Methods Of Assessment

Cardiovascular Autonomic Reflex Tests

CAN might be classified as being subclinical or clinical, dependent upon whether clinical manifestations are present. Subclinical autonomic neuropathy usually accompanies distal symmetrical polyneuropathy, but might only be evident by cardiovascular reflex testing (Table 1). Conventionally, the integrity of autonomic function is assessed indirectly by assessing cardiovascular reflexes. A consensus statement of the American Diabetes Association and the American Academy of Neurology in 1988 recommended that a battery of tests should be performed to assess autonomic function (8). Although the precise choice of tests remains debated, these might include HRV to deep respiration and the change in heart rate on assuming upright posture (predominantly tests of parasympathetic function), the change in systolic and diastolic blood pressure on standing,

Table 1

Commonly Used Techniques to Diagnose CAN

Tests of predominantly parasympathetic integrity

Heart rate variability to deep breathing (usually at six breaths per minute): Assessments include standard deviation, coefficient of variation, expiratory: inspiratory difference and ratio, mean circular resultant of vector analysis, spectral analysis (mid [0.05-0.15 Hz] and high [0.15-0.5 Hz] frequency fluctuations) Heart rate response on standing: Assessments include maximum/minimum 30:15 ratio (i.e., longest and shortest R-R intervals at about beat 30 and 15, respectively), or the longest and shortest R-R intervals between beats 20-40 and 5-25, respectively Tests of predominantly sympathetic integrity

Postural systolic blood pressure fall: Assessed by a systolic blood pressure fall >20 mmHg or a diastolic blood pressure fall >10 mmHg together with symptoms within 2 minutes of standing upright Spectral analysis: low (0.01-0.05 Hz) frequency fluctuations

Blood pressure response to sustained handgrip: Assessed using a handgrip dynamometer held at 30% maximum for 5 minutes (abnormality is a rise of diastolic blood pressure of <10 mmHg)

Head up tilt table testing: Assessed by measured heart rate response and blood pressure change to a 60° head up tilt Quantitative sudomotor axon reflex test: Assessed using a cholinergic agonist to test skin postganglionic sudomotor function Plasma norepinephrine: supine and standing Scintigraphic techniques: Positron emission tomography using [11C] metahydroxyephedrine Single photon emission tomography using [123I] metaiodobenzylguanidine Tests of both parasympathetic and sympathetic integrity

Valsalva ratio: Assessed by maintaining an exhaling pressure of 40 mmHg for 15 seconds and calculating the ratio of the longest R-R interval after the manoeuvre to the shortest interval during the manoeuvre the blood pressure response to sustained handgrip (predominantly tests of sympathetic function), and the Valsalva ratio (tests both parasympathetic as well as sympathetic integrity) (40). These tests can be utilized to stage the severity of CAN, with the mildest degree consisting isolated deficits in heart rate response to deep breathing, and the most severe when postural hypotension is also present (these stages correlate well with the impact of CAN on patient outcome in longitudinal studies). In 1992, the recommendations were updated to recommend that the heart rate response to deep respiration, the Valsalva ratio, and the blood pressure response to standing were suitable for the assessment of longitudinal progression of CAN (41).

There are many different methods for assessing HRV (15). Perhaps the "gold standard" measure is power spectral analysis, which can indirectly quantify defects in sympathetic and vagal innervation of the heart. The power spectral density of the R-R interval time series can be measured by a 256-point fast-Fourier transformation and can be determined in low (0.01-0.05 Hz), mid (0.05-0.15 Hz), and high (0.15-0.5 Hz) frequency ranges. The low and high frequency components are thought to reflect primarily sympathetic and parasympathetic integrity, respectively. Sympathetic nervous system responsiveness can also be explored by evaluating heart rate frequency responses on head up tilt table testing. The postural responses are determined by evaluating the difference between measurements made in the supine and the tilt positions (42). HRV during standardized head up tilt table testing under paced breathing has demonstrated that increased postural change (supine to upright) in the low-frequency component power predicted an increased risk for cardiac death (42), consistent with a detrimental effect of augmented sympathetic nervous system tone and/or reactivity.

Scintigraphic Characterization of Cardiac Sympathetic Integrity

As discussed earlier, CAN has also been evaluated using more direct techniques utilizing radiolabeled analogs of norepinephrine, which are actively taken up by cardiac sympathetic nerve terminals (Fig. 2). The most widely utilized tracer is MIBG (43-45), a guanethidine derivative. This nonmetabolized tracer is taken up into the postganglionic presynaptic sympathetic nerve terminals and stored in synaptic vesicles (46) and (Fig. 2) its retention can be assessed by single photon emission computed tomography. [123I]-MIBG uptake in the heart can be quantified in counts per minute per mL tissue, which is normalized to injected dose and body weight. [123I]-MIBG uptake is calculated in myocardial regions of interest (25) and normalized to the highest pixel value in the LV and expressed as a percentage of this value. A semiquantitative analysis can then be performed, which involves blinded observers scoring images using a scoring system for each segment, which might range from no detectable tracer to normal tracer retention and a "defect score" obtained.

HED also undergoes highly specific and rapid uptake into sympathetic nerve varicosities through norepinephrine transporters (uptake-1) (Fig. 2). Like MIBG, HED is metabolically stable, is not metabolized but is continuously recycled into and out of the neuron (46). Its neuronal retention requires intact vesicular storage and is also potentially susceptible to changes in synaptic norepinephrine levels making it a useful tool to assess cardiac sympathetic nerve fiber integrity and potentially tone. [11C]-HED has been extensively evaluated in both subjects with diabetes (26,29,31) and in subjects with neuronal loss secondary to ischemic heart disease (47). The myocardial retention of [11C]-HED can be performed semiquantitatively or quantitatively. In subjects with diabetes, the heterogeneity of regional LV [11C]-HED retention can be compared with the normal nondiabetic values by calculating a z-score with sectors that have a z-score higher than a predefined cut-off value (often 2.5) being defined as abnormal. An increase of heterogeneity is consistent with LV denervation (26,29,31). The "extent" of the heterogeneity is usually expressed as the percentage of sectors that are abnormal. Additionally, changes in absolute regional [11C]-HED retention can be quantified using a "retention index" approach (29), which corrects [11C]-HED retention for myocardial tracer delivery. Unfortunately, direct comparison of [11C]-HED and [123I]-MIBG to detect CAN complicating diabetes has not been reported.

Although both scintigraphic techniques are clearly able to detect early cardiac CAN and accurately chart its progression, the significance of early deficits detected by this methodology remains unclear. For example, the natural history of small (<10%) distal deficits of LV sympathetic innervation which have been identified in many patients with diabetes is not well-understood, and extensive age-adjusted normative databases are not

Fig. 2. Imaging the cardiac sympathetic nerve terminal using positron emission tomography and [11C]m^iahydroxyephedrine ([11C]HED). [11C]HED undergoes highly specific and rapid uptake into sympathetic nerve varicosities through norepinephrine transporters (uptake-1) and is continuosly recycled. Unlike norepinephrine, [11C]HED is not metabolized by monoamine oxidase but its neuronal retention requires intact vesicular storage. As it competes with norepinephrine for neuronal reuptake, it is also potentially susceptible to changes in synaptic norepinephrine levels making it a useful tool to assess both cardiac sympathetic nerve fiber integrity and potentially tone.

Fig. 2. Imaging the cardiac sympathetic nerve terminal using positron emission tomography and [11C]m^iahydroxyephedrine ([11C]HED). [11C]HED undergoes highly specific and rapid uptake into sympathetic nerve varicosities through norepinephrine transporters (uptake-1) and is continuosly recycled. Unlike norepinephrine, [11C]HED is not metabolized by monoamine oxidase but its neuronal retention requires intact vesicular storage. As it competes with norepinephrine for neuronal reuptake, it is also potentially susceptible to changes in synaptic norepinephrine levels making it a useful tool to assess both cardiac sympathetic nerve fiber integrity and potentially tone.

Table 2

Clinical and Subclinical Manifestations of Cardiovascular Autonomic Neuropathy

Clinical

Resting and fixed tachycardia Abnormal exercise tolerance

Orthostatic and postprandial hypotension Supine hypertension

Hemodynamic instability during anesthesia Cardiac denervation syndrome Silent myocardial ischemia Sudden cardiac death in patients with and without myocardial ischemia

Subclinical

Increased resting myocardial blood flow Increased cardiac sympathetic tone Impaired cardiac ejection fraction, abnormal systolic function, decreased diastolic filling, LV hypertrophy, myocardial apoptosis Failure to augment heart rate. Pooling of splanchnic blood Reduction of diurnal blood pressure variation, relative nocturnal sympathetic predominance and incipient nephropathy

QT prolongation, altered ventricular repolarization, heterogeneous cardiac sympathetic tone yet available. Hence, the utility of these tools is undoubtedly mostly for research purposes to determine the pathophysiological effects of cardiac sympathetic dysinnervation complicating diabetes and to quantitate the effects of therapeutic interventions in randomized clinical trials.

The interpretation of findings using sympathetic neurotransmitter analogs is also complicated by the fact that in addition to being a marker for nerve fiber dysfunction or loss, alterations in sympathetic nervous system tone may also profoundly affect the retention of these tracers. For example, in the isolated rat heart model, elevated concentrations of norepinephrine in the perfusion increase neuronal HED clearance rates, suggesting that neuronal "recycling" of HED can be disrupted by high synaptic norepinephrine levels (48). Additionally, myocardial retention of MIBG has been reported to be inversely related to plasma catecholamines in subjects with pheochromocytoma (49). These findings were proposed to reflect competition with endogenous catecholamines for uptake into neuronal storage vesicles (50). Therefore, increased synaptic norepinephrine might be a potential explanation for the reduction of cardiac [nC]HED retention in these subjects. Direct measurement of cardiac norepinephrine spill-over will be required to confirm the etiology of this defect.

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