subjected to power spectral and time-domain analysis. 5. Midazolam caused a decrease in the high-frequency and an increase in the low-frequency components of the power spectral density plot, and in addition reduced the mean R-R interval and R-R variability expressed as the interquartile difference, and pNN50. There were no significant changes in the sensitivity of the baroreflex or in the systolic, diastolic and average blood pressures. 6. This decrease in variability of heart period, particularly at a controlled respiratory frequency, strongly suggests that cardiac vagal tone in man can be regulated by gamma-aminobutyric acid neurons.

Sleep and blood pressure: spontaneous baroreflex sensitivity in dippers and non-dippers.

OBJECTIVE: Baroreflex sensitivity (BRS) increases during sleep, whereas arterial blood pressure falls. Some hypertensive patients do not have a nocturnal fall in blood pressure (non-dippers). The objective was to ascertain whether there is a difference between 24 h BRS values in dippers and non-dippers that might account for the difference in nocturnal blood pressure behaviour. DESIGN: In a group of consecutive untreated hypertensive patients undergoing 24 h ambulatory intra-arterial blood pressure (IABP) monitoring, 18 were non-dippers i.e., their mean IABP during sleep failed to drop by 10% of their waking IABP. Each non-dipper was matched for age and waking IABP with two dippers. The BRS had previously been assessed with the "Oxford' bolus phenylephrine technique; spontaneous BRS was assessed throughout the 24 h period by off-line computer analysis of spontaneous variations in IABP and R-R interval. RESULTS: In both groups there was a significant increase in spontaneous BRS during sleep (P < 0.0001 for dippers, P < 0.0001 for non-dippers). There was no significant difference between spontaneous BRS in dippers and non-dippers, when they were either awake or asleep. CONCLUSION: BRS did not differ significantly between dippers and non-dippers, when they were either awake or asleep. Changes in BRS during sleep are not likely to account for the abnormal dipping pattern in a minority of hypertensives and are not likely to contribute to the normally observed nocturnal fall in blood pressure.