Imaging of cardiac autonomic function in diabetes mellitus:  123I-metaiodobenzylguanidine with SPECT and 11C-hydroxyephedrine with PET1

Michael R. Freeman, Anatoly Langer
Division of Cardiology, Department of Medicine, St Michael’s Hospital, 
University of Toronto, Canada
Correspondence: Dr Michael R. Freeman, St Michael’s Hospital, 30 Bond Street, Suite 7-081 Queen, Toronto, Ontario M5B 1W8, Canada. Tel: +1 416 864 5895, fax: +1 416 864 5914, e-mail: freemanm@smh.toronto.on.ca

Introduction
Patients with diabetes mellitus and autonomic dysfunction have a worse prognosis,[1] including an increase in sudden death,[2,3] than do diabetic patients without autonomic dysfunction. Autonomic neural function has generally been assessed indirectly by standardized bedside maneuvers.[4] However, several investigators using imaging techniques,[5,6] muscle biopsy,[7] or heart rate variability (HRV)[8] have suggested that these maneuvers are insensitive at detecting autonomic dysfunction. Myocardial imaging with 123I-labeled metaiodobenzylguanidine (MIBG), a norepinephrine analog that shares the same uptake mechanism into sympathetic nerve terminals,[9,10] is a direct, noninvasive, and quantitative assessment of cardiac sympathetic autonomic dysfunction. SPECT imaging is performed with concurrent evaluation of myocardial perfusion by 201thallium or 99mTc-sestamibi. In addition, newer radiotracers such as 11C-hydroxyephedrine (HED) have become available to evaluate cardiac sympathetic function with PET. HED is stored in cardiac presynaptic sympathetic nerve terminals and accurately assesses sympathetic innervation.[11]

Imaging methodology and normal distribution
Metaiodobenzylguanidine SPECT
In the fasting state, patients are injected with 5–8 mCi 123I-MIBG intravenously for assessment of sympathetic denervation. Imaging is usually performed 5 h after injection. However, early imaging allows for the assessment of washout rates. Increased washout rates are an indication of sympathetic denervation. It is important to correct for perfusion abnormalities[12] with either thallium or sestamibi since initial uptake of MIBG is dependent upon blood flow. We and others[12–14] have previously reported and validated this methodology which corrects MIBG defects for assessment of perfusion by 99mTc-sestamibi or 201thallium by means of dual tomographic imaging. Visual or quantitative assessment of the images for the presence, location, and severity of MIBG defects is performed to define the presence of abnormal sympathetic innervation. The ratio of lung, liver, or mediastinal uptake to myocardial uptake evaluates the presence or absence of diffuse abnormalities of sympathetic function.
MIBG uptake by SPECT imaging in normal man is not uniform in that there is lower uptake of MIBG at the apex than at the middle two-thirds of the left ventricle.[12] There is also lower uptake at the base and the inferior wall. It is therefore necessary to perform quantitative analysis of MIBG images in comparison with normal limits to evaluate the presence and extent of sympathetic dysfunction in diabetic subjects. An example of a normal subject and a diabetic patient is shown in Figure 1.

Figure 1A. Representative short axis slices (HSA) of 99mTc-sestamibi (normal perfusion) on the top and 123I-MIBG on the bottom (larger inferior defect).
Figure 1A. Representative short axis slices (HSA) of 99mTc-sestamibi (normal perfusion) on the top and 123I-MIBG on the bottom (larger inferior defect).

Hydroxyephedrine PET
Intravenous infusion of 20 mCi 11C-HED over 1 h is performed with dynamic PET acquisition. Myocardial perfusion is evaluated usually with 13N-ammonia. Although the uptake of HED was less in the inferior wall (69 ± 7%) than in the lateral wall (82 ± 6%), this difference was not statistically significant, and thus the authors concluded that HED uptake is homogeneous.[15] PET imaging corrects for tissue attenuation and therefore is likely more accurate in evaluating the sympathetic distribution than MIBG SPECT imaging.

Imaging in diabetes mellitus
MIBG uptake in diabetic patients is reduced at all levels of the left ventricle and in all vascular territories with the exception of the septum. The most prominent defects are seen in the inferior wall.[12–14] Diabetic patients have greater MIBG defects than do normal subjects (13 ± 15% vs. 2 ± 2%, P < 0.0001),[12] and have a lower MIBG heart/lung ratio (1.22 ± 0.18 vs. 1.56 ± 0.28, P = 0.05). In addition, diabetic patients with autonomic dysfunction, as defined by bedside hemodynamic maneuvers, have larger MIBG defects than do those with no autonomic dysfunction.[12–14] In addition to regional abnormalities of MIBG uptake in diabetic patients, there is evidence that this process is more generalized throughout the myocardium. The heart and mediastinal[16] or lung[12] ratios are significantly reduced in diabetic patients.
Most evaluations of MIBG have been performed in type 2 (noninsulin-dependent) diabetic patients but recent studies show that type 1 (insulin-dependent) diabetic patients, even early in their disease, have MIBG abnormalities. Turpeinen et al[14] suggested that type 1 diabetic patients have less severe sympathetic denervation than do type 2 patients. However, even in newly diagnosed insulin-dependent diabetics, inferior and apical MIBG abnormalities are common.[17]
Similarly, HED abnormalities are common in diabetic patients, with a frequency of 40% in diabetics with no clinical evidence of autonomic dysfunction. Almost all diabetic patients with clinical autonomic dysfunction have reduced HED retention and/or marked heterogeneity. The HED studies suggest proximal myocardial hyperinnervation accompanied by distal denervation.[11,15] Interestingly, these abnormalities of autonomic function are associated with altered myocardial blood flow and coronary flow reserve.[15]

Prognostic value
The presence of MIBG abnormalities may predict a higher cardiac event rate in diabetic patients. Myocardial MIBG uptake is reduced in diabetic patients with stress-induced left ventricular dysfunction.[18] A linear correlation was found between left ventricular ejection fraction during handgrip and MIBG uptake. Thus, the greater the MIBG abnormality, the more depressed was the left ventricular function. Diabetic patients with hypertension have more profound MIBG abnormalities than do normotensive subjects, and the presence of extensive defects predicts higher mortality.[19] Therefore MIBG imaging abnormalities may predict patients who are at high risk of left ventricular dysfunction, propensity for ventricular arrhythmia, and death.
The presence of concurrent hyperinnervation and denervation, as suggested by HED imaging,[11] is a plausible pathophysiologic link to the excess of sudden death that is evident in the diabetic population. This exaggerated sympathetic imbalance may put these patients at greater risk of ventricular arrhythmias and sudden death.

Relationship with other indicators of autonomic function
There is a striking difference in the extent of MIBG uptake abnormalities in diabetics with, compared with those without, autonomic dysfunction as defined by the five reproducible 
bedside hemodynamic maneuvers commonly performed to assess clinical autonomic function. Autonomic dysfunction is defined as an abnormal response to two of the five hemodynamic tests. After MIBG uptake was corrected for any perfusion abnormalities, patients with autonomic dysfunction on quantitative analysis had larger MIBG defects than did those without autonomic dysfunction (17.2 ± 17.0% vs. 3.3 ± 5.2%, P = 0.0001).[12,20] In diabetic patients, MIBG abnormalities were also significantly more frequent than those detected by bedside hemodynamic maneuvers, suggesting superior sensitivity of the former.
The frequency and temporal domain measures of HRV are also commonly performed to evaluate cardiac autonomic function. We[20] and others[21] have shown a relationship between HRV and MIBG abnormalities in diabetic patients. Comparison of HRV measures in diabetic patients with and without abnormal bedside maneuvers is shown in Table I. 

Table I. Lipoprotein particles in type 2 diabetes and their atherogenic potential.

 

 

The 15 patients without autonomic dysfunction had a significantly smaller lower frequency component and standard deviation (SD) than the 36 patients with autonomic dysfunction. A correlation of MIBG defect size with HRV measurements is shown in Figure 2. A weak but significant inverse relationship was detected between the size of MIBG mismatch and the measure of sympathetic modulation of HRV expressed as the area under the curve of the low frequency band (r = -0.38, P = 0.006) (Figure 2A)  and total power (r = -0.37, P = 0.007). Similarly there was a correlation with the area under the high frequency component (r = -0.33, P = 0.02) (Figure 2B).


Figure 2A. Relationship between MIBG defect size and the high frequency component of HRV. AD, autonomic dysfunction.
Figure 2B. Relationship between MIBG defect size and the low frequency component of HRV.

All of the MIBG and HRV measures presented were assessed for their independent ability to identify autonomic dysfunction using multivariate logistic regression analysis with both forward and backward selection. The only significant variable was the quantitative assessment of MIBG mismatch (c2 = 20.2, P = 0.0005). Myocardial MIBG uptake predicts autonomic function in patients with diabetes mellitus and is significantly related to indices reflecting sympathetic neural modulation of HRV.

Therapeutic importance
Since autonomic dysfunction predicts higher mortality in diabetic patients, it is conceivable that improvement of autonomic function may also improve outcome. The impact of therapy on autonomic dysfunction is generally unknown and MIBG imaging may allow the sequential evaluation of autonomic function and thus predict those patients with an improved prognosis. Schnell et al[22] have shown that in long-term diabetic patients, MIBG abnormalities do not change in size or severity over a 3-year period. The same authors using HED have, however, shown that in early diabetes, cardiac autonomic function as assessed by MIBG may improve with aggressive metabolic control.[23] In a single case study treatment of diabetic neuropathy with epalrestat the washout rate and heart/mediastinal ratio of MIBG improved. In insulin-dependent diabetic patients near-normoglycemia prevented the progression of MIBG abnormalities over a 4-year period, whereas poor glycemic control resulted in significant progression of MIBG abnormalities.[24]

Conclusions
SPECT and PET imaging using MIBG and HED are sensitive techniques for the evaluation of autonomic function in patients with diabetes mellitus. Abnormalities of regional uptake and retention are common and are directly related to other measures of autonomic dysfunction. These techniques have potential for assessment of therapeutic interventions in diabetic patients and for the evaluation of prognosis. Early detection of these abnormalities and the ability to evaluate their extent and severity should lead to a more focused therapeutic approach in the management of these patients. 

REFERENCES

 
1: Ann Intern Med 1980 Feb;92(2 Pt 2):308-11 Related Articles, Books, LinkOut

Assessment of cardiovascular effects in diabetic autonomic neuropathy and prognostic implications.

Ewing DJ, Campbell IW, Clarke BF.

Cardiovascular effects of diabetic autonomic neuropathy include postural hypotension, resting tachycardia, and, possibly, painless myocardial infarction. Involvement of cardiovascular reflexes in diabetes can be assessed using simple noninvasive tests: the Valsalva maneuver, beat-to-beat heart rate variation, the heart rate response to standing, postural fall in blood pressure, and the sustained handgrip test. Tests of parasympathetic function appear to be abnormal more frequently and earlier in cardiac autonomic involvement, whereas sympathetic damage usually occurs later and is associated with clinical symptoms. When test results are abnormal, in association with symptoms suggestive of autonomic neuropathy, the prognosis is grave. Some sudden deaths that occur may be due to abnormal autonomic reflexes.

PMID: 7356219 [PubMed - indexed for MEDLINE]
 
2: Br Med J 1975 Jul 5;3(5974):15-7 Related Articles, Books, LinkOut

Defective innervation of heart in diabetic autonomic neuropathy.

Lloyd-Mostyn RH, Watkins PJ.

Heart rate responses to autonomic stimulation and inhibition were studied in 13 diabetic autonomic neuropathy. Parasympathetic function was impaired in all patients and sympathetic function in most. One patient's heart appeared to be totally denervated. The consequences of cardiac denervation include tachycardia, a fixed heart rate, and a possible tendency to cardiac dysrhythmias, which caused spontaneous cardiac arrests in three patients.

PMID: 1131653 [PubMed - indexed for MEDLINE]
 
3: Lancet 1978 Apr 29;1(8070):935-6 Related Articles, Books, LinkOut

Cardiorespiratory arrest in diabetic autonomic neuropathy.

Garcia-Bunuel L.

Publication Types:
  • Letter


PMID: 76869 [PubMed - indexed for MEDLINE]

 
4: Diabetes 1978 Dec;27(12):1167-74 Related Articles, Books, LinkOut

Assessment of methods for estimating autonomic nervous control of the heart in patients with diabetes mellitus.

Bennett T, Farquhar IK, Hosking DJ, Hampton JR.

A comparison of the cardiac responses to a variety of maneuvers that modify cardiac vagal tone was made in nondiabetic and diabetic subjects. We concluded that assessment of heart rate variability by reference to standard deviation of R-R intervals is unhelpful; that a single deep breath is a more potent stimulus for heart rate change than repeated deep breaths in diabetic subjects; and that measurement of this response together with the bradycardia evoked by the Valsalva maneuver obviate the need to perform invasive investigations, such as the estimation of baroreflex sensitivity, or tedious procedures, such as apneic face immersion. In a small number of subjects, heart responses to lower body, negative pressure provided information not forthcoming from other tests.

PMID: 720771 [PubMed - indexed for MEDLINE]
 
5: Diabetes 1992 Sep;41(9):1069-75 Related Articles, Books, LinkOut

Noninvasive detection of cardiac sympathetic nervous dysfunction in diabetic patients using [123I]metaiodobenzylguanidine.

Mantysaari M, Kuikka J, Mustonen J, Tahvanainen K, Vanninen E, Lansimies E, Uusitupa M.

Department of Clinical Physiology, Kuopio University Hospital, Finland.

The association between clinical autonomic dysfunction and myocardial MIBG accumulation was investigated. The study groups comprised 6 male diabetic patients with autonomic neuropathy (ANP+ group), 6 male diabetic patients without autonomic neuropathy (ANP-group), and 6 male nondiabetic control subjects. The mean age was comparable in all groups, and the subjects had no evidence of coronary heart disease. Reduced heart-rate variation in a deep-breathing test was used as a criterion for autonomic neuropathy. Immediately after injection, the peak net influx rate of MIBG to myocardium was significantly (P less than 0.05) reduced in both diabetic groups. At 6 hr after MIBG injection, the MIBG uptake of the myocardium was significantly (P less than 0.05) smaller in the ANP+ group than in the control group. In the ANP- group, the MIBG uptake of the myocardium was between that of the ANP+ group and that of the control group. Our data show that reduced myocardial MIBG accumulation is associated with autonomic dysfunction in diabetic patients, but it can occur to a lesser extent also in diabetic patients without apparent autonomic neuropathy. The measurement of the myocardial MIBG accumulation is a promising new method to detect cardiac sympathetic nervous dysfunction in diabetic patients.

PMID: 1499860 [PubMed - indexed for MEDLINE]
 
6: Diabetes 1995 May;44(5):543-9 Related Articles, Books, LinkOut

Myocardial m-[123I]iodobenzylguanidine scintigraphy for the assessment of adrenergic cardiac innervation in patients with IDDM. Comparison with cardiovascular reflex tests and relationship to left ventricular function.

Kreiner G, Wolzt M, Fasching P, Leitha T, Edlmayer A, Korn A, Waldhausl W, Dudczak R.

Department of Medicine II, University of Vienna, Austria.

Cardiac imaging using m-[123I]iodobenzylguanidine (mIBG) reflects sympathetic myocardial innervation. In patients with insulin-dependent diabetes mellitus (IDDM), the following were studied: 1) the prevalence of derangements of cardiac autonomic innervation as detected by mIBG scintigraphy in comparison with cardiovascular reflex tests and 2) the relationship between adrenergic cardiac innervation and left ventricular (LV) function. Twenty-four patients with IDDM without overt heart disease were studied after silent coronary artery disease was excluded by 201Tl scintigraphy. Cardiac innervation was evaluated by both mIBG scintigraphy (tomographic imaging) and cardiovascular reflex tests. Systolic (ejection fraction [EF] percentage) and diastolic (peak filling rate [PFR] defined as end-diastolic volumes per second [EDV/s]) LV function were determined by equilibrium radionuclide angiography at rest and during bicycle exercise. mIBG scintigraphy was also performed in 10 control subjects. All control subjects exhibited a normal myocardial mIBG distribution. Among diabetic patients, only six had normal mIBG scans (group 1), whereas 18 had evidence of regional adrenergic denervation (group 2). Reflex tests suggested cardiac autonomic neuropathy in only seven of these patients (P < 0.01 vs. mIBG). All patients had a normal EF at rest. However, group 2 showed an impaired response to exercise as indicated by a smaller increase in EF (5 +/- 6 vs. 13 +/- 5%, P < 0.05) and a lower PFR (5.9 +/- 0.8 vs. 7.3 +/- 1.2 EDV/s, P < 0.01). Myocardial mIBG scintigraphy reveals that in patients with IDDM, sympathetic myocardial dysinnervation is much more common than previously thought. Furthermore, subclinical LV dysfunction is related to derangements of adrenergic cardiac innervation.

PMID: 7729613 [PubMed - indexed for MEDLINE]
 
7: Diabetes 1993 Mar;42(3):375-80 Related Articles, Books, LinkOut

Comment in:


Muscle sympathetic nerve activity is reduced in IDDM before overt autonomic neuropathy.

Hoffman RP, Sinkey CA, Kienzle MG, Anderson EA.

Department of Pediatrics, College of Medicine, University of Iowa, Iowa City 52242.

Studies of heart-rate variability have demonstrated that abnormal cardiac parasympathetic activity in individuals with IDDM precedes the development of other signs or symptoms of diabetic autonomic neuropathy. To determine whether IDDM patients have impaired sympathetic activity compared with normal control subjects before the onset of overt neuropathy, we directly recorded MSNA. We also examined the effects of changes in plasma glucose and insulin on sympathetic function in each group. MSNA was recorded by using microneurographic techniques in 10 IDDM patients without clinically evident diabetic complications and 10 control subjects. MSNA was compared during a 15-min fasting baseline period and during insulin infusion (120 mU.m-2.min-1) with 30 min of euglycemia. A cold pressor test was performed at the end of euglycemia. Power spectral analysis of 24-h RR variability was used to assess cardiac autonomic function. IDDM patients had lower MSNA than control subjects at baseline (8 +/- 1 vs. 18 +/- 3 burst/min, P < 0.02). MSNA increased in both groups with insulin infusion (P < 0.01) but remained lower in IDDM patients (20 +/- 3 vs. 28 +/- 3 burst/min, P < 0.01). In the IDDM group, we found no relationships between MSNA and plasma glucose, insulin, or HbA1c concentrations. BP levels did not differ at rest or during insulin. Heart-rate variability and the MSNA response to cold pressor testing in IDDM patients did not differ from those in healthy control subjects. IDDM patients had reduced MSNA at rest and in response to insulin. The lower MSNA is not attributable to differences in plasma glucose or insulin, but, rather, is most likely an early manifestation of diabetic autonomic neuropathy that precedes impaired cardiac parasympathetic control.

PMID: 8432407 [PubMed - indexed for MEDLINE]

 
8: Circulation 1992 Nov;86(5):1443-52 Related Articles, Books, LinkOut

Impaired circadian modulation of sympathovagal activity in diabetes. A possible explanation for altered temporal onset of cardiovascular disease.

Bernardi L, Ricordi L, Lazzari P, Solda P, Calciati A, Ferrari MR, Vandea I, Finardi G, Fratino P.

Department of Internal Medicine, First Medical Clinics, University of Pavia, Italy.

BACKGROUND. Diabetic subjects have a high incidence of cardiovascular accidents, with an altered circadian distribution. Abnormalities in the circadian rhythm of autonomic tone may be responsible for this altered temporal onset of cardiovascular disease. METHODS AND RESULTS. To assess circadian changes of sympathovagal balance in diabetes, we performed 24-hour power spectral analysis of RR interval fluctuations in 54 diabetic subjects (age, 44 +/- 2 years) with either normal autonomic function or mild to severe autonomic neuropathy and in 54 age-matched control subjects. The power in the low-frequency (LF, 0.03-0.15 Hz) and high-frequency (HF, 0.18-0.40 Hz) bands was considered an index of relative sympathetic and vagal activity, respectively. Diabetic subjects with autonomic abnormalities showed a reduction in LF compared with control subjects (5.95 +/- 0.12 In-msec2 versus 6.73 +/- 0.11, p < 0.001) and an even greater reduction in LF, particularly during the night and the first hours after awakening (5.11 +/- 0.18 In-msec2 versus 6.52 +/- 0.14, p < 0.001). Day-night rhythm in sympathovagal balance was reduced or absent in diabetic subjects compared with control subjects. CONCLUSIONS. Diabetic subjects with or without signs of autonomic neuropathy have a decreased vagal activity (and hence a relatively higher sympathetic activity) during night hours and at the same time of the day, during which a higher frequency of cardiovascular accidents has been reported. These observations may provide insight into the increased cardiac risk of diabetic patients, particularly if autonomic neuropathy is present.

PMID: 1423958 [PubMed - indexed for MEDLINE]
 
9: J Nucl Med 1981 Jan;22(1):22-31 Related Articles, Books, LinkOut

Myocardial imaging with a radioiodinated norepinephrine storage analog.

Wieland DM, Brown LE, Rogers WL, Worthington KC, Wu JL, Clinthorne NH, Otto CA, Swanson DP, Beierwaltes WH.

Meta-iodobenzylguanidine (M-IBG), an iodinated aromatic analog of the hypotensive drug quanethidine, localizes in the heart of the rat, dog, and rhesus monkey. A comparative study of tissue distribution in the dog has been performed with five myocardiophilic agents: thallium-201, I-125 16-iodohexadecanoic acid, H-3 norepinephrine, C-14 guanethidine and I-125 M-IBG. The last two compounds give heart concentrations and heart-to-blood concentration ratios similar to those of thallium-201. Planar and tomographic images of the hearts of the dog and rhesus monkey were obtained using I-131 or I-123 labeled M-IBG. Blocking studies with reserpine suggest that a major component of myocardial retention of M-IBG is sequestration within the norephinephrine storage vesicles of the adrenergic nerves. The localization of M-IBG in other organs with rich sympathetic innervation and the relative insensitivity of myocardial uptake to a wide range of loading doses lend additional support for a neuronal mode of retention.

PMID: 7452352 [PubMed - indexed for MEDLINE]
 
10: Circulation 1988 Nov;78(5 Pt 1):1192-9 Related Articles, Books, LinkOut

Abnormal I-123 metaiodobenzylguanidine myocardial washout and distribution may reflect myocardial adrenergic derangement in patients with congestive cardiomyopathy.

Henderson EB, Kahn JK, Corbett JR, Jansen DE, Pippin JJ, Kulkarni P, Ugolini V, Akers MS, Hansen C, Buja LM, et al.

Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, Dallas 75235-9047.

I-123 metaiodobenzylguanidine (MIBG) is a new radiopharmaceutical with properties that allow the characterization of the sympathetic innervation of several organ systems. In this study, we used MIBG with tomographic imaging to evaluate noninvasively the differences in myocardial sympathetic innervation in 14 healthy volunteers and 16 patients with severe dilated cardiomyopathy (CM). Initial (15-minute) images demonstrated no significant differences in MIBG concentration in the hearts of patients with CM and of healthy volunteers. However, the myocardial retention of MIBG was significantly reduced in the patients with CM. Expressed as the percent washout from 15 to 85 minutes, the patients with CM had a 28 +/- 12% washout rate compared with 6 +/- 8% in the controls (p less than 0.001). A small subset of patients from each group imaged at 4-hour intervals demonstrated even greater disparity in washout rates. In addition, the patients with CM had significantly greater heterogeneity in the MIBG activity distribution within the myocardial images. There was 47 +/- 15% intraimage variability in MIBG distribution in the patients with CM and 22 +/- 9% variation in the controls (p less than 0.001). We conclude from these data that the myocardial distribution and kinetics of MIBG in images obtained from patients with CM differ significantly from those of controls and that the MIBG patterns may be used as a relatively noninvasive means to evaluate the severity of altered adrenergic innervation in the hearts of these patients.

PMID: 3180378 [PubMed - indexed for MEDLINE]
 
11: Circulation 1998 Sep 8;98(10):961-8 Related Articles, Books, LinkOut
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Cardiac sympathetic dysinnervation in diabetes: implications for enhanced cardiovascular risk.

Stevens MJ, Raffel DM, Allman KC, Dayanikli F, Ficaro E, Sandford T, Wieland DM, Pfeifer MA, Schwaiger M.

Department of Internal Medicine, University of Michigan, Ann Arbor 48109-0678, USA. stevensm@umich.edu

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 beta-blockade in these subjects.

PMID: 9737515 [PubMed - indexed for MEDLINE]
 
12: J Am Coll Cardiol 1995 Mar 1;25(3):610-8 Related Articles, Books, LinkOut
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Metaiodobenzylguanidine imaging in diabetes mellitus: assessment of cardiac sympathetic denervation and its relation to autonomic dysfunction and silent myocardial ischemia.

Langer A, Freeman MR, Josse RG, Armstrong PW.

Department of Medicine, St. Michael's Hospital, University of Toronto, Ontario, Canada.

OBJECTIVES. This study in patients with diabetes mellitus was undertaken 1) to evaluate cardiac sympathetic innervation in diabetic patients using metaiodobenzylguanidine (MIBG) imaging; 2) to study the relation between autonomic function assessed by clinical maneuvers and abnormalities in MIBG uptake; and 3) to examine the basis for our previous observation of an association between abnormalities in autonomic nervous system dysfunction and silent myocardial ischemia. BACKGROUND. The clinical detection of autonomic dysfunction in diabetes mellitus has been linked to both abnormal perception of pain, including angina, and poor prognosis. METHODS. Uptake of MIBG was measured by dual-isotope imaging in 23 normal subjects and 65 asymptomatic diabetic patients. Silent myocardial ischemia was defined as the presence of a reversible perfusion defect in patients with ST segment depression. RESULTS. The MIBG uptake in the diabetic patients was significantly lower than that in normal subjects in the apex (67 +/- 17% vs. 82 +/- 7%, p = 0.0001), distal third (77 +/- 11% vs. 85 +/- 3%, p = 0.0001), proximal third (77 +/- 9% vs. 84 +/- 3%, p = 0.0001) and base (71 +/- 9% vs. 80 +/- 4%, p = 0.0001) of the left ventricle. Similarly, MIBG uptake was variable across different vascular territories. When MIBG uptake was corrected for perfusion abnormalities, diabetic patients had a greater MIBG uptake defect than normal subjects on visual score assessment (16 +/- 13 vs. 8 +/- 7%, p = 0.0002) and on quantitative MIBG mismatch assessment (13 +/- 15% vs. 2 +/- 2%, p = 0.0001). Diabetic patients with versus without autonomic dysfunction had more extensive MIBG uptake mismatch (17 +/- 17% vs. 4 +/- 6%, p = 0.0001). There was a greater diffuse abnormality in diabetic patients with versus without silent myocardial ischemia detected by sestamibi/MIBG uptake ratio (68 +/- 35% vs. 19 +/- 33%, p = 0.001). CONCLUSIONS. Sympathetic cardiac innervation in normal subjects is inhomogeneous. In contrast to normal subjects, diabetic patients have evidence of a significant reduction in MIBG uptake, most likely on the basis of autonomic dysfunction. Furthermore, diabetic patients with silent myocardial ischemia have evidence of a diffuse abnormality in MIBG uptake, suggesting that abnormalities in pain perception may be linked to sympathetic denervation.

PMID: 7860904 [PubMed - indexed for MEDLINE]
 
13: Diabetes 1996 Jun;45(6):801-5 Related Articles, Books, LinkOut

Reduced myocardial 123I-metaiodobenzylguanidine uptake in newly diagnosed IDDM patients.

Schnell O, Muhr D, Weiss M, Dresel S, Haslbeck M, Standl E.

Diabetes Research Institute, Schwabing City Hospital, Munich, Germany.

123I-labeled metaiodobenzylguanidine (123I-MIBG) scintigraphy is a novel technique for the assessment of cardiac sympathetic dysinnervation. To evaluate defects of the cardiac autonomic nervous system at the onset of IDDM, this technique together with conventional electrocardiogram (ECG)-based cardiac reflex tests and measurement of the QT interval was applied to 22 newly diagnosed metabolically stabilized IDDM patients without myocardial perfusion abnormalities (99mTc-labeled methoxyisobutylisonitrile scintigraphy) and 9 matched control subjects. Seventeen diabetic patients (77%), but none of the control subjects, were observed to have a reduced global myocardial uptake of 123I-MIBG. In contrast, only two diabetic patients (9%) demonstrated an ECG-based cardiac autonomic neuropathy (two or more of five age-related cardiac reflex tests abnormal) (P < 0.001). In newly diagnosed IDDM patients, the uptake of 123I-MIBG was reduced more in the posterior myocardial region compared with the lateral and apical region (P < 0.01, P = 0.03). The septal myocardial region exhibited a smaller uptake than the lateral myocardial region (P = 0.02). The maximum/minimum 30:15 ratio correlated with the global, anterior, lateral, and septal myocardial uptake of 123I-MIBG (P < 0.05, P < 0.05, P < 0.01, P < 0.05). A correlation between global and regional myocardial 123I-MIBG uptake and HbA1c or QT interval was not observed. Newly diagnosed metabolically stabilized IDDM patients without myocardial perfusion defects show evidence of cardiac sympathetic dysinnervation, as indicated by a reduction of 123I-MIBG uptake, at a significant higher proportion than ECG-based cardiac autonomic neuropathy. Furthermore, they present with regional differences of myocardial 123I-MIBG uptake.

PMID: 8635656 [PubMed - indexed for MEDLINE]
 
14: Diabetes Care 1996 Oct;19(10):1083-90 Related Articles, Books, LinkOut

Demonstration of regional sympathetic denervation of the heart in diabetes. Comparison between patients with NIDDM and IDDM.

Turpeinen AK, Vanninen E, Kuikka JT, Uusitupa MI.

Department of Clinical Nutrition, University of Kuopio, Finland. anu.turpeinen@uka.fi

OBJECTIVE: Global myocardial uptake of 123I-metaiodobenzylguanidine (MIBG) has been shown to be decreased in diabetic patients with autonomic neuropathy, indicating cardiac sympathetic dysfunction. However, possible differences in myocardial MIBG distribution between NIDDM and IDDM diabetic patients are not known. RESEARCH DESIGN AND METHODS: Regional myocardial distribution of 123I-MIBG was studied in seven male IDDM patients (age 45 +/- 2 years, duration of diabetes 30 +/- 3 years, means +/- SE) and 13 NIDDM patients (8 men, 5 women, age 59 +/- 2 years, duration of diabetes 10 +/- 1 years). A dual-tracer single-photon emission tomography was carried out with 123I-MIBG and 99mTc-methoxyisobutylisonitrrile to asses simultaneously myocardial sympathetic innervation and perfusion at rest. Conventional autonomic nervous function tests, power spectral analysis of heart rate variability, and echocardiography were performed for assessments of autonomic function and cardiac dimensions and function. RESULTS: Autonomic nervous function tests and echocardiography showed similar results in IDDM and NIDDM patients. Despite this, global myocardial MIBG uptake (0.43 +/- 0.04 vs. 0.59 +/- 0.06, P = 0.03) and MIBG heart-to-liver ratio (0.59 +/- 0.03 vs. 0.68 = 0.03, P = 0.05) were lower in NIDDM compared with IDDM patients. Regional distribution of MIBG uptake and regional MIBG/perfusion ratio revealed significantly reduced uptake in NIDDM patients especially in the inferoposterior segments of the left ventricle compared with IDDM patients. Difference in age between NIDDM and IDDM patients did not explain the results. CONCLUSIONS: Reduced myocardial MIBG uptake was found in NIDDM patients compared with the uptake in IDDM patients, particularly involving inferoposterior segments. Regional sympathetic damage not detectable with conventional autonomic function tests is relatively common in NIDDM.

PMID: 8886553 [PubMed - indexed for MEDLINE]
 
15: J Am Coll Cardiol 1998 Jun;31(7):1575-84 Related Articles, Books, LinkOut
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Scintigraphic assessment of regionalized defects in myocardial sympathetic innervation and blood flow regulation in diabetic patients with autonomic neuropathy.

Stevens MJ, Dayanikli F, Raffel DM, Allman KC, Sandford T, Feldman EL, Wieland DM, Corbett J, Schwaiger M.

Department of Internal Medicine, University of Michigan, Ann Arbor, USA. stevensm@umich.edu

OBJECTIVES: This study sought to evaluate whether regional sympathetic myocardial denervation in diabetes is associated with abnormal myocardial blood flow under rest and adenosine-stimulated conditions. BACKGROUND: Diabetic autonomic neuropathy (DAN) has been invoked as a cause of unexplained sudden cardiac death, potentially by altering electrical stability or impairing myocardial blood flow, or both. The effects of denervation on cardiac blood flow in diabetes are unknown. METHODS: We studied 14 diabetic subjects (7 without DAN, 7 with advanced DAN) and 13 nondiabetic control subjects without known coronary artery disease. Positron emission tomography using carbon-11 hydroxyephedrine was used to characterize left ventricular cardiac sympathetic innervation and nitrogen-13 ammonia to measure myocardial blood flow at rest and after intravenous administration of adenosine (140 microg/kg body weight per min). RESULTS: Persistent sympathetic left ventricular proximal wall innervation was observed, even in advanced neuropathy. Rest myocardial blood flow was higher in the neuropathic subjects (109 +/- 29 ml/100 g per min) than in either the nondiabetic (69 +/- 8 ml/100 g per min, p < 0.01) or the nonneuropathic diabetic subjects (79 +/- 23 ml/100 g per min, p < 0.05). During adenosine infusion, global left ventricular myocardial blood flow was significantly less in the neuropathic subjects (204 +/- 73 ml/100 g per min) than in the nonneuropathic diabetic group (324 +/- 135 ml/100 g per min, p < 0.05). Coronary flow reserve was also decreased in the neuropathic subjects, who achieved only 46% (p < 0.01) and 44% (p < 0.01) of the values measured in nondiabetic and nonneuropathic diabetic subjects, respectively. Assessment of the myocardial innervation/blood flow relation during adenosine infusion showed that myocardial blood flow in neuropathic subjects was virtually identical to that in nonneuropathic diabetic subjects in the distal denervated myocardium but was 43% (p < 0.05) lower than that in the nonneuropathic diabetic subjects in the proximal innervated segments. CONCLUSIONS: DAN is associated with altered myocardial blood flow, with regions of persistent sympathetic innervation exhibiting the greatest deficits of vasodilator reserve. Future studies are required to evaluate the etiology of these abnormalities and to evaluate the contribution of the persistent islands of innervation to sudden cardiac death complicating diabetes.

PMID: 9626837 [PubMed - indexed for MEDLINE]
 
16: Eur J Nucl Med 1996 Apr;23(4):401-6 Related Articles, Books, LinkOut

Evaluation of cardiac sympathetic neuronal integrity in diabetic patients using iodine-123 metaiodobenzylguanidine.

Kim SJ, Lee JD, Ryu YH, Jeon P, Shim YW, Yoo HS, Park CY, Lim SG.

Department of Diagnostic Radiology and Nuclear Medicine, Yonsei University, College of Medicine, 134 Shincheon-dong, Seodaemun-gu, Seoul, 120-752, Korea.

Autonomic dysfunction is associated with increased mortality in diabetic patients. To evaluate the cardiac autonomic dysfunction in these patients, a prospective study was undertaken using iodine-123 metaiodobenzylguanidine (MIBG) single-photon emission tomography (SPET). The study groups consisted of ten diabetic patients with cardiac autonomic neuropathy (group I) and six without autonomic neuropathy (group II). Autonomic nervous function tests, thallium scan, radionuclide ventriculographic data including ejection fraction and wall motion study, and 24-h urine catecholamine levels were evaluated. 123I-MIBG SPET was performed at 30 min and 4h following injection of 3 mCi of 123I-MIBG in groups I and II and in normal subjects (n=4). On planar images, the heart to mediastinum (H/M) ratio was measured. Defect pattern and severity of MIBG uptake were qualitatively analysed on SPET. Compared with control subjects, diabetic patients had a reduced H/M ratio regardless of the presence of clinical autonomic neuropathy. There was no difference in H/M ratio between groups I and II. On SPET images, focal or diffuse defects were demonstrated in all patients in group I, and in five of the six patients in group II. The extent of defects tended to be more pronounced in group I than in group II. In conclusion, 123I-MIBG scan was found to be a more sensitive method than clinical autonomic nervous function tests for the detection of autonomic neuropathy in diabetes.

PMID: 8612660 [PubMed - indexed for MEDLINE]
 
17: Diabet Med 1997 Jan;14(1):57-62 Related Articles, Books, LinkOut

Partial restoration of scintigraphically assessed cardiac sympathetic denervation in newly diagnosed patients with insulin-dependent (type 1) diabetes mellitus at one-year follow-up.

Schnell O, Muhr D, Dresel S, Weiss M, Haslbeck M, Standl E.

Diabetes Research Institute, Munich, Germany.

Diabetic neuropathy is thought to comprise a reversible metabolic and an irreversible structural component of neuronal abnormality. To investigate whether the cardiac sympathetic denervation recently described in newly diagnosed, but metabolically stabilized, diabetic patients without myocardial perfusion abnormalities reflects transient or permanent sympathetic abnormalities, 123-I-metaiodobenzylguanidine (123-I-MIBG) scintigraphy was performed in 16 patients with insulin-dependent (Type 1) diabetes mellitus (IDDM) 1 year after initial assessment and diagnosis. All patients had been treated with an intensified insulin therapy for 1 year. HbA1c had fallen from 11.5 +/- 2.0% to 6.3 +/- 0.9% (p < 0.001). The global myocardial 123-I-MIBG uptake (score 1-6) had improved in 7 patients at 1 year, remained unchanged in 7, and deteriorated in 2 patients. Regionally, the myocardial uptake score of the posterior and septal regions had improved significantly (p < 0.01, p = 0.02) with a mean uptake score in the groups of 3.8 +/- 1.1 and 3.4 +/- 1.2 at diagnosis versus 2.6 +/- 0.5 and 2.5 +/- 0.9 at 1 year. Myocardial uptake scores of the anterior, lateral, and apical regions had also improved in 7, 6, and 9 patients, but the mean changes of these scores did not reach significance. The study demonstrates that scintigraphically assessed cardiac sympathetic denervation in newly diagnosed, but metabolically stabilized, IDDM patients is partially reversed with improved metabolic control after 1 year of intensified insulin therapy. We suggest that even in the early stage of IDDM, cardiac sympathetic dysfunction is composed of reversible and irreversible neuronal abnormalities.

PMID: 9017355 [PubMed - indexed for MEDLINE]
 
18: J Am Coll Cardiol 1998 Feb;31(2):404-12 Related Articles, Books, LinkOut
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Myocardial dysfunction and adrenergic cardiac innervation in patients with insulin-dependent diabetes mellitus.

Scognamiglio R, Avogaro A, Casara D, Crepaldi C, Marin M, Palisi M, Mingardi R, Erle G, Fasoli G, Dalla Volta S.

Division of Cardiology, University of Padua Medical School, Italy.

BACKGROUND: Insulin-dependent diabetes mellitus (IDDM) is associated with an increased incidence of heart failure due to several factors, and in some cases a specific cardiomyopathy has been suggested. OBJECTIVES: This study sought to assess the mechanisms of exercise-induced left ventricular (LV) dysfunction in asymptomatic patients with IDDM in the absence of hypertensive or coronary artery disease. METHODS: Fourteen consecutive patients with IDDM were enrolled (10 men, 4 women; mean [+/- SD] age 28.5 +/- 6 years); 10 healthy subjects matched for gender (7 men, 3 women) and age (28.5 +/- 3 years) constituted the control group. LV volume, LV ejection fraction (LVEF) and end-systolic wall stress were calculated by two-dimensional echocardiography at rest and during isometric exercise. LV contractile reserve was assessed by post-extrasystolic potentiation (PESP) obtained by transesophageal cardiac electrical stimulation and dobutamine infusion. Myocardial iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy was performed to assess adrenergic cardiac innervation. RESULTS: Diabetic patients were classified into group A (n = 7), with an abnormal LVEF response to handgrip (42 +/- 7%), and group B (n = 7), with a normal response (72 +/- 8%). Baseline LVEF was normal in both group A and B patients (60 +/- 6% vs. 61 +/- 7%, p = NS). In group A patients, the LV circumferential wall stress-LVEF relation showed an impairment in LVEF disproportionate to the level of LV afterload. No significant changes in LVEF occurred during dobutamine (60 +/- 6% vs. 64 +/- 10%, p = NS), whereas PESP significantly increased LVEF (60 +/- 6% vs. 74 +/- 6%, p < 0.001); PESP at peak handgrip normalized the abnormal LVEF (42 +/- 7% vs. 72 +/- 5%, p < 0.001); and MIBG uptake normalized for body weight or for LV mass was lower than that in normal subjects (1.69 +/- 0.30 vs. 2.98 +/- 0.82 cpm/MBq per g, p = 0.01) and group B diabetic patients (vs. 2.79 +/- 0.94 cpm/MBq per g, p = 0.01). Finally, a strong linear correlation between LVEF at peak handgrip and myocardial MIBG uptake normalized for LV mass was demonstrated in the study patients. CONCLUSIONS: Despite normal contractile reserve, a defective blunted recruitment of myocardial contractility plays an important role in determining exercise LV dysfunction in the early phase of diabetic cardiomyopathy. This abnormal response to exercise is strongly related to an impairment of cardiac sympathetic innervation.

PMID: 9462586 [PubMed - indexed for MEDLINE]
 
19: Eur J Nucl Med 1999 Oct;26(10):1310-6 Related Articles, Books, LinkOut
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Use of iodine-123 metaiodobenzylguanidine scintigraphy to assess cardiac sympathetic denervation and the impact of hypertension in patients with non-insulin-dependent diabetes mellitus.

Tamura K, Utsunomiya K, Nakatani Y, Saika Y, Onishi S, Iwasaka T.

Department of Internal Medicine, Keihanna Hospital, Hirakata City, Osaka, Japan.

The objectives of this clinical study using iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy were (a) to evaluate cardiac sympathetic denervation in non-insulin-dependent diabetes mellitus (NIDDM) patients with and without hypertension and (b) to investigate the relation between cardiac sympathetic denervation and prognosis in NIDDM patients. We compared clinical characteristics and MIBG data [heart to mediastinum (H/M) ratio and % washout rate (WR)] in a control group and NIDDM patients with and without hypertension. MIBG scintigraphy was performed in 11 controls and 82 NIDDM patients without overt cardiovascular disease except for hypertension (systolic blood pressure >/=140 and/or diastolic blood pressure >/=90 mmHg). After MIBG examination, blood pressure was measured regularly in all NIDDM patients. There were significant differences between 65 normotensive and 17 hypertensive NIDDM patients with respect to age (55+/-11 vs 63+/-12 years, respectively, P<0.05), prevalence of diabetic retinopathy (12% vs 35%, respectively, P<0.05) and systolic blood pressure (120+/-12 vs 145+/-16 mmHg, respectively, P<0.001). The H/M ratio in hypertensive NIDDM patients was significantly lower than in the control group (1. 81+/-0.29 vs 2.27+/-0.20, respectively, P<0.01). During the follow-up period (18+/- 12 months), 17 NIDDM patients newly developed hypertension after MIBG examination. There were no significant differences in their clinical characteristics compared with persistently normotensive or hypertensive NIDDM patients. %WR in patients with new onset hypertension was significantly higher than in the control group (30.88%+/-16.87% vs 12.89%+/-11.94%, respectively, P<0.05). Moreover, in these patients %WR correlated with duration from the date of MIBG scintigraphy to the onset of hypertension (r=-0.512, P<0.05). Five NIDDM patients died during the follow-up period (four newly hypertensive patients and one normotensive patient). There were significant statistical differences between the control group and non-survivors in terms of age (54+/-11 vs 73+/-11 years, respectively, P<0.01), H/M ratio (2. 27+/- 0.20 vs 1.64+/-0.36, respectively, P<0.01) and %WR (12. 89%+/-11.94% vs 42.52%+/-22.39%, respectively, P<0.01). In conclusion, cardiac sympathetic denervation using MIBG scintigraphy observed in hypertensive NIDDM patients, and was more profound in non-survivors. MIBG scintigraphy proved useful for the evaluation of NIDDM patients with new onset hypertension, and it was found that NIDDM patients with abnormalities on MIBG scintigraphy needed to be observe carefully.

Publication Types:
  • Clinical Trial


PMID: 10541830 [PubMed - indexed for MEDLINE]

 
20: Am J Cardiol 1997 Jul 15;80(2):247-50 Related Articles, Books, LinkOut
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Relation of direct assessment of cardiac autonomic function with metaiodobenzylguanidine imaging to heart rate variability in diabetes mellitus.

Freeman MR, Newman D, Dorian P, Barr A, Langer A.

Department of Medicine, St. Michael's Hospital, University of Toronto, Ontario, Canada.

Myocardial metaiodobenzylguanidine uptake predicts autonomic function in patients with diabetes mellitus and is significantly related to indexes reflecting sympathetic neural modulation of heart rate variability.

PMID: 9230179 [PubMed - indexed for MEDLINE]
 
21: Diabet Med 1996 Mar;13(3):266-72 Related Articles, Books, LinkOut

A novel method for the assessment of autonomic neuropathy in type 2 diabetic patients: a comparative evaluation of 123I-MIBG myocardial scintigraphy and power spectral analysis of heart rate variability.

Murata K, Sumida Y, Murashima S, Matsumura K, Takeda H, Nakagawa T, Shima T.

Third Department of Internal Medicine, Mie University School of Medicine, Japan.

The correlation between the degree of sympathetic denervation measured through 123I-MIBG Myocardial Scintigraphy and Power Spectral Analysis of consecutive R-R records was investigated in order to evaluate their potential application for the assessment of myocardial autonomic neuropathy in patients with diabetes mellitus. This study comprised 42 patients with Type 2 diabetes. Low frequency (0.02-0.09 Hz) components of the power spectral density were measured as markers of sympathetic activity. The myocardial uptake of 123I-MIBG was measured by using the single photon emission computed tomography (SPECT) and the early and delayed images were recorded. Scoring from 0 to 3 of the 123I-MIBG uptake of various cardiac segments (7) was performed and the total uptake was calculated. The washout rate in the whole myocardium was determined. The values obtained in the group with diabetic autonomic neuropathy (DAN) without orthostatic hypotension (OH) were significantly lower as compared to those of the (DAN (-)) group in the delayed images. The washout rate of the OH (-) group was also significantly higher than the DAN (-) group. There was significant difference between the images and the washout rate of OH (+) and OH (-) groups. There was a significant correlation between Power Spectral Analysis and SPECT (early, delayed images, and washout rate). Of these, the delayed image showed the strongest correlation (r = 0.55, p < 0.01). Further, the QTc interval showed a significant inverse correlation with the delayed image (r = -0.44, p < 0.05). In conclusion, these results suggest that the cardiac 123I-MIBG scintigraphy could be a useful method for the assessment of the myocardial autonomic neuropathy in patients with diabetes mellitus.

PMID: 8689849 [PubMed - indexed for MEDLINE]
 
22: J Diabetes Complications 1997 Sep-Oct;11(5):307-13 Related Articles, Books, LinkOut
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Three-year follow-up on scintigraphically assessed cardiac sympathetic denervation in patients with long-term insulin-dependent (type I) diabetes mellitus.

Schnell O, Muhr D, Weiss M, Kirsch CM, Haslbeck M, Tatsch K, Standl E.

Diabetes Research Institute, Schwabing City Hospital, Munich, Germany.

Scintigraphy using I-123-metaiodobenzylguanidine (I-123-MIBG) and Tc-99m-methoxyisobutylisonitrile (Tc-99m-MIBI) allows assessment of the cardiac sympathetic innervation and the myocardial perfusion. To investigate the natural history of cardiac sympathetic denervation in long-term diabetic patients without myocardial perfusion defects, global and regional I-123-MIBG and Tc-99m-MIBI uptake was determined (score 1-6; 1 = normal uptake, 6 = no uptake) in 22 patients with insulin-dependent (type I) diabetes mellitus (IDDM) at 3-year follow-up. All patients were treated with intensive insulin therapy and HbA1c was 8.0% +/- 1.0% at entry compared with 7.9% +/- 1.1% at follow-up. Cardiac sympathetic denervation (I-123-MIBG uptake score > 2), initially observed in 18 patients, was detectable in 21 patients at follow-up. The global myocardial I-123-MIBG uptake score deteriorated in eight patients, remained unchanged in 11 and improved in three patients. The changes in mean global I-123-MIBG uptake score (3.5 +/- 1.0 versus 3.8 +/- 0.8) were not significant. Reduction of the anterior, lateral, posterior, septal, and apical I-123-MIBG uptake did not progress significantly during follow-up. The mean uptake score of the posterior myocardial region (4.7 +/- 0.8) was smaller than the uptake score of the anterior (3.0 +/- 1.1, p = 0.001), lateral (3.2 +/- 0.9, p < 0.001) and septal (4.1 +/- 1.1, p < 0.05) myocardial regions. At follow-up, moderate myocardial perfusion defects (global Tc-99m-MIBI uptake score = 3) were detectable in four patients. Our study demonstrates that scintigraphically assessed cardiac sympathetic denervation does neither significantly regress nor progress on the average in a group of long-term IDDM patients during a 3-year follow-up. Thus, it is concluded that cardiac sympathetic abnormalities are a persistent, yet frequent phenomenon in long-term IDDM patients.

PMID: 9334913 [PubMed - indexed for MEDLINE]
 
23: Metabolism 1999 Jan;48(1):92-101 Related Articles, Books, LinkOut

Regression and progression of cardiac sympathetic dysinnervation complicating diabetes: an assessment by C-11 hydroxyephedrine and positron emission tomography.

Stevens MJ, Raffel DM, Allman KC, Schwaiger M, Wieland DM.

Department of Internal Medicine, University of Michigan, Ann Arbor 48109-0678, USA.

Cardiovascular denervation complicating diabetes has been implicated in sudden cardiac death potentially by altering myocardial electrical stability and impairing myocardial blood flow. Scintigraphic evaluation of cardiac sympathetic integrity has frequently demonstrated deficits in distal left ventricular (LV) sympathetic innervation in asymptomatic diabetic subjects without abnormalities on cardiovascular reflex testing. However, the clinical significance and subsequent fate of these small regional defects is unknown. This study reports the results of a prospective observational study in which positron emission tomography (PET) with (-)-[11C]-meta-hydroxyephedrine ([11C]-HED) was used to evaluate the effects of glycemic control on the progression of small regional LV [11C]-HED retention deficits in 11 insulin-dependent diabetic subjects over a period of 3 years. The subjects were divided into two groups based on attained glycemic control during this period: group A contained six subjects with good glycemic control (individual mean HbA1c <8%), and group B contained five subjects with poor glycemic control (individual mean HbAlc > or =8%). Changes in regional [11C]-HED retention were compared with reference values obtained from 10 healthy aged-matched nondiabetic subjects. At baseline, abnormalities of [11C]-HED retention affected 7.3%+/-1.4% and 9.9%+/-6.6% of the LV in group A and B subjects, respectively, with maximal deficits of LV [ C]-HED retention involving the distal myocardial segments. At the final assessment in group A, the extent of the deficits in [11C]-HED retention decreased to involve only 1.7%+/-0.7% of LV (P<.05 v. baseline scan), with significant increases in [11C]-HED retention occurring in both the distal and proximal myocardial segments. In contrast, in group B with poor glycemic control, the extent of [11C]-HED deficits increased to involve 34%+/-3.5% of the LV (P<.01 v. baseline), with retention of [11C]-HED significantly decreasing in the distal segments ([11C]-HED retention index, 0.066+/-0.003 v. 0.057+/-0.002, P<.05, at baseline and final assessment, respectively). Poor glycemic control was associated with increased heterogeneity of LV [11C]-HED retention, since three of five group B subjects developed abnormally increased [11C]-HED retention in the proximal myocardial segments. In conclusion, defects in LV sympathetic innervation can regress or progress in diabetic subjects achieving good or poor glycemic control, respectively. In diabetic subjects with early cardiovascular denervation, institution of good glycemic control may prevent the development of myocardial sympathetic dysinnervation and enhanced cardiac risk.

PMID: 9920151 [PubMed - indexed for MEDLINE]
 
24: Clin Nucl Med 1999 Jun;24(6):418-20 Related Articles, Books, LinkOut

I-123 MIBG cardiac imaging in diabetic neuropathy before and after epalrestat therapy.

Utsunomiya K, Narabayashi I, Nakatani Y, Tamura K, Onishi S.

Department of Radiology, Osaka Medical College, Japan. keitau@interlog.com

I-123 metaiodobenzylguanidine (MIBG) scintigraphy is a new method to evaluate cardiac sympathetic nerve disturbance in patients with diabetes mellitus. Epalrestat specifically inhibits aldose reductase and improves diabetic neuropathy. The authors report a case of improvement in cardiac sympathetic dysfunction using MIBG scintigraphy with epalrestat therapy. In this case, epalrestat effectively reversed diabetic neuropathy, and MIBG scintigraphy was useful to evaluate the effect of epalrestat.

PMID: 10361937 [PubMed - indexed for MEDLINE]

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