Early atherosclerosis is retarded by improved long-term blood glucose control in patients with IDDM.

Microangiopathy is retarded by improved blood glucose control in patients with IDDM. Whether or not this is true for macroangiopathy (atherosclerosis) has remained unclear. A total of 59 patients (44 +/- 1.5 years, previous HbA1C 9.4 +/- 0.2%, mean +/- SE) with IDDM were investigated. Of the 59 patients, 31 had been randomized to long-term intensified conventional insulin treatment (ICT), and the remaining 28 had received standard insulin treatment (ST). Blood glucose control was significantly better in the ICT patients with an HbAlc value (mean of 29 values during 10 years) of 7.1 +/- 0.1% compared with the ST patients' 8.2 +/- 0.2% (P < 0.0001). With high-frequency ultrasound, endothelial function was measured as flow-mediated dilation of the right brachial artery. The carotid arteries were scanned for plaques, intima-media thickness was measured, and arterial wall stiffness was calculated in the right common carotid artery. These measurements correlate with manifest and/or risk factors for coronary atherosclerosis. The patients in the ST group had stiffer arteries (P = 0.011) and thicker intima-media in the left common carotid artery (P = 0.009) than those in the ICT group. Patients with lower HbA1c generally had better endothelial function (P = 0.028) and less stiff arteries (P = 0.009). Better blood glucose control in patients with IDDM is related not only to less microangiopathy but also to a slower development of atherosclerosis.

Laser Doppler flow-meter assessment of iontophoretically applied norepinephrine on human finger skin circulation.

A miniaturized technique to administer vasoactive substances iontophoretically into the human finger skin and to continuously assess the resulting reaction of the vessels is described. Cutaneous blood flow is measured with a laser Doppler flow-meter. The technique has been used in 9 healthy volunteers with norepinephrine as test substance. The described method is a convenient way to evaluate the effects of transdermally applied vasoactive substances in a semiquantitative way without risking central effects of the substance to influence the registered blood flow.

Heart rate variability in patients with epilepsy.

Autonomic function was studied by the use of spectral analysis of heart-rate variability in patients with epilepsy in relation to type of epilepsy and anti-epileptic drug therapy. A total of 21 patients with juvenile myoclonic epilepsy (JME) and 21 with temporal lobe epilepsy (TLE) were included; 18 patients were treated with carbamazepine (CBZ), 16 with valproate (VPA) and seven with phenytoin (PHT). One healthy drug free control, matched for age and sex, was selected for each patient. Patients and controls underwent an ambulatory 24 h EKG. Heart-rate variability was analyzed in time and frequency domains. Patients with TLE had significantly lower S.D. of the RR-intervals, lower low frequency power and a lower low frequency/high frequency power ratio than their controls. A lower low frequency/high frequency power ratio was the only significant difference between the JME patient group and their controls. Treatment, however, may have had a considerable influence on the heart rate variability in the epilepsy patients. Patients on CBZ had significantly lower S.D. of RR-intervals, low frequency power and a low frequency/ high frequency power ratio than did their matched healthy drug free controls. The ratio of low frequency/high frequency power was also lower in patients on VPA compared with their controls, but apart from that no differences could be demonstrated between this treatment group and the controls. In conclusion, patients with epilepsy appear to have an altered autonomic control of the heart, with a reduction in some heart-rate variability measures, suggesting a decreased sympathetic tone, which may be related to the drug therapy or the epilepsy as such. Further studies are warranted to explore these changes and their possible relevance for sudden death in epilepsy.

Markers of risk after acute myocardial infarction. A comparison of clinical variables, ambulatory and exercise electrocardiography, echocardiography, and stress echocardiography.

BACKGROUND: Short-term mortality after myocardial infarction has decreased continuously among members of selected populations. Nonetheless, the long-term prognosis among members of unselected populations remains bad. Further research in risk stratification is therefore needed. In the present study we tested the additive value of clinical variables, echocadiography, ambulatory electrocardiography, exercise testing, and stress echocardiography in assessing the long-term prognosis after acute myocardial infarction. METHODS: Two-dimensional echocardiography and ambulatory electrocardiography (analysis of ST-segment changes and of heart rate variability) were performed for 74 patients aged < 75 years who had had an acute myocardial infarction. Before their discharge from hospital, 70 patients were subjected to a combined exercise test and stress echocardiography. The time of follow-up was > or = 3 years. RESULTS: During follow-up 18 patients died, and 38 suffered cardiac events defined as death, nonfatal reinfarction and the need for revascularization. We first tested 31 covariates in a univariate regression analysis. A subsequent multivariate analysis was performed in two stages. During the first of these, clinical variables (a history of systemic hypertension, infarct localization, and diabetes mellitus) and variables derived from noninvasive tests (new-onset wall-motion abnormality during stress echocardiography, ST-segment depression and heart-rate variability during ambulatory electrocardiography, the ejection fraction by echocardiography at rest, and the double product during exercise tests) predicted mortality. After the second stage, however, the only remaining independent predictors of mortality were the presence of a new-onset wall-motion abnormality (P < 0.0001, relative risk 13.5, 95% confidence interval 3.6-51.3), ST-segment depression during ambulatory electrocardiography (P = 0.003, relative risk 5.0, 95% confidence interval 1.7-15.7) and a decreased heart rate variability (P = 0.007). CONCLUSIONS: The only variables that were of independent value in assessing the long-term mortality were those expressing residual myocardial ischemia and the cardiovascular sympatho-vagal balance. It is, therefore, recommended that one should monitor these variables for patients recovering from an acute myocardial infarction.

Habitual snorers and sleep apnoics have abnormal vascular reactions of the soft palatal mucosa on afferent nerve stimulation.

A local disturbance in the afferent nerves involved in the reflexogenic dilation of the upper airways (UAs) could contribute to the increased collapsibility seen in patients with obstructive sleep apnea (OSA). Laser Doppler perfusion monitoring, combined with electrical stimulation, is a method for investigating the afferent nerve regulation of the microcirculation. It was used in the mucosa of the soft palate in 35 patients with various degrees of UA obstruction and in 13 control subjects, all nonsmoking men. In a majority of snorers and patients with mild OSA, stimulation induced an exaggerated vasodilation, compared with controls. In contrast, in patients with severe OSA, the vasodilation was significantly reduced, compared with controls. These signs of disturbances in the microcirculation support the hypothesis of a local progressive afferent nerve lesion in heavy snorers with or without OSA.

Carotid baroreflexes during hemodialysis.

In 9 regular hemodialysis patients, the carotid baroreceptor reflex was studied using standardized carotid sinus stimulation by neck suction. All patients were studied during predialysis conditions (recirculation), and during dialysis using dialyzate sodium concentrations of 145 and 133 mmoles/l. Baroreceptor stimulation was performed during the recirculation period and after 120-266 minutes of combined dialysis and ultrafiltration. Dialysis alone with either sodium concentration tended to decrease blood pressure. Heart rate as well as plasma renin activity increased significantly during dialysis with either procedure. In contrast to the findings in healthy subjects, heart rate was not influenced by neck suction, possibly reflecting a vagal neuropathy in uremic patients. However, carotid sinus stimulation decreased systolic pressure during recirculation to the same extent as has been found in healthy subjects. Furthermore, the blood pressure response to neck suction was enhanced during dialysis. These findings suggest that the blood pressure decrease during dialysis can not be explained by defective blood pressure control by the carotid sinus baroreceptors.

24-hour ECG frequency-domain measures in preeclamptic and healthy pregnant women during and after pregnancy.

OBJECTIVE: The aim of the present study was to evaluate the autonomic balance in women with preeclampsia and in healthy women during and after pregnancy by means of a 24-h ECG Holter recording combined with power spectral analysis. METHODS: Fifteen preeclamptic and 15 healthy women underwent 24-h Holter monitoring in the 32nd-36th week of gestation and 3-6 months postpartum. The power spectrum of the maternal electrocardiogram was analyzed with an autoregressive algorithm. MAIN OUTCOME MEASURES: The power spectrum contains two major components: a low-frequency peak, primarily attributed to sympathetic tone, and a high-frequency peak, reflecting vagal tone. RESULTS: The power spectrum of maternal heart rate variability did not differ between preeclamptic and normal women during pregnancy. After delivery, the amplitude of all components became significantly higher than those during pregnancy, with one exception: the high-frequency component in the patients who had been preeclamptic. In a comparison of the two groups, the high-frequency component after delivery was significantly lower in women who had preeclampsia than in normal healthy women (p = 0.03). CONCLUSIONS: During pregnancy, the power spectrum is reduced and cannot be used to distinguish between patients with preeclampsia and normal healthy women. Three to 6 months after delivery, the high-frequency component is still reduced in the preeclamptic group of women. This indicates an impaired vagal modulation even in the nonpregnant state in this group of women, unlike those who had a normotensive pregnancy.

Alpha 2-adrenoceptor inhibition in patients with vibration white fingers.

In healthy subjects the physiological vasoconstriction to local cooling has been linked to sympathetic adrenoceptors of the alpha2-subtype. The present study was designed to determine if the vasoconstriction in response to local cooling in patients suffering from vibration white fingers can be diminished by alpha2-adrenoceptor inhibition. Six men with vibration white fingers, verified in a cold provocation test, were examined. To study the effect of local skin cooling blood flow was measured with laser doppler technique on the dorsum of dig. II or III. The temperature of the laser doppler probe was regulated by Peltier elements. Temperature could be lowered from 30 degrees C to 20 degrees C within 30s. Measurements were performed before and after local inhibition of the alpha2-adrenoceptors. This was achieved by the introduction of the selective alpha2-adrenoceptor inhibitor, rauwolscine, into the finger skin by iontophoresis. During control conditions local cooling consistently resulted in a marked vasoconstriction. Inhibition of the alpha2-adrenoceptors by rauwolscine completely abolished this effect. The present data indicate that substances inhibiting alpha2-adrenoceptors may be of therapeutic value in patients with vibration white fingers.

Non-invasive techniques used to monitor peripheral circulatory changes induced by nitroglycerin.

The antianginal effect of nitroglycerin is mainly mediated by its pronounced effects on peripheral vessels. These include an increased venous distensibility as well as a dilating effect on large arteries, a decreased arterial stiffness and an increased muscular and skin blood flow. These changes have been used to monitor and to assess the effects of various nitroglycerin preparations in numerous studies. The most frequently used techniques to demonstrate peripheral effects of nitroglycerin are summarized.

Influence of age on sensitivity and effector mechanisms of the carotid baroreflex.

In 30 healthy subjects aged 20--48 years the hemodynamic response to carotid sinus stimulation (neck suction -40 mmHg) was studied. Heart rate, arterial pressure and cardiac output (dye dilution technique) were measured. In order to evaluate the effect of age on carotid sinus function the material was subdivided into two arbitrary subgroups, aged up to 30 years (n = 15) respectively 30 years and above (n = 15). Carotid sinus stimulation induced a significantly greater reduction in mean arterial pressure in the younger group compared to the older group. The heart rate reduction was, on the average, slightly greater in the younger group though the difference was not significant. In both groups a significant decrease in cardiac output contributed to the demonstrated reduction in mean arterial pressure. As the decrease in cardiac output was, on the average, slightly smaller in the younger group, the results indicate that the greater blood pressure response in the younger group was due to a greater reduction in peripheral vascular resistance. This is further supported by the finding of a significant correlation between changes in total peripheral vascular resistance, elicited by carotid sinus stimulation and age.

Alpha-adrenoceptors in the vessels of human finger skin.

To characterize alpha-adrenoceptors in the blood vessels of finger skin the effects of selective alpha-1 and alpha-2 adrenoceptor agonists and antagonists on skin blood flow were studied in vivo. The vasoactive substances were administered into the skin by iontophoresis and the effects on blood flow were evaluated with a laser-doppler. After blockade of alpha-1 adrenoceptors with doxazosine, the blood flow reduction induced by the alpha-1 selective agonist, phenylephrine, was diminished but not that caused by the alpha-2 selective agonist, B-HT 933. In contrast, after alpha-2 selective blockade by rauwolscine, phenylephrine but not B-HT 933 caused a marked decrease in blood flow. The results are compatible with the concept that postjunctional alpha-adrenoceptors in human finger skin vessels are of both alpha-1 and alpha-2 subtypes.

Is vibration white finger a primary sympathetic nerve injury?

Changes in the sympathetic nerve system have been suggested as the pathophysiological mechanism underlying vibration white finger (VWF). The aim of the present study was to investigate if experimental support for such a mechanism could be found in VWF. Drugs with a known effect on sympathetic alpha receptors were administered into the finger skin by iontophoresis and their effects on blood flow in the same area evaluated using a laser Doppler technique. The effects of noradrenaline (stimulating alpha-1 and alpha-2 receptors), phenylephrine (an alpha-1 stimulator), and B-HT 933 (an alpha-2 stimulator) were studied in 12 patients with vibration white finger and 12 healthy controls. The reactions to noradrenaline and B-HT 933 were similar in both patients and controls, but the reaction of the patients to phenylephrine was significantly weaker than the controls. In additional experiments in six patients and six controls concentration effect curves to phenylephrine were derived. The curves for the patients were shifted to the right--that is, they reacted less strongly than the controls at all doses of the drug which induced an appreciable vasoconstriction. The results of this study are compatible with the hypothesis that the alpha-1 receptor mediated responses are weakened in VWF. The predominance of alpha-2 receptors in the digital arteries has, on the basis of animal experiments, been suggested as a possible mechanism for Raynaud's phenomenon.

Effect of mental stress on baroreceptor-mediated changes in blood pressure and heart rate and on plasma catecholamines and subjective responses in healthy men and women.

The aim of this study was to determine whether carotid sinus baroreceptor reflexes are impaired by moderate mental stress. In 12 healthy subjects (6 men, 6 women) baroreceptors were stimulated by static neck suction (at -40 mm Hg) for repeated 2-minute periods during mental stress and control conditions. Heart rate, arterial blood pressure, and levels of plasma catecholamines were measured, and self-reports of effort and distress were obtained. Mental stress, which was induced by a color-word conflict task, increased mean levels of heart rate (+12.4 beats/min; p less than 0.001) and systolic blood pressure (+11.8 mm Hg; p; less than 0.001). The onset of mental stress induced increases in plasma adrenaline and noradrenaline concentrations of 45.8% (p less than 0.08) and 17.6% (p less than 0.05), respectively. The increase in systolic blood pressure was significantly greater in men than in women (p less than 0.01). During mental stress, men had significantly higher levels of plasma adrenaline (p less than 0.05). In both sexes neck suction induced a significant decrease in heart rate and systolic blood pressure; these effects were essentially the same during mental stress and control. The results suggest that nonspecific mental stress does not substantially influence the ability of carotid sinus baroreceptors to decrease heart rate or blood pressure in response to sustained changes in baroreceptor input. The possibility that transient changes influence reflex activity is discussed.

Effect of tobacco use on vibration white finger disease.

In a cohort of 245 men with vibration white finger disease, the effects of tobacco use on the symptoms of the disease and the results of a cold provocation test were studied. The tobacco habits of 111 patients were confirmed by measurement of nicotine and cotinine in plasma. In a subgroup the cold provocation test was repeated after nicotine absorption according to individual habits. Patients with advanced disease as measured on a symptom scale were found to use tobacco more often and to have higher cotinine levels than patients with less advanced disease. Pathologic test results were found more frequently among users of tobacco than among nonusers. Habitual use of tobacco seems to aggravate the symptoms of vibration white finger disease and to result in an increased reactivity in a cold provocation test.

The effect of amitriptyline on forearm blood flow.

The local effect of intra-arterial infusion of amitriptyline (AT) on forearm blood flow was studied in seven healthy subjects. AT was infused at rates of 0.05, 0.10, 0.15, and 0.20 mg-min--1 for periods of 5 min. Forearm blood flow showed a dose-dependent increase when the dose exeeded 0.10 mg-min--1. On the highest dose level the blood flow increased on an average by 73%. No systemic effects, as reflected by changes in heart rate, blood pressure, and blood flow in the contralateral forearm, were observed during the infusion. The present data indicate a dilatating effect of AT on resistance vessels possibly mediated by an alpha-adrenergic blockade.

Digital blood pressure after local cooling as a diagnostic tool in traumatic vasospastic disease.

Measurement of digital blood pressure before and after local cooling was performed in 10 men with traumatic vasospastic disease (TVD), 10 men who worked with vibrating tools but had no symptoms in arms or hands, and 10 men who had never worked with vibrating tools. The reduction in finger systolic pressure was significantly larger in the group with TVD than in either of the reference groups (p less than 0.001). There was no difference between the two reference groups. Nine of the 10 patients with TVD had a larger reduction in their finger systolic pressure after local cooling than anyone in either control group. The effects of two different room temperatures (17 degrees C and 23 degrees C) were evaluated. At the higher temperature the overlap between patients with TVD and controls was greater. The method described seems a feasible way to obtain an objective verification of TVD.

Vibration white finger and digital systolic pressure during cooling.

A cold provocation test (measurement of finger systolic pressure during combined body and local finger cooling) was performed on 111 male patients exposed to vibration and with a typical history of cold induced white finger. A new method of calculating the test result is described--namely, digital systolic blood pressure in the cooled test finger as a percentage of the systolic pressure in the arm (DP%). The conventional way of calculating the result, the systolic pressure in the cooled test finger as a percentage of the systolic pressure in the test finger when heated to 30 degrees C, corrected for changes in systemic pressure by the use of a reference finger (FSP%), requires the measurement of the systolic pressure in a reference finger. The two ways of calculating the test results give a similar sensitivity (74% for FSP%, 79% for DP% if all histories are regarded as true) but the new method does not require pressure measurements in a reference finger. This makes the test easier to perform and the result easier to understand.

Raynaud's phenomenon caused by beta-receptor blocking drugs. Improvement after treatment with a combined alpha- and beta-blocker.

Twenty-four hypertensive patients reported vasospastic symptoms in their hands during treatment with beta-blocking drugs with different pharmacological properties. Twenty patients had symptoms when staying indoors and 11 did not always experience complete relief of symptoms following active rewarming attempts. Finger systolic blood pressures were measured after standardized local cooling. In 15 patients, blood pressure decreased to a pathological level during this procedure. Previous beta-blockade was changed to combined alpha- and beta-blockade with labetalol given twice daily in a mean dose of 259 mg/day for 3 months. After this period, most patients showed a decreased temperature sensitivity both objectively and subjectively. Blood pressure control was maintained at the previous level. Heart rate increased significantly during treatment with labetalol. Labetalol offers an alternative treatment to patients suffering from vasospastic side-effects of beta-blockers.

Cooling augments platelet-induced contraction of peripheral arteries of the dog.

The effect of cooling on platelet-induced contractions was studied. Rings of canine saphenous arteries were suspended for isometric tension recording in organ baths filled with aerated physiological salt solution. Norepinephrine, 5-hydroxytryptamine, and autologous aggregating platelets all caused contractions that were augmented by cooling the bath content from 37 to 24 degrees C. These contractions were inhibited, in a concentration-dependent manner, by the serotonergic antagonist ketanserin. The alpha 1-adrenergic antagonist, prazosin, in concentrations causing progressive inhibition of contractions evoked by norepinephrine did not affect the response to either 5-hydroxytryptamine or platelets. Aggregating platelets were found to release 5-hydroxytryptamine in sufficient amounts to account for the observed contractions. Pretreatment of platelets with the cyclo-oxygenase inhibitor meclofenamate reduced the amount of thromboxane liberated by aggregating platelets but did not influence evoked contractions. These observations suggest that aggregating platelets cause contraction of the canine saphenous artery by releasing 5-hydroxytryptamine. They demonstrate that cooling markedly augments contractions of peripheral arterial smooth muscle caused by aggregating platelets.