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(Circulation. 1998;98:961-968.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Cardiac Sympathetic Dysinnervation in Diabetes

Implications for Enhanced Cardiovascular Risk

Martin J. Stevens, MD; David M. Raffel, PhD; Kevin C. Allman, MD; Firat Dayanikli, MD; Edward Ficaro, PhD; Tracy Sandford, RN; Donald M. Wieland, PhD; Michael A. Pfeifer, MD; ; Markus Schwaiger, MD

From the Divisions of Endocrinology and Metabolism (M.J.S., T.S.) and Nuclear Medicine (D.M.R., K.C.A., F.D., E.F., D.M.W., M.S.), Department of Internal Medicine, University of Michigan, Ann Arbor, Mich, and Diabetes Research and Treatment Center (M.A.P.), Southern Illinois University School of Medicine, Springfield, Ill.

	Abstract

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Background—Regional cardiac sympathetic hyperactivity predisposes to malignant arrhythmias in nondiabetic cardiac disease. Conversely, however, cardiac sympathetic denervation predicts increased morbidity and mortality in severe diabetic autonomic neuropathy (DAN). To unite these divergent observations, we propose that in diabetes regional cardiac denervation may elsewhere induce regional sympathetic hyperactivity, which may in turn act as a focus for chemical and electrical instability. Therefore, the aim of this study was to explore regional changes in sympathetic neuronal density and tone in diabetic patients with and without DAN.

Methods and Results—PET using the sympathetic neurotransmitter analogue ¹¹C-labeled hydroxyephedrine ([¹¹C]-HED) was used to characterize left ventricular sympathetic innervation in diabetic patients by assessing regional disturbances in myocardial tracer retention and washout. The subject groups comprised 10 diabetic subjects without DAN, 10 diabetic subjects with mild DAN, 9 diabetic subjects with severe DAN, and 10 healthy subjects. Abnormalities of cardiac [¹¹C]-HED retention were detected in 40% of DAN-free diabetic subjects. In subjects with mild neuropathy, tracer defects were observed only in the distal inferior wall of the left ventricle, whereas with more severe neuropathy, defects extended to involve the distal and proximal anterolateral and inferior walls. Absolute [¹¹C]-HED retention was found to be increased by 33% (P<0.01) in the proximal segments of the severe DAN subjects compared with the same regions in the DAN-free subjects (30%; P<0.01 greater than the proximal segments of the mild DAN subjects). Despite the increased tracer retention, no appreciable washout of tracer was observed in the proximal segments, consistent with normal regional tone but increased sympathetic innervation. Distally, [¹¹C]-HED retention was decreased in severe DAN by 33% (P<0.01) compared with the DAN-free diabetic subjects (21%; P<0.05 lower than the distal segments of the mild DAN subjects).

Conclusions—Diabetes may result in left ventricular sympathetic dysinnervation with proximal hyperinnervation complicating distal denervation. This combination could result in potentially life-threatening myocardial electrical instability and explain the enhanced cardioprotection from ß-blockade in these subjects.

Key Words: diabetes mellitus • nervous system, autonomic • imaging • ventricles

	Introduction

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Diabetic autonomic neuropathy (DAN) is a common complication of diabetes, present in up to 40% of insulin-dependent diabetic patients at diagnosis.¹ It has been invoked as a cause of sudden cardiac death in diabetic subjects both with and without myocardial ischemia.^{2 3 4 5 6 7} Absent heart rate variability secondary to DAN is predictive of both left ventricular failure and increased mortality.⁶ Left ventricular function has been reported to be depressed in 59% of diabetic subjects with DAN compared with only 8% of those without DAN.⁷ Longitudinal studies of DAN subjects have typically shown 5-year mortality rates ranging between 16% and 53%,^{2 3 4} with the highest mortality rates corresponding to advanced cardiovascular sympathetic denervation.⁴ In contrast, regional cardiac sympathetic hyperactivity is associated with the development of malignant ventricular arrhythmias and cardiac death in nondiabetic humans and animals, particularly when accompanied by reduced protective parasympathetic tone and myocardial ischemia.^{8 9 10} The association of increased cardiovascular mortality with decreased cardiac sympathetic innervation in severe DAN appears somewhat paradoxical, as does the enhanced protective effects of ß-adrenergic receptor blockade in these subjects.^{11 12 13 14}

Radiolabeled analogues of norepinephrine are actively taken up by the sympathetic nerve terminals of the heart and thereby permit direct regional assessment of cardiac sympathetic integrity. Cardiac scanning with ¹²³I-labeled metaiodobenzylguanidine ([¹²³I]-MIBG) has identified sympathetic denervation in most diabetic subjects with normal cardiovascular reflex testing,^{15 16 17} with abnormalities of MIBG retention correlating with left ventricular dysfunction.¹⁶ The radiotracer ¹¹C-labeled hydroxyephedrine ([¹¹C]-HED) has recently been developed as a norepinephrine analogue for PET.^{18 19 20} This has been shown to undergo highly specific uptake and retention in the sympathetic nerve terminals,^{18 19 20} which thus facilitate the quantitative regional characterization of sympathetic neuronal dysfunction and loss.¹⁹ Studies using [¹¹C]-HED have shown that its retention is preferentially reduced in the distal left ventricular myocardium by diabetes.¹⁹ We speculated that this distal denervation in DAN may elsewhere induce regional sympathetic hyperactivity, which could potentially become a focus of electrical and chemical instability.

In this article, we report the results of a study in which PET using [¹¹C]-HED was used to characterize sympathetic neuronal density and function in the proximal myocardial segments of diabetic subjects with and without DAN.

	Methods

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Subjects
The diabetic subjects were recruited from consecutive presentations to the Michigan Diabetes Research and Training Center Clinical Core. All the diabetic subjects included in this study had undergone assessment of myocardial perfusion with PET and [¹³N]NH₃ at rest and during maximal adenosine stimulation (140 µg · kg^-1 · min^-1)^{21 22 23} within a 6-month period preceding this study to confirm the absence of coronary artery disease (CAD). The inclusion criteria for all diabetic subjects included a diagnosis of type 1 diabetes, age between 20 and 65 years, the absence or presence of DAN (as defined below), and the absence of any risk factors for other causes for neuropathy (determined by a medical history, family history, history of medications, occupational history, history of exposure to toxins, physical and neurological examinations, and laboratory studies). Exclusion criteria included preexisting cardiovascular disease, including CAD, congestive heart failure, known arrhythmias, documented ventricular structural abnormalities and valvular disease, peripheral vascular disease, and uncontrolled hypertension; a history of primary dyslipidemia requiring therapy; a creatinine clearance <70 mL/min; or a history of previous kidney, pancreas, or cardiac transplantation.

Diabetic subjects were categorized by cardiovascular reflex testing into diabetic subjects without DAN (DAN free), diabetic subjects with mild DAN, and subjects with severe DAN. These diabetic subjects were compared with healthy age-matched nondiabetic subjects (3 men, 7 women). Clinical details are given in Table 1. DAN-free diabetic subjects (6 men, 4 women) were selected on the basis of having 1 abnormality on standardized testing and no symptoms of DAN. Mild DAN subjects (5 men, 5 women) had 2 to 3 abnormal cardiac autonomic function tests (4 had symptoms from delayed gastric emptying), and severe DAN subjects (4 men, 5 women) had 4 abnormal cardiac autonomic function tests and symptoms attributable to autonomic neuropathy. All severe DAN subjects reported early satiety, nausea, periodic vomiting, persistent constipation with periodic episodes of diarrhea, and dizziness on standing. Four suffered from periodic episodes of urinary retention requiring catheterization. Written informed consent was obtained from all patients, and the study protocol was approved by the institutional review board of the University of Michigan.

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics of Experimental Group

Autonomic Function Testing
Cardiovascular autonomic neuropathy was assessed by use of a battery of autonomic function tests to evaluate heart rate variability. All subjects were fasted and had abstained from both prescription and nonprescription medications on the day of assessment. Subjects were instructed to delay their morning insulin injection until after testing and were excluded if they had experienced a hypoglycemic episode within 8 hours of testing. Blood glucose values were within the range of 8 to 14 mmol/L during the assessment period.

Heart rate variability was measured for 6 minutes with patients in the supine position breathing at a fixed rate of 5 breaths per minute by standardized protocol.²⁴ First, the E/I ratio²⁵ (R-R_max/R-R_min) over 25 breaths was determined. Spectral analysis was then used to quantify defects in sympathetic and vagal innervation of the heart.²⁶ The power spectrum of heart rate variability was determined in low (0.01 to 0.05 Hz), middle (0.05 to 0.15 Hz), and high (0.15 to 0.5 Hz) frequency ranges. Abnormality was defined as results that were below the 2.3 percentile for age.²⁷ A 5-minute postural study was also performed in which the change in the blood pressure on standing was assessed after 20 minutes of the patient lying supine. The lowest standing systolic pressure was used to calculate postural change in blood pressure. The Valsalva maneuver²⁴ was then performed twice, and the mean Valsalva ratio was calculated.

PET Studies and Image Construction
Patients taking medications or substances (including caffeine) known to interfere with neuronal uptake of norepinephrine analogues abstained from such substances for 2 weeks before study. Cardiac PET imaging was performed in a whole-body PET scanner (model CTI 931 and Siemens/ECAT 931) with 20 mCi of [¹¹C]-HED and 20 mCi of [¹³N]NH₃.¹⁹ This scanner has 8 circular detector rings that allow the simultaneous acquisition of 15 contiguous transaxial images (oriented perpendicular to the sagittal and coronal planes of the body) with a slice thickness of 6.75 mm. After introduction of a 22-gauge intravenous cannula into the antecubital vein and placement of the tomograph with the aid of a scout image, a 15-minute transmission study with a retractable germanium-68 ring source was performed to correct emission data for tissue attenuation. Dynamic scan acquisition was initiated simultaneously with the injection of [¹¹C]-HED. The image acquisition protocol comprised 15 images with varying frame duration (6x30, 2x60, 2x150, 2x300, 2x600, and 1x1200 seconds). The emission data were corrected for attenuation and reconstructed by filtered backprojection with a Hanning filter with a cutoff frequency of 1.12 cycles per 1 cm to produce images with a resolution of 9 to 10 mm at full width at half-maximum in-plane. A Sun workstation (Sun Microsystems) was used to realign the images perpendicular to the long axis of the left ventricle, yielding 8 short-axis views (slice thickness, 0.8 cm) of myocardial tracer distribution extending from the apex to the base of the left ventricle. After waiting 1 hour for the [¹¹C] to decay after the end of data acquisition, we evaluated resting myocardial perfusion using [¹³N]NH₃.

Polar Map Generation
Circumferential count-profile analysis was performed on each of the 8 short-axis images. Each short-axis slice was divided into 36 angular regions of interest ("sectors"), and the myocardial concentration of [¹¹C]-HED in each sector, as determined from the mean PET counts in the sector, was calculated. Regional variation in myocardial retention of [¹¹C]-HED was determined from the mean PET counts in each of the 288 sectors (8 images times 36 sectors per image) divided by the value found in the sector containing the maximum mean PET counts. These normalized [¹¹C]-HED retention data were then displayed as polar coordinate maps of relative tracer activity ([¹¹C]/[¹³N]) from the short-axis blood flow and the 40- to 60-minute postinjection [¹¹C]-HED images. The left ventricular myocardium was depicted on the map with the apex at the center. The mean relative tracer activity value was determined¹⁹ within each left ventricular region (divided into apical, anterior, septal, inferior, and lateral myocardial segments). Apical values were obtained by averaging together all sectors in the 2 most apical short-axis slices. Distal values for the other segments were obtained by averaging together the appropriate sectors in the 3 planes adjacent to the 2 apical planes. Similarly, the corresponding proximal values were obtained by use of the final 3 short-axis slices toward the base of the heart. Reference values were obtained from a separate group of normal subjects. They were processed and averaged together to determine the homogeneity of retention in the healthy left ventricle. No regional differences in relative [¹¹C]-HED retention were found in the normal subjects, which was in agreement with previous reports¹⁹ and confirms homogeneous uptake of [¹¹C]-HED within the normal left ventricle.

The heterogeneity of regional left ventricular [¹¹C]-HED retention in each diabetic patient was compared with the normal reference distribution by calculating a z score, z_i=(q_i-µ_i)/_i, where q_i is the relative [¹¹C]-HED retention value in the ith sector value of the diabetic polar map, and µ_i and _i are the mean and SD of the relative [¹¹C]-HED retention in the ith sector of the reference polar map. In the diabetic subjects, sectors that had a z score >2.5 (ie, the relative [¹¹C]-HED retention in the patient's sector was less than the corresponding sector mean relative [¹¹C]-HED retention in the reference subjects by >2.5 SD) was defined as abnormal. Thus, the calculated z scores represent a validated¹⁹ measure of the individual subject's myocardial tracer retention heterogeneity, with an increase in heterogeneity being consistent with distal left ventricular denervation.¹⁹ The "extent" of the heterogeneity was expressed as the percentage of sectors in the polar map that were abnormal, ie, z_i>2.5.

Retention Index Calculation
To quantify changes in regional myocardial uptake of [¹¹C]-HED, absolute [¹¹C]-HED retention in the proximal and distal left myocardium was measured with a "retention index" approach as previously reported¹⁹ that corrects [¹¹C]-HED retention for myocardial tracer delivery. Absolute tissue retention of [¹¹C]-HED between 40 and 60 minutes after injection was measured for distal and proximal anterior, septal, inferior, and lateral myocardial segments by averaging the appropriate sectors from the last 2 frames of the dynamic data set. Mean tracer counts per pixel within the myocardial regions were determined. To correct this measurement for the amount of tracer delivered to the myocardium, retention was divided by the total counts in the blood over the time period from injection to 60 minutes later. Total blood counts were determined from the area under the time-activity curve for a small region of interest (5x5 pixels) placed at the center of the left ventricular blood pool on a basal plane. This yielded a [¹¹C]-HED retention index as follows: retention index (mL blood · min^-1 · mL tissue^-1) equals tissue counts between 40 and 60 minutes divided by blood counts from time 0 to 60 minutes.

For plots of time-activity data, the measured PET counts were converted to units of megabecquerel per milliliter by multiplying by the PET scanner calibration factor, which has units of megabecquerel per milliliter per PET count. This calibration factor is determined weekly by imaging a 20-cm cylindrical flood phantom filled with an aqueous solution of [¹⁸F] at a known concentration.

Quantitative Evaluation of Regional Myocardial Perfusion
PET using [¹³N]NH₃ allows accurate quantification of regional myocardial blood flow,^{21 22} with the flow values agreeing closely with those obtained by invasive techniques.²³ The time course of tracer distribution in myocardium and blood was defined by dynamic image acquisition using a previously described method.^{21 23} After the transmission scan, 20 mCi of [¹³N]NH₃ was administered into the antecubital vein over 30 seconds. Dynamic scan acquisition for this study was initiated with varying frame duration (12x10 seconds/6x30 seconds/2x300 seconds). Twelve myocardial regions per plane were defined in the 8 planes in the last time frame of the dynamic study sequence. After correction for subject motion, the dynamic image set was sampled, and 96 (8 planesx12 regions) time-activity curves were stored for further analysis. Arterial input function was determined from circular regions at the 2 most basal planes corresponding to the large blood pool at the center of the largest left ventricle diameter of the resliced images. A previously validated tracer kinetic model²³ for [¹³N]NH₃ was used to calculate regional myocardial blood flow in milliliters per gram per minute. This 3-compartment model represents vascular and extravascular [¹³N]NH₃, as well as metabolically trapped ¹³N, which comprises glutamine.²³ In this model, the delivery and extraction of [¹³N]NH₃ (which is >90%²⁸), are used as an estimate of myocardial blood flow.²³

Statistical Analysis
Statistical analysis was performed by use of Super ANOVA (Abacus Concepts Inc). Differences among experimental groups were detected by ANOVA, and the significance of differences between these groups was assessed by the Student-Newman-Keuls multiple range test. If the variances for the variables were found to differ significantly, a logarithmic transformation was performed that corrected the unequal variances. All analyses were then performed on the transformed data. Data in the text are given as mean±SD. Significance was defined at P=0.05.

	Results

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Regional Myocardial Perfusion
The presence of regional discrete perfusion defects consistent with occult CAD were evaluated by visual and quantitative analyses of myocardial blood flow at rest. All subjects had homogeneous [¹³N]NH₃ retention on visual inspection of standardized color-coded blood flow images taken from the vertical and horizontal long axes and the distal and proximal short axes of the left ventricle. Resting regional myocardial blood flow was similar in nondiabetic and DAN-free diabetic subjects but was increased by 26% to 46% in the subjects with mild and severe DAN, respectively (Table 2). Resting global flow was higher in all myocardial segments in the DAN subjects compared with the other subject groups, with no regional differences in flow emerging.

View this table: [in this window] [in a new window]   Table 2. Regional Myocardial Perfusion in Different Subject Groups

Regional Ventricular [¹¹C]-HED Retention
Abnormalities of regional [¹¹C]-HED retention in the 3 groups of diabetic subjects are shown in Figure 1. Of the 10 DAN-free subjects, 4 were found to have regional abnormalities in [¹¹C]-HED retention, affecting from 4% to 8% of the left ventricular map (5±2%). Of the 10 mild DAN subjects, 9 were also found to have similar tracer defects affecting from 3% to 17% of the left ventricular map (6±5%, P=NS versus DAN-free subjects). All severe DAN subjects were found to have extensive [¹¹C]-HED retention defects, ranging from 21% to 79% of the left ventricular area (48±19%, P<0.01 versus mild DAN and DAN-free diabetic subjects). In the mild DAN subjects, defects were observed only in the distal inferior wall of the left ventricle, whereas in the severe DAN subjects, defects extended to involve the distal and proximal anterolateral and inferior walls. The ability of the currently available reflex tests of autonomic function to correctly classify subjects free of DAN (specificity) was 0.86, and their ability to correctly classify those with DAN (sensitivity) was 0.67.

View larger version (10K): [in this window] [in a new window]   Figure 1. Extent of regional [11C]-HED retention abnormalities detected in left ventricle in DAN-free diabetic subjects and diabetic subjects with mild and severe DAN on reflex testing. Data shown as percentage of sectors in left ventricular (LV) polar map with relative [11C]-HED retention >2.5 SD of reference values. P<0.05, severe DAN versus DAN-free and mild DAN subjects.

Measurements of the absolute tissue retention index for [¹¹C]-HED in the proximal and distal myocardial segments in the DAN-free diabetic subjects were not significantly different from those of the healthy nondiabetic subjects, consistent with previous reports.^{19 28} Absolute [¹¹C]-HED retention was found to be increased by 33% (P<0.01) in the proximal segments of the severe DAN subjects compared with the same regions in the DAN-free subjects (30%; P<0.01 greater than the proximal segments of the mild DAN subjects) (Figure 2). The increase in [¹¹C]-HED retention in the proximal segments of the severe DAN subjects appeared not to reflect increased tracer delivery because myocardial blood flow was not significantly different in these segments compared with the mild DAN subjects (Table 2). Distally, [¹¹C]-HED retention was decreased in severe DAN by 33% compared with the DAN-free diabetic subjects (P<0.01) (and 21% [P<0.05] compared with mild DAN subjects) (Figure 2). The 14% reduction in absolute [¹¹C]-HED retention in the distal myocardial segments of the mild DAN subjects was not statistically different from the DAN-free diabetic subjects (P=0.1).

View larger version (44K): [in this window] [in a new window]   Figure 2. Comparison of absolute [11C]-HED retention in proximal versus distal myocardial segments in healthy nondiabetic subjects, DAN-free diabetic subjects, and diabetic subjects with mild and severe DAN. *P<0.05 vs other groups; **P<0.01 vs other groups; P<0.01 vs proximal segments. LV indicates left ventricle.

Figure 3A demonstrates the PET images taken from a 35-year-old female subject with severe DAN who, after 33 years of diabetes, had both symptoms of DAN (gastroparesis, bladder dysfunction, and postural hypotension) and abnormalities in all her autonomic function tests. Blood flow images appear normal. [¹¹C]-HED retention, however, was markedly heterogeneous, with only the proximal anterior cardiac segments demonstrating visible [¹¹C]-HED retention. The tracer retention index was abnormally elevated in the proximal segments (0.219±0.02 min^-1) and decreased distally (0.050±0.002 min^-1) (Figure 3B).

View larger version (80K): [in this window] [in a new window]   Figure 3. HED PET images from a 35-year-old female with severe DAN. A, Left ventricle short- and long-axis blood flow and [11C]-HED images. Blood flow images appear normal (top), but abnormalities of [11C]-HED retention are extensive, with only proximal cardiac segments being visible with abnormally high [11C]-HED retention (bottom). B, Surface plot of z-score polar map from same subject. Calculated z scores for each sector of the [11C]-HED retention index polar map are plotted on the z axis of the surface plot. z Score data are encoded in the surface plot a second way by superimposition of a color table. Yellow and white regions are >2.5 SD above the healthy control mean [11C]-HED retention index. Blue regions are >2.5 SD below the control mean. Septal and inferior walls of the polar map are indicated along the x and y axes, respectively. DSA indicates distal short axis; PSA, proximal short axis; HLA, horizontal long axis; and VLA, vertical long axis.

To explore neuronal synaptic vesicular integrity in the proximal and distal myocardial segments, comparative regional time-activity curves were generated in a severe DAN subject after administration of 20 mCi of [¹¹C]-HED followed 60 minutes later by 20 mCi of [¹¹C]-labeled epinephrine (Figure 4). Unlike HED, epinephrine is a substrate for monoamine oxidase,²⁸ so its neuronal retention is largely dependent on highly efficient vesicular storage.²⁸ Regional time-activity curves for [¹¹C]-labeled epinephrine paralleled those generated with [¹¹C]-HED, suggesting that vesicular storage mechanisms are intact in the proximal myocardial segments but defective distally.

View larger version (17K): [in this window] [in a new window]   Figure 4. Time-activity curves comparing regional washout of [11C]-HED and [11C]-epinephrine (EPI) in a 36-year-old male with severe DAN. Washout of [11C]-epinephrine parallels [11C]-HED in both proximal (base) and distal (apical) myocardial segments.

Sympathetic hyperactivity and increased regional norepinephrine levels competitively decrease the retention of sympathetic neurotransmitter analogues, including HED, by accelerating their washout.¹⁸ However, under resting conditions, no significant washout of [¹¹C]-HED is normally observed in healthy nondiabetic myocardium.²⁸ Regional [¹¹C]-HED time-activity washout curves were therefore used to explore whether sympathetic tone was elevated (and hence washout was increased) in the proximal myocardial segments of the severe DAN subjects. In these subjects, no washout of [¹¹C]-HED was observed in the proximal segments, because tissue [¹¹C]-HED activity was constant between 6.25 and 50 minutes (Figure 5). In contrast, in the distal myocardial segments of the severe DAN subjects, rapid [¹¹C]-HED retention washout was observed over this time period. We have previously reported that administration of desipramine to healthy subjects decreases [¹¹C]-HED retention throughout the left ventricle by 50 minutes after injection to 34% of control values.²⁸ Therefore, the lack of washout of [¹¹C]-HED in the proximal myocardial segments of severe DAN patients paralleled that observed in healthy myocardium, but its accelerated washout in the distal myocardium is observed in healthy subjects only after the administration of desipramine.

View larger version (12K): [in this window] [in a new window]   Figure 5. Comparison of [11C]-HED washout in proximal versus distal myocardial segments of subjects with severe DAN. Data shown as [11C]-HED tissue activity in proximal and distal myocardial segments at 50 minutes expressed as percentage of initial (6.25 minutes) activity. *P<0.01 vs basal and 50-minute proximal segments.

	Discussion

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We have used PET and [¹¹C]-HED to directly explore regional changes in sympathetic neuronal density and tone in diabetic subjects with differing severity of DAN. Abnormalities of cardiac sympathetic innervation were detected in 40% of DAN-free diabetic subjects, with deficits beginning distally but sparing the proximal myocardial segments even in severe DAN subjects. In severe DAN, absolute [¹¹C]-HED retention was found to be paradoxically increased in the proximal myocardial segments, while distally [¹¹C]-HED retention was decreased. No appreciable washout of the tracer was observed in the proximal segments, consistent with increased sympathetic innervation but normal regional tone. In the distal myocardium, increased [¹¹C]-HED washout in severe DAN reproduced that observed in the myocardium of desipramine-treated healthy subjects,²⁸ suggesting distal neuronal uptake-1 dysfunction or neuronal loss. These data suggest that diabetes may result in left ventricular sympathetic dysinnervation with proximal hyperinnervation accompanying distal denervation, which in combination could result in potentially life-threatening myocardial electrical instability.

The marked heterogeneity of regional [¹¹C]-HED retention in severe DAN suggests that diabetes can provoke an extreme imbalance of left ventricular sympathetic innervation. [¹¹C]-HED is taken up into the neuron by energy-dependent uptake-1,^{18 29} is nonmetabolized, and thus marks the location of functioning sympathetic nerve terminals. The retention of [¹¹C]-HED in the heart is dependent on continuous recycling into and out of the neuron,^18,29 and its neuronal retention requires intact vesicular storage. Nonneuronal [¹¹C]-HED retention is low, and its extraction from blood to the neuronal axoplasm very high,²⁹ suggesting that its increased retention in the proximal myocardium reflects an increased number of neuronal terminals with intact uptake-1 and vesicular storage. Alternatively, because the net tissue uptake of [¹¹C]-HED is flow limited,²⁹ increased myocardial [¹¹C]-HED retention could result from an increase in myocardial blood flow. Resting myocardial blood flow was higher in DAN subjects than in nondiabetic and DAN-free diabetic subjects, which may reflect the resting tachycardia that accompanies DAN.^{4 5} However, comparison of blood flow in the proximal myocardium of mild and severe DAN subjects did not reveal a difference, suggesting that differences in tracer delivery could not explain the increase in tracer retention in these segments in the severe DAN subjects. The integrity of neuronal vesicular storage in the proximal myocardial segments of severe DAN subjects was confirmed by the demonstration that washout of [¹¹C]-labeled epinephrine paralleled [¹¹C]-HED, because nonvesicular epinephrine would be rapidly metabolized.²⁹ In contrast, enhanced washout of [¹¹C]-HED in the distal myocardial segments of the severe DAN subjects parallels that observed in the myocardium of desipramine-pretreated normal subjects²⁸ (albeit of greater magnitude in DAN, potentially reflecting incomplete pharmacological block of neuronal uptake-1) and suggests that failure of distal [¹¹C]-HED retention in DAN specifically reflects impaired neuronal tracer uptake resulting from uptake-1 dysfunction or neuronal loss.

Proximal myocardial hyperinnervation could result from a persistent increase in axonal sprouting and regeneration that normally precede organ reinnervation.^{30 31} Dense innervation of the proximal versus distal myocardium may contribute to its resistance to denervation and serve as a foundation for ventricular reinnervation, which normally proceeds from the base of the heart to the apex.³² In nondiabetic animals, organ reinnervation after partial denervation requires axonal sprouting and hyperinnervation initially within the islands of remaining innervation,^{30 31} which then becomes downregulated as distal reinnervation is completed. In severe DAN, failure of successful distal reinnervation may lead to a sustained increase in proximal neuronal density. Increased proximal myocardial [¹¹C]-HED retention was not observed in the mild DAN subjects in whom the extent of the distal [¹¹C]-HED retention defect averaged only 13% of that observed in the severe DAN subjects. It is thus tempting to speculate that there may exist a threshold for distal left ventricular denervation to initiate unsuccessful proximal regeneration and repair.

We proposed that sympathetic hyperactivity may be present in the proximal myocardium of the severe DAN subjects. In experimental diabetes, increased sympathetic tone has been etiologically invoked in nerve conduction slowing,³³ and increased sympathetic activity in the rat diabetic myocardium is reported to precede chronic sympathetic denervation.^{34 35} Increased regional norepinephrine levels resulting from increased sympathetic tone would be expected to decrease [¹¹C]-HED retention and accelerate washout.¹⁸ However, the findings that [¹¹C]-HED retention was increased and washout was unchanged in the proximal myocardial segments in severe DAN suggest that sympathetic tone was not abnormally elevated in these regions.

In DAN, cardiac sympathetic dysinnervation in conjunction with parasympathetic denervation^{4 5} may contribute to the excess of cardiac deaths in diabetic patients.^{2 3 4 5 6 11 12 13 14} In nondiabetic subjects, decreased protective parasympathetic tone and heterogeneous sympathetic cardiac innervation are thought to contribute to sudden death.^{36 37 38 39} Increased regional sympathetic innervation may predispose to ventricular fibrillation by decreasing the arrhythmogenic threshold.³⁹ Regional cardiac sympathetic hyperactivity increases the risk of cardiac arrhythmias during myocardial ischemia,^{10 37} and selective cardiac sympathetic denervation or ß-blockers^{11 12 13 14 37} reduce the risk of both cardiac arrhythmias and sudden death in these patients, implicating regional sympathetic imbalance as a factor promoting arrhythmogenesis. Diabetic patients have increased mortality after myocardial infarction,^{11 12 13 14 40 41 42} which may reflect the extent of CAD or increased susceptibility to other triggering factors,^{40 41 42} including autonomic imbalance.^{2 3 4 5 6 7} The decrease in heart rate variability observed in the DAN subjects in this study, despite preservation of proximal myocardial sympathetic innervation, is consistent with regional or global myocardial parasympathetic denervation,^{4 5} which may contribute to electrical imbalance. In diabetes, DAN has been directly implicated in depressed diastolic filling and decreased resting left ventricular ejection fraction.^{16 43} In diabetic subjects complicated by myocardial infarction, DAN is predictive of both increased mortality and left ventricular failure.⁴⁴

Compared with nondiabetic subjects, diabetic patients experience greater cardioprotection with ß-blockade^{11 12 13 14} with highly significant reductions in postinfarct mortality¹³ despite poorer risk factor profiles, implicating a role for cardiac adrenergic hyperactivity. In DAN patients, ß-blockade with atenolol typically slows the elevated resting heart rate,⁴⁵ an effect that requires residual sympathetic tone and is thus consistent with our demonstration of persistent sympathetic innervation even in advanced DAN. Potentially, proximal myocardial sympathetic hyperinnervation could promote regional myocardial perfusion imbalances by decreasing myocardial vascularity,⁴⁶ by stimulating vascular hyperreactivity,⁴⁷ and by contributing to paradoxical coronary vasoconstriction,⁴⁸ thereby increasing cardiac mortality. In addition, increased norepinephrine levels in these proximal segments may contribute to malignant arrhythmogenesis by precipitating myocardial necrosis⁴⁹ secondary to increased intracellular calcium and free radical injury.⁵⁰ Therefore, these islands of hyperinnervation may be the focus of electrical, chemical, and vascular instability, particularly if denervation hypersensitivity is also present.

In summary, our studies have demonstrated that diabetes may result in left ventricular sympathetic dysinnervation with proximal hyperinnervation complicating distal denervation. This exaggerated sympathetic imbalance may contribute to the accelerated rate of cardiac death in diabetes. Therefore, instead of avoiding the use of ß-blocking drugs in DAN, we may need to reconsider their potential benefits in this group of high-risk patients.

	Acknowledgments

 
This work was supported in part by grant RO1-HL-47543 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. Patients were recruited and characterized in the Clinical Implementation Core of the Michigan Diabetes Research and Training Center. We express our gratitude to the University of Michigan Medical Cyclotron and Radiochemistry Unit for the production of the [¹¹C]-HED and to the PET suite technologists for performing the scintigraphic studies. We would like to thank Dr D.A. Greene for his editorial comments.

	Footnotes

 
Reprint requests to Dr Martin J. Stevens, Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Michigan, 5570 MSRB II, Box 0678, 1150 W Medical Center Dr, Ann Arbor, MI 48109-0678.

Received January 29, 1998; revision received April 7, 1998; accepted April 22, 1998.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Hilsted J, Jeensen SB. A simple test for autonomic neuropathy in juvenile diabetics. Acta Med Scand. 1979;205:385–387.[Medline] [Order article via Infotrieve]

2. O'Brien OA, McFadden JP, Corrall RJM. The influence of autonomic neuropathy on mortality in insulin-dependent diabetes. Q J Med. 1991;290:495–502.

3. Rathman W, Ziegler D, Jahnke M, Haastert B, Gries FA. Mortality in diabetic patients with cardiovascular autonomic neuropathy. Diabet Med. 1993;10:820–824.[Medline] [Order article via Infotrieve]

4. Ewing DJ, Campbell IW, Clarke BF. The natural history of diabetic autonomic neuropathy. Q J Med. 1980;49:95–108.[Abstract/Free Full Text]

5. Page MM, Watkins PJ. The heart in diabetes: autonomic neuropathy and cardiomyopathy. Clin Endocrinol Metab. 1977;6:377–388.[Medline] [Order article via Infotrieve]

6. Fava S, Azzopardi J, Muscatt HA, Fenech FF. Factors that influence outcome in diabetic subjects with myocardial infarction. Diabetes Care. 1993;16:1615–1618.[Abstract]

7. Zola B, Kahn JK, Juni JE, Vinik AI. Abnormal cardiac function in diabetic patients with autonomic neuropathy in the absence of ischemic heart disease. J Clin Endocrinol Metab. 1986;63:208–214.[Abstract/Free Full Text]

8. Willich SN, Maclure M, Mittleman M, Arntz H-R, Muller JE. Sudden cardiac death: support for the role of triggering in causation. Circulation. 1993;87:1442–1450.[Abstract/Free Full Text]

9. Lown B, Verrier RL. Neural activity and ventricular fibrillation. N Engl J Med. 1976;294:1165–1170.[Medline] [Order article via Infotrieve]

10. Schwartz PJ, Randall WC, Anderson EA, Engel BT, Friedman M, Hartley LH, Pickering TG, Thoresen CE, for Task Force 4. Sudden cardiac death: nonpharmacologic interventions. Circulation. 1987;76(pt 2):I-215–I-219.

11. Hjalmarson A, Elmfeldt D, Herlitz J, Holmberg S, Malek I, Nyberg G, Ryden L, Swedberg K, Vedin A, Waagstein F, Waldenstrom A, Waldenstrom J, Wedel H, Wilhelmsen L, Wilhelmsson C. Effect on mortality of metoprolol in acute myocardial infarction: a double-blind randomized trial. Lancet. 1981;2:123–127.

12. Beta-blocker Heart Attack Trial Research Group. A randomized trial of propranolol in patients with acute myocardial infarction, I: mortality results. JAMA. 1982;247:1707–1714.[Abstract/Free Full Text]

13. Norwegian Multicentre Study Group. Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med. 1981;304:801–807.[Abstract]

14. Australian and Swedish Pindolol Study Group. The effect of pindolol on the two year mortality after complicated myocardial infarction. Eur Heart J. 1983;4:367–375.[Abstract/Free Full Text]

15. Mantysaari M, Kuikka J, Mustonen J, Tahvanainen K, Vanninen E, Lansimies E, Uusitupa M. Noninvasive detection of cardiac sympathetic nervous dysfunction in diabetic patients using [123]metaiodobenzylguanidine. Diabetes. 1992;41:1069–1075.[Abstract]

16. Kreiner G, Woltzt M, Fasching P, Leitha T, Edlmayer A, Korn A, Waldhausl W, Dudczak R. Myocardial m-[¹²³I]iodobenzylguanidine scintigraphy for the assessment of adrenergic cardiac innervation in patients with IDDM. Diabetes. 1995;44:543–549.[Abstract]

17. Langer A, Freeman ME, Josse RG, Armstrong PW. Metaiodobenzylguanidine imaging in diabetes mellitus: assessment of cardiac sympathetic denervation and its relation to autonomic dysfunction and silent myocardial ischemia. J Am Coll Cardiol. 1995;25:610–618.[Abstract]

18. DeGrado TR, Hutchins GD, Toorongian SA, Wieland DM, Schwaiger M. Myocardial kinetics of carbon-11-meta-hydroxyephedrine (HED): retention mechanisms and effects of norepinephrine. J Nucl Med. 1993;34:1287–1293.[Abstract/Free Full Text]

19. Allman KC, Stevens MJ, Wieland DM, Hutchins GD, Wolfe ER, Greene DA, Schwaiger M. Noninvasive assessment of cardiac diabetic neuropathy by C-11 hydroxyephedrine and positron emission tomography. J Am Coll Cardiol. 1993;22:1425–1432.[Abstract]

20. Rosenspire KC, Haka MS, Van Dort ME, Jewett DM, Gildersleeve DL, Schwaiger M, Wieland DM. Synthesis and preliminary evaluation of [c-11] meta-hydroxyephedrine, a false transmitter agent for heart neuronal imaging. J Nucl Med. 1990;31:1328–1334.[Abstract/Free Full Text]

21. Schwaiger M, Musik O. Assessment of myocardial perfusion by positron emission tomography. Am J Cardiol. 1991;67:35D–43D.[Medline] [Order article via Infotrieve]

22. Bergman S, Herrero P, Markham J, Weinheimer C, Walsh M. Noninvasive quantification of myocardial blood flow in human subjects with oxygen-15-labeled water and positron emission tomography. J Am Coll Cardiol. 1989;14:639–652.[Abstract]

23. Hutchins GD, Schwaiger M, Rosenspire KC, Krivokapich J, Schelbert H, Kuhl DE. Noninvasive quantitation of regional blood flow in the human heart using N-13 ammonia and dynamic positron emission tomographic imaging. J Am Coll Cardiol. 1990;15:1032–1042.[Abstract]

24. Ewing DJ, Clarke BF. Diagnosis and management of diabetic autonomic neuropathy. BMJ. 1982;285:916–918.

25. Sundkvist G, Almer L-O, Lilga B. Respiratory influences on heart rate in diabetes mellitus. Br Heart J. 1979;1:924–925.

26. Akselrod S, Gordon D, Ubel FA, Shannon DC, Barger AC, Chen RJ. Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to beat cardiovascular control. Science. 1981;213:220–222.[Abstract/Free Full Text]

27. Ziegler D, Laux G, Dannehl K, Spuler M, Muhlen H, Mayer P, Gries FA. Assessment of cardiovascular autonomic function: age-related normal ranges and reproducibility of spectral analysis, vector analysis, and standard tests of heart rate variation and blood pressure responses. Diabetic Med. 1992;9:166–175.[Medline] [Order article via Infotrieve]

28. Raffel DM, Corbett JR, del Rosario RB, Gildersleeve DL, Chiao P-C, Schwaiger M, Wieland DM. Clinical evaluation of C-11 phenylephrine: an MAO-sensitive marker of cardiac sympathetic neurons. J Nucl Med. 1996;37:1923–1931.[Abstract/Free Full Text]

29. Raffel DM, Corbett JR, Schwaiger M, Wieland DM. Mechanism-based strategies for mapping heart sympathetic function. Nucl Med Biol. 1995;22:1019–1026.[Medline] [Order article via Infotrieve]

30. Tuttle JB, Steers WD, Albo M, Nataluk E. Neural input regulates tissue NGF and growth of the adult rat urinary bladder. J Auton Nerv Syst. 1994;49:147–158.[Medline] [Order article via Infotrieve]

31. Diamond J, Holmes M, Coughlin M. Endogenous NGF and nerve impulses regulate the collateral sprouting of sensory axons in the skin of the adult rat. J Neurosci. 1992;12:1454–1466.[Abstract]

32. Kaye MP, Wells DJ, Tyce GM. Nerve growth factor-enhanced reinnervation of surgically denervated canine heart. Am J Physiol. 1979;236:H624–H628.

33. Cameron NE, Cotter MA, Low PA. Nerve blood flow in early experimental diabetes in rats: relation to conduction deficits. Am J Physiol. 1991;261:E1–E8.[Abstract/Free Full Text]

34. Felton SY, Peterson RG, Shea PA, Besch HR, Felton DL. Effects of streptozotocin diabetes on the noradrenergic innervation of the rat heart: a longitudinal histofluorescence and neurochemical study. Brain Res Bull. 1982;8:593–607.[Medline] [Order article via Infotrieve]

35. Akiyama N, Okumura K, Watanabe Y, Hashimoto H, Ito T, Ogawa K, Satake T. Altered acetylcholine and norepinephrine concentrations in diabetic rat hearts. Diabetes. 1989;38:231–236.[Abstract]

36. Kleiger RE, Miller JP, Bigger JT, Moss AJ, for the Multicenter Postinfarction Research Group. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol. 1987;59:256–262.[Medline] [Order article via Infotrieve]

37. Schwartz PJ, Motolese M, Pollavini G, Lotto A, Ruberti U, Trazzi R, Bartorelli C, Zanchetti A, for the Italian Sudden Death Prevention Group. Prevention of sudden cardiac death after a first myocardial infarction by pharmacologic or surgical antiadrenergic interventions. J Cardiovasc Electrophysiol. 1992;3:2–16.

38. Algra A, Tijssen JGP, Roelandt JRTC, Pool J, Lubsen J. Heart rate variability from 24-hour electrocardiography and the 2-year risk for sudden death. Circulation. 1993;88:180–185.[Abstract/Free Full Text]

39. Wilhelmsson C, Vedin JA, Wilhelmsen L, Tibblin G, Werko L. Reduction of sudden death after myocardial infarction by treatment with alprenolol: preliminary results. Lancet. 1974;2:1157–1160.[Medline] [Order article via Infotrieve]

40. Jaffe AS, Spadaro JJ, Schectman K, Roberts R, Geltman EM, Sobel BE. Increased congestive heart failure after myocardial infarction of modest extent in patients with diabetes mellitus. Am Heart J. 1984;108:31–37.[Medline] [Order article via Infotrieve]

41. Gundersen T, Kjekshus JT. Timolol treatment after myocardial infarction in diabetic patients. Diabetes Care. 1983;6:285–290.[Abstract]

42. Smith JW, Marcus FI, Serokman R, for the Multicentre Postinfarction Research Group. Prognosis of patients with diabetes mellitus after acute myocardial infarction. Am J Cardiol. 1984;54:718–721.[Medline] [Order article via Infotrieve]

43. Kahn J, Zola B, Juni J, Vinik A. Radionucleotide assessment of left ventricular diastolic filling in diabetes mellitus with and without cardiac autonomic neuropathy. J Am Coll Cardiol. 1986;7:1303–1309.[Abstract]

44. Fava S, Azzopardi J, Muscatt HA, Fenech FF. Factors that influence outcome in diabetic subjects with myocardial infarction. Diabetes Care. 1993;16:1615–1618.

45. Reid W, Ewing DJ, Harry JD, Smith HJ, Neilson JMM, Clarke BF. Effects of ß-adrenoreceptor blockade on heart rate and physiological tremor in diabetics with autonomic neuropathy: a comparative study of epanolol, atenolol and pindolol. Br J Clin Pharmacol. 1987;23:383–389.[Medline] [Order article via Infotrieve]

46. Torry RJ, Connell PM, O'Brien DM, Chilian WM, Tomanek RJ. Sympathectomy stimulates capillary but not precapillary growth in hypertrophic hearts. Am J Physiol. 1991;260:H1515–H1521.[Abstract/Free Full Text]

47. Whall CW, Myers MM, Halpern W. Norepinephrine sensitivity, tension development and neuronal uptake in resistance arteries from spontaneously hypertensive and normotensive rats. Blood Vessels. 1980;17:1–15.[Medline] [Order article via Infotrieve]

48. Koltai M, Jermendy G, Kiss V, Wagner M, Pogatsa G. The effects of sympathetic nerve stimulation and adenosine on coronary circulation and heart function in diabetes mellitus. Acta Physiol Hung. 1984;63:119–125.[Medline] [Order article via Infotrieve]

49. Cruickshank JM, Neil-Dwyer G, Degaute J, Hayes Y, Kuurne T, Kytta J, Vincent JL, Carruthers ME, Patel S. Reduction of stress/catecholamine-induced cardiac necrosis by beta₁-selective blockade. Lancet. 1987;2:585–589.[Medline] [Order article via Infotrieve]

50. Haggendal J, Jonsson L, Johansson G, Bjurstrom S, Carlsten J, Thoren-Tolling K. Catecholamine-induced free radicals in myocardial cell necrosis on experimental stress in pigs. Acta Physiol Scand. 1987;131:447–452.[Medline] [Order article via Infotrieve]

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