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Original Studies |
Turku PET Centre (H.L., P.N., T.E., J.K.) and Departments of Medicine (P.N., T.R.), Clinical Physiology (M.L.), and Clinical Chemistry (P.K.) of Turku University, FIN-20521 Turku, Finland; and Department of Clinical Physiology and Nuclear Medicine (C.M.), Rigshospitalet University Hospital, DK-2100 Copenhagen, Denmark
Address correspondence and requests for reprints to: Dr. Hanna Laine, Turku PET Centre, Turku University Central Hospital, P.O. Box 52, FIN-20521 Turku, Finland. E-mail: hannal{at}pet.tyks.fi
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Abstract |
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The purpose of this study was to investigate whether physiological hyperinsulinemia affects myocardial blood flow and flow reserve in healthy subjects. Additionally, the role of the sympathetic nervous system in regulating insulin’s effects on coronary perfusion was tested.
We used positron emission tomography and oxygen-15-labeled water to measure myocardial blood flow and coronary flow reserve in 16 healthy nonobese men (age, 34 ± 4 yr; maximal aerobic capacity, 32 ± 3 mL·g -1·min -1; blood pressure, 118 ± 10/65 ± 8 mm Hg) at fasting and during euglycemic hyperinsulinemic clamp (1 mU·kg-1·min-1 for 80 min). To study the role of the sympathetic nervous system, each subject was studied twice: once after administration of dexamethasone (dexa+) for 2 days (2 mg per day) and once without previous medication (dexa-). All studied subjects had normal left ventricular mass, function, and findings in stress echocardiography.
Resting myocardial blood flow was 0.76 ± 0.19 mL·g-1·min-1, and a significant increase in flow was detected after adenosine infusion (140 µg/kg·min for 5 min iv), both in the basal fasting state (P < 0.001) and during hyperinsulinemia (P < 0.001). However, the flow response to adenosine was significantly higher during hyperinsulinemia, thus leading to a higher hyperemic flow (3.38 ± 0.97 vs. 4.28 ± 1.57 mL·g-1·min-1, basal vs. hyperinsulinemic, P < 0.01) and higher coronary flow reserve (4.6 ± 1.2 vs. 5.8 ± 1.9, respectively, P < 0.05). Pretreatment with dexamethasone did not significantly change the resting blood flow [0.72 ± 0.22 vs. 0.76 ± 0.19 mL·g-1·min-1, dexa+ vs. dexa-, not significant (NS)], the adenosine stimulated flow (3.56 ± 1.49 vs. 3.38 ± 0.97 mL·g-1·min-1, respectively, NS), or the hyperinsulinemic adenosine-stimulated blood flow (4.68 ± 1.74 vs. 4.28 ± 1.57 mL·g-1·min-1, respectively, NS). Coronary flow reserves in the basal state (5.3 ± 2.7 vs. 4.6 ± 1.2 mL·g-1·min-1, dexa+ vs. dexa-, NS) and during hyperinsulinemia (6.8 ± 2.9 vs. 5.8 ± 1.9 mL·g-1·min-1, respectively, NS) tended to be (but were not) significantly higher after dexamethasone treatment.
These results demonstrate that insulin acts as a vasodilatory hormone also in the coronary vasculature. Because the insulin-induced increment of myocardial flow reserve remained unchanged by dexamethasone pretreatment, centrally mediated sympathetic activation seems not to play a major role in regulating insulin action on myocardial perfusion in healthy subjects.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Previous human studies of insulin’s effects on the heart have mainly focused on insulin’s metabolic effects (5, 6, 7, 8), and physiological hyperinsulinemia has not been found to effect cardiac hemodynamics in resting conditions (5, 9). On the other hand, glucose-insulin-potassium infusion (GIK) has been found to increase coronary sinus blood flow (10) and enhance left ventricular function during acute myocardial infarction (11) or prolonged ischemia in humans (12). However, whether these effects of GIK were related to insulin or the hyperglycemia caused by GIK (10) is unknown. Previous animal studies have shown that hyperinsulinemia dilates coronary vasculature (13, 14). These results of animal studies and the results of human GIK studies suggest that insulin also has effects on myocardial vasculature and perfusion. Furthermore, a recent study reported that acute physiological hyperinsulinemia produces cardiac vagal withdrawal and sympathetic activation in humans (15). This finding raises the possibility that the sympathetic nervous system, a major mediator of insulin’s vascular actions in the peripheral tissues (16, 17), might also modulate insulin action on myocardial perfusion. Dexamethasone treatment abolishes insulin-induced sympathetic activation in healthy humans (18, 19) and can thus be applied to investigate the role of the sympathetic nervous system in modulating insulin action.
The present study was undertaken to determine whether and how insulin affects myocardial blood flow and flow reserve in healthy humans. Myocardial blood flow, hyperemic adenosine-stimulated flow, and flow reserve were determined after an overnight fast and during euglycemic hyperinsulinemic clamp (1 mU/kg·min) using positron-emission tomography (PET) and oxygen-15-labeled water ([15O]H2O). To study the role of the sympathetic nervous system on insulin’s effects on myocardial vasculature, each subject was studied twice [with and without previous dexamethasone treatment (dexa+ and dexa-, respectively)].
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Sixteen nonsmoking asymptotic males volunteered for the study.
The characteristics of the subjects are shown in Table 1
. The subjects were healthy, as judged
by their history and physical examination, and were not taking any
medication. All subjects were normotensive and had normal glucose
tolerance, blood counts, and electrolytes. Echocardiographically
determined left ventricular mass, dimensions, and function, as well as
the stress echocardiographies and electrocardiograms, were normal in
all studied subjects.
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All PET studies were performed after an overnight fast; and additionally, the subjects were instructed to avoid all caffeine-containing drinks and foods for 12 h before the PET studies. Each subject was studied twice: once after the administration of dexamethasone for 2 days (0.5 mg x 4 per day) and once without previous medication. The 2 study days were performed in a random order. On each study day, myocardial perfusion was measured three times: first, at rest; and second, after administration of adenosine (140 µg/kg·min for 5 min iv). Thereafter, euglycemic hyperinsulinemic clamp (20) (1 mU/kg·min) was started and continued for 60 min before the second iv infusion of adenosine (140 µg/kg·min for 5 min iv) and the third perfusion measurement. The euglycemic clamp was continued until the end of the third perfusion measurement. Normoglycemia was maintained using a variable rate of infusion of 20% glucose. Electrocardiogram and heart rate were monitored continuously during the studies. Blood pressure was monitored with an automatic oscillometric blood pressure monitor (OMRON HEM-705C, Omron Healthcare, Hamburg, Germany) during the PET study. The study protocol was accepted by the Joint Commission on Ethics of the Turku University and Turku University Central Hospital. Each subject gave written informed consent.
Production of [15O]CO and [15O]H2O
For production of 15O, a low-energy deuteron accelerator Cyclone 3 was used (Ion Beam Application Inc., Louvain-la-Neuve, Belgium). [15O]CO was produced in a conventional way (21). 15O-labeled water was produced using dialysis techniques in a continuously working water module (22). Sterility and pyrogenity tests for water and chromatographic analysis for gases were performed to verify the purity of the products.
Image acquisition, processing, and corrections
The subjects were placed in a supine position in a 15-slice ECAT 931/08–12 tomograph (Siemens/CTI Inc., Knoxville, TN). After the transmission scan, the subjects’ nostrils were closed, and they inhaled [15O]CO for 2 min through a three-way inhalation flap-valve (0.14% CO mixed with room air). After the inhalation, 2 min were allowed for carbon monoxide to combine with hemoglobin in red blood cells before a 4-min static scan was started. During the scan period, three blood samples were drawn at 2-min intervals, and blood radioactivity was measured immediately with a well counter (Bicron 3MW3/3; Bicron Inc., Newbury, OH). A 10-min period was allowed for [15O]CO radioactive decay before the flow measurements. Flow was measured at rest and starting 60 seconds after iv administration of adenosine (140 µg/kg·min, over a period of 5 min). [15O]H2O was injected iv, and dynamic scanning was started for 6 min (6 x 5 sec, 6 x 15 sec, and 8 x 30 sec). All data were corrected for dead time, decay, and photon attenuation and reconstructed into a 128 x 128 matrix. The final in-plane resolution in reconstructed and Hann-filtered (0.3 cycles/sec) images was 9.5 mm (full width, half maximum).
Calculation of regional blood flow
Regions of interest (ROIs) were drawn in the lateral, anterior, and septal wall of the left ventricle, in four representative transaxial slices, in each study, as previously described (23). The ROIs outlined in the baseline images were copied to the images obtained after adenosine administration. Values of regional myocardial blood flow (expressed in milliliters per gram of tissue per minute) were calculated, according to the previously published method, using the single-compartment model (24, 25).
The arterial input function was obtained from the left ventricular time activity curve, using a previously validated method (26), in which corrections were made for the limited recovery of the left ventricular ROI and the spillover from the myocardial signals. No regional differences were found in myocardial perfusion. Therefore, to enhance accuracy and statistics of the flow measurements, the average blood flow of global myocardium was calculated and used in further analysis. The myocardial flow reserve was defined as a ratio of the myocardial blood flow during adenosine infusion to the flow at rest (27), and the hyperinsulinemic flow reserve was defined as a ratio of the myocardial blood flow during simultaneous adenosine and insulin infusions to the flow at rest.
Echocardiographic examination
To rule out silent coronary heart disease, the subjects underwent a rest and a bicycle exercise echocardiographic examination. All echocardiographic recordings and analyses were performed by the same experienced investigator (M. Luotolahti) using a commercially available ultrasound scanner (Acuson 128XP/10, Acuson Inc., Mountain View, California). Standard echocardiographic views of the left ventricle were obtained, and cardiac dimensions were measured first at rest. Thereafter, an upright bicycle-ergometer exercise test was performed by increasing work load by 20 watts at 1-min intervals. The test was continued until extreme fatigue or 90% of the predicted maximum heart rate was achieved. The echocardiograms were recorded before and immediately after the exercise. All subjects had a normal exercise capacity, were asymptomatic, had no diagnostic changes for ischemia in electrocardiograms, and had no wall motion disturbances either at rest or immediately after the maximal exercise.
Analytical procedures
Venous blood samples were taken after 12 h of overnight fast in the PET study morning. Plasma glucose was determined every 5–10 min, during insulin clamp, by the glucose oxidase method (28). Serum insulin was measured by RIA kit (Pharmacia, Uppsala, Sweden). Serum total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride concentrations were measured, using standard enzymatic methods (Roche Molecular Biochemicals GmbH, Mannheim, Germany), with a fully automated 704 analyzer (Hitachi Ltd., Tokyo, Japan). HDL-cholesterol was measured after polyethyleneglycol (molecular weight 6000, final concentration 10%) precipitation (29). The low-density lipoprotein cholesterol concentration was calculated by using the Friedewald formula (30). Plasma epinephrine and norepinephrine were measured as previously described (31).
Statistical methods
The results are expressed as mean ± SD. Paired t tests were used when appropriate. The effect of dexamethasone treatment on flow values, the responses to adenosine infusion with and without hyperinsulinemia, and the interaction of these variables were tested using the ANOVA of repeated measures (32). P-values less than 0.05 were interpreted as statistically significant. All statistical tests were performed with a statistical analysis system (SAS Institute, Inc., Cary, NC).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Metabolic and hormonal characteristics of the study subjects are
given in Table 2. Dexamethasone treatment
did not change fasting insulin, glucose, or free fatty acid (FFA)
concentrations. During hyperinsulinemia, serum insulin and plasma
glucose concentrations were comparable in the 2 study days, but the
average FFA levels were slightly higher after dexamethasone treatment
(Table 2). Insulin-stimulated whole-body glucose uptake was reduced by
50% (from 31.0 ± 11.0 to 15.6 ± 8.3 µmol/kg·min,
P < 0.001) with dexamethasone treatment.
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). Dexamethasone treatment reduced
the insulin-induced increment of norepinephrine but had no significant
effect on fasting norepinephrine or epinephrine values (Table 2). Hemodynamic measurements during PET
Blood pressures, heart rates, and rate-pressure products during
the 2 study days are presented in Table 3. Adenosine administration induced a
significant increase in heart rates and rate-pressure products, both
basally and during hyperinsulinemia. No difference in blood pressure
values was detected after adenosine stimulation or after insulin and
adenosine stimulations (Table 3). Dexamethasone treatment did not
change basal blood pressures, heart rates, rate pressure products, or
their responses to adenosine (Table 3).
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Resting myocardial blood flow was 0.76 ± 0.19
mL·g-1·min-1 and
adenosine infusion increased myocardial blood flow significantly, both
in the basal fasting state and during hyperinsulinemia (Fig. 1). The flow responses to adenosine were
significantly higher during hyperinsulinemia, thus leading to a higher
hyperemic flow (3.38 ± 0.97 vs. 4.28 ± 1.57
mL·g-1·min-1, basal
vs. hyperinsulinemic, P < 0.01) and higher
coronary flow reserve (4.6 ± 1.2 vs. 5.8 ± 1.9,
respectively, P < 0.05).
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). Coronary flow reserves in the basal state
(5.3 ± 2.7 vs. 4.6 ± 1.2
mL·g-1·min-1, dexa+
vs. dexa-, P = 0.34) and during
hyperinsulinemia (6.8 ± 2.9 vs. 5.8 ± 1.9
mL·g-1·min-1,
respectively, P = 0.26) tended to be higher but were
not significantly higher with than without dexamethasone treatment. |
Discussion |
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From previous studies, it has been concluded that the most important mediators of insulin’s cardiovascular actions are the L-arginine nitric oxide pathway and the sympathetic nervous system (33). Insulin has dual effects on blood flow. It increases blood flow in a time- and concentration-dependent fashion (34, 35, 36), via endothelium-dependent mechanisms, which can be abolished by inhibiting NO synthesis (16, 17). At physiological concentrations, insulin also increases sympathetic nerve activity, an effect counteracting (37) the vasodilatory effect of insulin in peripheral vasculature (16, 17). Recently, physiological increases of insulin have been demonstrated to increase also cardiac sympathetic activity in healthy humans, measured using power spectral analysis of heart rate variability (15).
During the last several years, insulin’s vascular actions have been widely studied. However, most of these studies have been performed in peripheral vasculature, and studies of insulin’s action on myocardial perfusion have been sparse. Moreover, all of the previous studies of insulin’s effects on myocardial vasculature have simply studied the effect of insulin on basal blood flow, and most of these studies have been performed in animals. In those experimental animal studies, where high supraphysiological doses of insulin were used (13, 14) or hypoglycemia was induced (13, 38), increase in coronary blood flow by insulin was reported. However, in other animal studies, where moderate insulin doses were applied and euglycemia was maintained, no significant changes were found in coronary blood flow (39, 40). These results are consistent with the two previous human studies, where insulin stimulation did not alter resting myocardial blood flow (5, 9). In the study of Thomassen et al. (1989), insulin stimulation (2 U bolus iv) did not change resting coronary sinus blood flow in subjects with coronary artery disease or normal coronary angiograms. Ferrannini et al. (1993) reported that hyperinsulinemic euglycemic clamp (1 mU/kg·min) induced no changes in great cardiac vein blood flow nor in cardiac hemodynamics in healthy subjects. In the present study, the effect of insulin on coronary vasoreactivity was examined during adenosine-induced hyperemia, and insulin was found to significantly increase coronary flow reserve and enhance myocardial blood flow response to adenosine. Thus, the present study demonstrates that insulin is capable of modulating coronary vasoreactivity in healthy humans and, therefore, insulin’s ability to act as a vasodilatory peptide not only in peripheral, but also in myocardial vasculature should be added to the diversity of biological actions of insulin.
The mechanism of insulin’s ability to enhance adenosine-stimulated myocardial perfusion and coronary flow reserve can not be directly answered by the present study. The adenosine-induced coronary flow response reflects the combined effect of endothelial-mediated vasodilatory function (41, 42, 43) and vascular smooth muscle relaxation (44) and has been used as an integrating measure of coronary reactivity (45, 46). Intravenous infusions of adenosine at a similar or smaller rates than used in the present study (140 µg/kg/min for 5 min iv) have been demonstrated to produce maximal coronary vasodilatation, comparable with that generated by intracoronary papaverine, in most normal subjects (44). Still, in the present study, we found that physiological hyperinsulinemia was able to further enhance the adenosine-induced coronary vasodilatation. Hypothetically, this effect of insulin could result from insulin’s ability to further increase vasodilatation or to reduce vasoconstriction. Previous in vitro studies have demonstrated that insulin induces vasodilatation by increasing cyclic guanosine monophosphate content, via an NO-dependent mechanism in human vascular smooth muscle cells (47) and by activating L-arginine transport and endothelial NO synthase in human endothelial cells (48). Recently, insulin has been demonstrated to activate a constitutive NO synthase in human vascular smooth muscle cells and to increase also cAMP concentrations (49). All of these mechanisms of insulin action provide possible explanation for the present finding of insulin’s ability to enhance adenosine-stimulated cardiac perfusion in healthy subjects.
Insulin’s sympathoexcitatory effects are supposed to be mediated, at least in part, by a central neural action (50, 51). Insulin crosses the blood brain barrier (52), and insulin receptors have been demonstrated in the central nervous system (53). In rats, when administered intracerebroventricularly, insulin stimulates sympathetic nervous activity (54), an effect that is abolished by anterolateral third-ventricle lesions (55). In humans, systemic insulin infusion stimulates norepinephrine spillover (56) and sympathetic nerve responses in skeletal muscle vasculature (57), whereas local insulin infusion into the forearm has no such stimulatory effect, indicating that insulin’s sympathoexcitatory actions are not mediated by local mechanism. In lean healthy humans, dexamethasone has been found to abolish insulin-induced sympathetic activation (18, 19) and increment of blood flow in skeletal muscles (18). This effect of dexamethasone has been suggested to be exerted either by inhibition of the transport of insulin from the plasma to the central nervous system, as evidenced in dog studies (58), and/or by altering central neural peptid release (19).
Dexamethasone treatment, for 48 h, was used in the present study to examine the role of the sympathetic nervous system on insulin’s effects on myocardial vasculature. Consistent with previous studies, we found that dexamethasone decreased sympathetic activity, given that the insulin-induced increment of norepinephrine was blunted after dexamethasone treatment. However, dexamethasone did not change insulin’s effect on coronary perfusion, nor did it change basal or hyperemic blood flows or coronary flow reserves significantly, suggesting that sympathetic activation seems not to play a major role in regulating insulin’s effects on cardiac perfusion in healthy subjects. These results are supported by a recent finding that, even though insulin increases sympathetic drive, both to skeletal and cardiac muscles (recorded using both power spectral analysis of heart rate variability and microneurographic recordings of muscle sympathetic nervous activity), the increased sympathetic drive is primarily targeted at skeletal muscle vasculature in healthy subjects (15). This is consistent with previous findings that, at a time when insulin induces more than 2-fold increases in muscle sympathetic activity, only moderate increases (6–7 beats/min) are detected in the heart rate of healthy subjects (18, 19).
In this study, only young healthy males were studied. We do not know whether the same results can be extrapolated for female subjects of the similar age or for older subjects. Furthermore, in several insulin-resistant states, coronary flow reserves have been found to be reduced in subjects with no coronary artery disease (59, 60, 61, 62), and whether insulin action on cardiac perfusion is altered in these subjects remains to be shown.
In summary, the results of the present study demonstrate that insulin acts as a vasoactive peptide, not only in human peripheral but also in myocardial vasculature. Furthermore, when the sympathetic stimulation normally produced by insulin was inhibited by dexamethasone treatment, insulin’s ability to stimulate coronary flow reserve was unaltered in healthy subjects. The findings suggest that, even though insulin-induced sympathetic activation is one of the most important mediators of insulin action in the peripheral circulation, it is not a major modulator of insulin’s effects on cardiac perfusion in healthy subjects. The present findings are of considerable clinical importance and urge performance of further studies addressing whether insulin resistance is associated with changes in insulin’s action on cardiac perfusion.
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Acknowledgments |
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Footnotes |
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Received September 22, 1999.
Revised January 26, 2000.
Accepted February 2, 2000.
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References |
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