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CLINICAL RESEARCH: DIABETES AND THE HEART

Sympathetic dysfunction in type 1 diabetes

Association with impaired myocardial blood flow reserve and diastolic dysfunction

Rodica Pop-Busui, MD^*,, Ian Kirkwood, MBBS^*, Helena Schmid, MD^*, Victor Marinescu, BS^*, Justin Schroeder, BS^*, Dennis Larkin, BS^*, Elina Yamada, MD, David M. Raffel, PhD and Martin J. Stevens, MD^*,*

^* Endocrinology and Metabolism
Cardiology
Nuclear Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical College of Ohio, Toledo, Ohio

Manuscript received November 24, 2003; revised manuscript received July 2, 2004, accepted September 14, 2004.

^* Reprint requests and correspondence: Dr. Martin J. Stevens, Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Michigan, 5570 MSRB II, Box 0678, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109-0678 (Email: stevensm{at}umich.edu).

	Abstract

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OBJECTIVES: This study was designed to explore the relationships of early diabetic microangiopathy to alterations of cardiac sympathetic tone and myocardial blood flow (MBF) regulation in subjects with stable type 1 diabetes.

BACKGROUND: In diabetes, augmented cardiac sympathetic tone and abnormal MBF regulation may predispose to myocardial injury and enhanced cardiac risk.

METHODS: Subject groups comprised healthy controls (C) (n = 10), healthy diabetic subjects (DC) (n = 12), and diabetic subjects with very early diabetic microangiopathy (DMA+) (n = 16). [¹¹C]meta-hydroxyephedrine ([¹¹C]HED) and positron emission tomography (PET) were used to explore left ventricular (LV) sympathetic integrity and [¹³N]ammonia-PET to assess MBF regulation in response to cold pressor testing (CPT) and adenosine infusion.

RESULTS: Deficits of LV [¹¹C]HED retention were extensive and global in the DMA+ subjects (36 ± 31% vs. 1 ± 1% in DC subjects; p < 0.01) despite preserved autonomic reflex tests. On CPT, plasma norepinephrine excursions were two-fold greater than in C and DC subjects (p < 0.05), and basal LV blood flow decreased (–12%, p < 0.05) in DMA+ but not in C or DC subjects (+45% and +51%, respectively). On adenosine infusion, compared with C subjects, MBF reserve decreased by 45% (p < 0.05) in DMA+ subjects. Diastolic dysfunction was detected by two-dimensional echocardiography in 5 of 8 and 0 of 8 consecutively tested DMA+ and DC subjects, respectively.

CONCLUSIONS: Augmented cardiac sympathetic tone and responsiveness and impaired myocardial perfusion may contribute to myocardial injury in diabetes.

Abbreviations and Acronyms   C = controls   CAN = cardiovascular autonomic neuropathy   CPT = cold pressor testing   CRP = C-reactive peptide   DC = diabetic control subjects   DMA+ = early microangiopathy   LV = left ventricle/ventricular   MBF = myocardial blood flow   PET = positron emission tomography   vWF = von Willebrand factor   ([11C]HED) = [11C]meta-hydroxyephedrine

Although the etiology of myocardial injury and dysfunction in diabetes uncomplicated by the presence of coronary vascular disease is not well understood, alterations of cardiac sympathetic innervation, tone, and responsiveness (7,8), coupled with abnormal myocardial blood flow (MBF) regulation (9–14), have emerged as potential contributing factors. In experimental diabetes, the initial development of cardiovascular autonomic neuropathy (CAN) is characterized by early augmentation of sympathetic tone (15,16), which may contribute to myocardial injury (15,17). Therefore, in diabetes, increased cardiac sympathetic nervous system activity and elevated cardiac synaptic norepinephrine (15,18) or enhanced myocardial norepinephrine sensitivity may provide a mechanistic explanation for myocardial injury predisposing to the development of impaired LV function and enhanced cardiac risk. We therefore wished to explore the hypothesis that early preclinical diabetic microangiopathy is complicated by abnormalities in cardiac sympathetic nervous system innervation and blood flow regulation, which could ultimately predispose to the development of cardiomyopathy.

	Methods

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Patient population.   Subjects with type 1 diabetes were recruited from the Michigan Diabetes Research and Training Center. Subject groups comprised healthy nondiabetic controls (C) (n = 10); healthy diabetic control subjects (DC) (n = 12); and diabetic subjects with very early microangiopathy (DMA+) (n = 16), defined by the presence of early nonproliferative diabetic retinopathy (n = 14) or early microalbuminuria (n = 2) and/or early peripheral neuropathy (n = 10). All subjects were matched for age and diabetes duration and were free from dyslipidemia and macrovascular complications (Table 1).

Criteria for retinopathy and nephropathy.   Retinopathy was graded by stereoscopic color photographs using the Early Treatment of Diabetic Retinopathy Scale (EDTRS) (19). The DC subjects were without retinopathy (level 10). Level 20 of the EDTRS was divided into two subgroups: level 20a, with 1 and <3 microaneurysms, and level 20b, with 3 microaneurysms. The DMA+ subjects were defined by level 20b to 35 retinopathy or microalbuminuria (20).

Criteria for neuropathy
Subjects were classified for neuropathy based on the results of cardiovascular autonomic function testing (21) (Table 2) and the Michigan Neuropathy Screening Instrument (MNSI) examination score (22). The DC subjects had no evidence of neuropathy; DMA+ had no or minimal evidence of neuropathy (<2 abnormal CAN reflex tests, normal MNSI examination score, normal or abnormal MNSI symptom score).

Evaluation of cardiac sympathetic innervation with [¹¹C]HED.   After the transmission scan, a 60-min dynamic PET image acquisition sequence was started as 20 mCi of [¹¹C]HED was injected over 30 s, as previously reported (8). After correction for attenuation, transaxial PET data were reoriented and re-sliced into short-axis view data sets (slice thickness 0.8 cm) for subsequent quantitative analyses.

Regional neuronal retention of [¹¹C]HED was quantified using a "retention index" approach (8) that corrects for tracer delivery. The heterogeneity of regional LV [¹¹C]HED retention in each diabetic subject was compared with the normal reference distribution by performing a z-score analysis. Sectors that had a z score >2.5 were defined as abnormal. The extent of [¹¹C]HED retention heterogeneity was expressed as the percentage of all sectors in the patient's polar map that were abnormal (i.e., had z scores >2.5).

Evaluation of regional MBF regulation with [¹³N]ammonia..   [¹³N]ammonia studies at rest and during stress were performed sequentially in a single session. The resting perfusion scan was started by initiating a 15-min dynamic PET acquisition sequence as 20 mCi of [¹³N]ammonia was intravenously injected (9). After 50 min, a cold pressor stress [¹³N]ammonia study was performed with stimulation starting 30 s before tracer injection. Blood pressure and heart rate were recorded at 1-min intervals. For the adenosine study, adenosine was infused intravenously over 6 min at 140 µg/kg/min to achieve maximal coronary vasodilatation (9). At 3 min, 20 mCi [¹³N]ammonia was injected over 30 s and imaged for 3 to 18 min. Blood pressure and heart rate were measured every minute during adenosine infusion and then at 10 and 18 min. Pressure-rate product was calculated as heart rate times systolic blood pressure divided by 100.

Regional MBF was estimated from the measured [¹³N]ammonia kinetics (23) as previously reported (9). Regional MBF reserve values were estimated by dividing the stress flow value by the resting flow value. Mean values of resting flow, stress flow, and MBF reserve were then determined for the same LV regions used in the [¹¹C]HED analysis.

Cold pressor testing (CPT).   The CPT to provoke sympathetic activation was performed by applying a bag filled with ice chips to the forehead for 2 min (24).

Echocardiography.   Two-dimensional echocardiography and pulsed tissue Doppler parameters were used to classify diastolic function (25). Data acquired included the ratio of peak flow velocities during early filling and atrial contraction (E/A ratio), Doppler tissue imaging of the mitral annulus early diastolic velocity (Ea), the mitral annular motion with atrial contraction (Aa), and the Doppler tissue imaging of the mitral annulus (Ea/Aa ratio). Left ventricular diastolic dysfunction was defined by an E/A ratio <1, or if >1, by an Ea/Aa ratio <1. Left ventricular mass was determined by the formula LV mass = 0.8 x 1.05 x (S + P + LVEDD)3 – (LVEDD)3, where S = LV septal thickness, P = LV posterior wall thickness, and LVEDD = LV end-diastolic diameter. The LV mass index was then determined (LV mass/body surface area). Abnormal LV mass index was defined by values 100 g/m² in women and 131 g/m² in men.

Oxidative stress measurements.   Urine F2 isoprostanes were measured by enzyme-linked immunosorbent assay. Plasma total radical-trapping antioxidant parameter was measured as previously reported (26).

Statistical analysis.   Statistical analysis was performed using Super ANOVA (Abacus Concepts Inc., Berkeley, California). The equality of experimental group means was tested by a one-way analysis of variance and, if significant, the differences were assessed by the Student-Newman-Keuls multiple-range test. If the variances for the variables differed significantly, logarithmic transformation was performed. All analyses were then performed on the transformed data. The significance of changes in measurements from baseline was determined using a paired t test. Significance was defined at the 0.05 level.

	Results

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Glycemic control was equivalent in diabetic subjects (Table 1). The urine microalbumin/creatinine ratio was not significantly different between DC and DMA+ subjects. Plasma lipid levels did not differ between groups. Ten DMA+ subjects either had symptoms consistent with peripheral neuropathy or one abnormal CAN reflect test (Table 2). However, none had an abnormal MNSI examination score.

DMA+ subjects demonstrate defects of LV[¹¹C]HED retention.   Deficits of distal LV [¹¹C]HED retention affected <1% of the LV (Fig. 1A) in DC subjects, but affected 36% of the LV in DMA+ subjects despite normal cardiovascular reflex testing. Unlike the small distal deficits of LV [¹¹C]HED retention identified in DC subjects, deficits of tracer retention in DMA+ subjects were more global, affecting both the basal as well as the distal segments (Fig. 1B).

View larger version (16K): [in this window] [in a new window]   Figure 1 (A) Extent of left ventricular (LV) [11C]meta-hydroxyephedrine ([11C]HED) retention deficits in different subject groups. Normalized [11C]HED retention data are displayed as polar coordinate maps of relative tracer activity ([11C]/[13N]). The "extent" of the heterogeneity is expressed as the percentage of sectors in the polar map that are abnormal, i.e., zi >2.5. p < 0.01 early microangiopathy (DMA+) versus diabetic control subjects (DC). Horizontal bars = mean value. (B) Left ventricular [11C]HED retention is globally decreased in a DMA+ subject. Quantitative assessment of LV [11C]HED retention (expressed as a retention index [RI]) demonstrated reduced retention in all LV sectors in a DMA+ subject (open plot) compared with the values obtained in nondiabetic control subjects (shaded plot).

Systemic hemodynamic responses to adenosine infusion.   No differences were observed in the hemodynamic response to adenosine infusion among the subject groups. The resting and adenosine stress pressure-rate products were similar in the C and diabetic subjects (data not shown).

MBF reserve during adenosine stimulation is reduced in DMA+ subjects.   Compared with C subjects (69 ± 9 ml/min/g of tissue), resting MBF was elevated in both the DC (85 ± 20 ml/100 g/min) and DMA+ (91 ± 13 ml/100 g/min) subjects (p < 0.05). During adenosine infusion, the increase in LV MBF was blunted in the DMA+ (204 ± 42 ml/100 g/min) compared with the DC (267 ± 126 ml/100 g/min) and C (275 ± 26 ml/100 g/min) subjects (p = 0.2). Finally, MBF reserve differed between groups (p < 0.01). Compared with C subjects, MBF reserve was reduced by 21% (p < 0.05) and 45% (p < 0.01) in the DC and DMA+ subjects, respectively (Fig. 2). The difference between DC and DMA+ subjects was also statistically significant (p < 0.05). In contrast to our previously reported findings in subjects with advanced CAN (9), LV MBF reserve did not differ regionally (data not shown).

View larger version (13K): [in this window] [in a new window]   Figure 2 Change in global myocardial blood flow reserve (MBFR) in response to adenosine infusion. [13N]ammonia positron emission tomography was used to explore MBF regulation in response to adenosine. p < 0.05 diabetic control subjects (DC) versus controls (C). p < 0.05 early microangiopathy (DMA+) versus C and DC. Horizontal bars = mean value.

DMA+ subjects demonstrate LV diastolic dysfunction.   Left ventricular function was assessed in consecutively recruited DMA+ (n = 8, mean age 50 ± 7 years, 5 men and 3 women) and DC (n = 8, mean age 44 ± 8 years, 4 men and 4 women) subjects who were within one year of completion of the other studies reported herein. No subject had abnormal systolic function. Six DMA+ subjects, but none of the DC subjects, exhibited diastolic dysfunction (Table 5). Three DMA+ subjects had an abnormal LV mass index, which was normal in all DC subjects.

	Discussion

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The extensive global deficits of [¹¹C]HED retention observed in DMA+ subjects despite good glycemic control differ markedly from previous findings in metabolically stable (8) or metabolically compromised (27) type 1 diabetic subjects, and they suggest an etiology other than neuronal loss or acute hyperglycemia-induced neuronal dysfunction. Moreover, these findings differ markedly from our previous findings in subjects with either early (28) or more severe (8,9) CAN (accompanied by abnormal CAN reflex tests), in whom deficits of [¹¹C]HED retention begin distally and then spread proximally and circumferentially, eventually resulting in islands of basal increased [¹¹C]HED retention (8,9,28).

Sympathetic neurotransmitter analogues such as [¹¹C]HED undergo highly specific and rapid uptake into sympathetic nerve varicosities via norepinephrine transporters ("uptake-1") (29). In the isolated rat heart elevated norepinephrine perfusion concentrations increase neuronal HED clearance rates, suggesting that neuronal "recycling" of HED is impaired by high synaptic norepinephrine levels (29). In the acute six-week diabetic rat heart, retention of LV [¹¹C]HED is inversely related to increased cardiac norepinephrine levels (16), which precedes cardiac small nerve fiber loss (M.J. Stevens, personal observations, 1999). Moreover, an inverse relationship of myocardial retention of metaiodobenzyl guanidine to plasma catecholamines occurs in subjects with pheochromocytoma (30), which is thought to reflect competition for uptake into neuronal storage vesicles (31). These data implicate increased synaptic norepinephrine as the most likely explanation for the reduction of cardiac [¹¹C]HED retention in DMA+ subjects. Direct measurement of cardiac norepinephrine spillover is, however, required to confirm the potential mechanism(s) of this defect.

In DMA+ subjects, systemic plasma norepinephrine excursions in response to CPT were exaggerated, consistent with enhanced cardiovascular sympathetic nervous system reactivity. The unchanged resting systemic plasma norepinephrine levels do not preclude an increase of basal cardiac adrenergic tone, as a similar disassociation has been identified in arrhythmogenic right ventricular cardiomyopathy, which is characterized by increased cardiac, but not systemic, sympathetic nerve activity (32). Although the mechanisms of increased norepinephrine responses in DMA+ subjects are unknown, depletion of nitric oxide (and hence dysinhibition) in sympathetic ganglia (33) and/or vascular endothelium (34) or vascular denervation (35) have been proposed. It is unclear as to whether cardiac norepinephrine responsiveness was increased in parallel. More detailed determination of systemic and regional norepinephrine kinetics in DMA+ subjects is required to confirm and extend these observations.

In DMA+ subjects, increased adrenergic reactivity was associated with increased oxidative stress, elevated CRP and plasma vWF antigen, and impaired MBF reserve, consistent with endothelial dysfunction. On CPT, however, the most abnormal blood flow responses were observed in the basal myocardial segments. Diabetes-induced endothelial dysfunction is expected to be global in the LV, suggesting that other factors such as variations in the density of LV sympathetic innervation may have contributed (16). These findings are consistent with our earlier identification of maximal impairment of MBF reserve in the innervated basal myocardium of diabetic subjects with advanced CAN (9). On sympathetic activation, augmented accumulation of norepinephrine, increased oxidative stress, and apoptosis (36) may have contributed to abnormal vascular reactivity. Paradoxic vasoconstriction responses (10,11,37) complicate coronary atherosclerosis. Our studies indicate that paradoxic coronary vasoconstriction can occur in type 1 diabetes in the absence of atheroma. (Alternatively, however, we cannot exclude the less likely possibility that globally impaired cardiac sympathetic function was principally the cause of the blunted MBF response.)

On adenosine infusion, global MBF reserve was reduced in DMA+ subjects to an extent that exceeded that observed in the DC subjects. Reduced MBF reserve has been reported in subjects with type 2 diabetes (11,12) as well as type 1 diabetes (9,12–14) and has been associated with impaired glucose control (38) or cardiovascular sympathetic denervation (9,14). We have now demonstrated that neither impairment of metabolic control nor the presence of cardiovascular denervation is a prerequisite for the development of impaired vasodilatory reserve. Although the mechanism(s) of this deficit is unknown, endothelial dysfunction, in concert with decreased myocardial vascularity (9,39), may be an important contributing factor.

In diabetes, a putative cardiomyopathy comprising myocardial interstitial and perivascular fibrosis (1) and apoptosis (2) has been linked to impaired LV function (3). Our preliminary studies identified diastolic dysfunction in five of eight consecutively recruited DMA+ subjects but none of the healthy DC subjects. Although the precise pathogenetic mechanisms are unclear, alterations of sympathetic tone could contribute to myocardial damage. For example, increased cardiac sympathetic tone may decrease myocardial vascularity (39), stimulate vascular hyperreactivity (40), increase mitochondrial reactive oxygen species production (17), perturb intracellular signaling (41), precipitate myocardial apoptosis (2,41), and promote myocardial remodeling (42). Therefore, in the course of the development of the microvascular complications of diabetes, elevated cardiac sympathetic tone may play a key pathogenetic role in the subsequent development of myocardial injury and dysfunction.

Conclusions.   In summary, subjects with stable type 1 diabetes and preclinical microangiopathy demonstrate wide-ranging abnormalities of cardiac sympathetic innervation and blood flow regulation, which may contribute to the subsequent development of myocardial injury. Limitations of our study include the relatively small subject number as well as the cross-sectional design, which, although it provides provocative new findings, does not directly address the role of these pathophysiologic changes in the development of impaired myocardial function. Future larger, prospective studies are needed to confirm these preliminary observations. Direct confirmation of the findings presented herein may form the rationale for the development of prophylactic treatment strategies aimed at reducing cardiac risk in diabetes.

	Footnotes

 
This work was supported in part by grants from the Juvenile Diabetes Research Foundation (to Dr. Stevens), the National Institutes of Health R01-DK52391 (to Dr. Stevens), a Veterans Administration Career Development Award (to Dr. Stevens), American Diabetes Association (to Dr. Stevens), and a University of Michigan General Clinical Research Center (GCRC) grant (to Dr. Stevens). The first two authors contributed equally to these studies.

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