Reduced cardiac ¹²³I-MIBG uptake reflects cardiac sympathetic dysfunction in Lewy body disease

Cardiac uptake of ¹²³I-meta-iodobenzylguanidine (MIBG), a physiologic analogue of norepinephrine, is reduced in patients with Parkinson disease (PD) and dementia with Lewy bodies (DLB).^1–7 Since MIBG is taken up and stored in sympathetic nerve endings, reduced levels in PD are considered to indicate myocardial postganglionic sympathetic dysfunction. In contrast, postganglionic sympathetic fibers remain intact in multiple system atrophy. MIBG uptake is reduced even in patients with very early PD according to the Hoehn-Yahr staging system, without clinically significant signs or symptoms of autonomic dysfunction.^1–7 It was reported that that tyrosine hydroxylase (TH)-immunoreactive nerve fibers in the heart are markedly decreased in PD, but not in multiple system atrophy,^8,9 suggesting that cardiac sympathetic denervation is responsible for decreased cardiac uptake of MIBG in PD.^8–10 Decreased cardiac uptake of MIBG in Lewy body disease (LBD) reflects cardiac sympathetic denervation, which precedes neuronal loss in sympathetic ganglia.⁸

It remains unclear, however, whether cardiac MIBG uptake is clinically related to autonomic dysfunction on conventional autonomic function testing in LDB. We therefore studied the relation between cardiac ¹²³I MIBG uptake and cardiovascular autonomic dysfunction in LBD.

METHODS

Cardiovascular autonomic response on the Valsalva maneuver (VM) and head-up tilt table (HUT) testing.

The VM was performed as described previously.^15,16 Systolic blood pressure (SBP) and RR intervals (RR) were measured by tonometry, using a noninvasive blood pressure monitoring system (CBM3000, Nihon Colin Co., Ltd., Komaki, Japan). The changes in SBP and RR were divided into four phases on the VM^17–20 (figure, A and B). Phase I is the inspiration phase. Phase II is the phase of blowing into the mouthpiece, with an increase in thoracic pressure to 40 mm Hg. SBP decreases in early phase II because of reduced cardiac output, in turn decreasing venous return and stroke volume, despite tachycardia caused by the withdrawal of cardiovagal control (phase II E, mm Hg). The decrease in SBP is arrested within 8 seconds at least. Late phase II is associated with an increase in blood pressure, reflecting the activation of vasomotor sympathetic nerves (phase II L, mm Hg). A transient fall in BP (phase III), lasting 1 to 2 seconds, occurs at the end of VM because of sudden drops in intrathoracic and abdominal pressures.¹⁷ Phase IV is the overshoot of blood pressure (phase IV, mm Hg) due to the activation of cardiac sympathetic nerves.¹⁸ Time intervals were determined for two periods of the VM, from the end of phase III to the complete return of SBP to the baseline value (blood pressure recovery time: PRT, s).²¹ Baroreceptor reflex sensitivity (BRS, ms/mm Hg) was derived from the correlation of RR with SBP during the early second phase of the VM.^15,16,21

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Figure Examples of blood pressure and RR interval profiles in a control subject (A) and patients with Lewy body disease (LBD) with autonomic failure (B)

Blood pressure (BP) fell in early phase II, but increased in late phase II because of an increase in efferent sympathetic gain in controls (A). In LBD with autonomic failure, there was no increase in BP, and BP decreased in late phase II (B). Transient BP overshoot in phase IV was noted in controls, but not in LBD with autonomic failure. Changes in RR intervals were lacking in LBD with autonomic failure as compared with controls. I: Phase I, II: phase II, III: phase III, IV: phase IV. SBP = systolic blood pressure, MBP = mean blood pressure, DBP = diastolic blood pressure.

We also measured changes in SBP on hut testing after the subjects rested for 20 minutes in the supine position.

RESULTS

The H/M ratio of cardiac ¹²³I-MIBG uptake in the patients with LBD was lower than that in the controls (1.47 ± 0.25 vs 2.41 ± 0.26, p < 0.0001). Phase II E did not differ significantly between the patients with LBD and the controls (27.2 ± 11.6 vs 22.9 ± 10.9). Phase II L, BRS, IVp, and PRT were significantly lower in the patients with LBD than in the controls (phase II L: 4.0 ± 8.4 vs 12.1 ± 6.0, p < 0.001; BRS: 1.9 ± 0.9 vs 4.2 ± 2.4, p < 0.01; phase IV: 8.8 ± 8.8 vs 20.1 ± 10.0, p < 0.001; PRT: 7.3 ± 5.5 vs 2.0 ± 0.8, p < 0.001). Patients with LBD had a significantly greater fall in SBP on HUT testing than did the controls (fall in SBP on HUT: 13.2 ± 13.7 vs –2.5 ± 10.2, p < 0.001).

Patients with DLB were older than those with PD or PDD. Disease duration did not differ significantly among these three groups. The Hoehn-Yahr stage was higher in patients with PDD than in patients with PD or those with DLB. Patients with PDD or DLB had lower cardiac ¹²³I-MIBG uptakes, phase II L, and phase IV and a longer PRT than did patients with PD. DLB had a higher phase II E and lower BRS as compared with PD. Patients with PDD or DLB had a greater fall in SBP on HUT testing than did patients with PD (table 1).

As for the correlation between the H/M ratio of cardiac ¹²³I-MIBG uptake and various indices of autonomic activity in LBD, H/M ratio did not correlate with phase II E, phase II L, PRT, or BRS. H/M ratio was, however, significantly related to phase IV (table 2). Cardiac ¹²³I-MIBG uptake began to decrease in association with the reduction in the overshoot of phase IV on the VM.

DISCUSSION

LBD was associated with cardiovascular autonomic dysfunction, as indicated by reduced cardiac ¹²³I-MIBG uptake and impaired cardiovascular autonomic function on the VM and HUT testing. Many studies have reported that cardiac ¹²³I-MIBG uptake is reduced in PD without autonomic failure.^1–7 Some studies have examined the association between cardiac ¹²³I-MIBG uptake and cardiovascular autonomic function in PD.^22,23 Cardiac sympathetic nerves are depleted in patients with DLB, independently of the duration of illness and the presence of orthostatic hypotension, and cardiac sympathetic denervation is a consistent histopathologic feature of LBD.^8,9 The morphologic degeneration of cardiac sympathetic nerves has been found in PD, associated with the nearly complete disappearance of TH-immunoreactive axons and marked decreases in NF-immunoreactive axons.¹⁰ Cardiac autonomic symptoms such as dyspnea on effort or palpitations in LBD might be associated with reduced cardiac ¹²³I-MIBG uptake. Despite these findings, whether reduced cardiac ¹²³I-MIBG uptake correlates with cardiovascular autonomic dysfunction in LBD has remained a matter of debate.

We examined the relation between cardiac ¹²³I-MIBG uptake and various indices of cardiovascular autonomic activity by means of the VM and HUT testing. Reduced cardiac ¹²³I-MIBG uptake was not related to phase II E, phase II L, BRS, PRT, or fall in SBP on HUT, but correlated with the transient BP overshoot in phase IV on the VM.

Early phase II (phase II E) is characterized by a fall in BP due to reduced cardiac output and shortening of RR intervals caused by the attenuation of cardiovagal control. BRS is derived from the significant correlation between RR intervals and BP during this period and mainly reflects parasympathetic cardiovagal function of the sinus node. Late phase II (phase II L) is characterized by increased BP and reflects vasomotor sympathetic function, i.e., the activation of efferent sympathetic signals to muscle and an increase in plasma norepinephrine concentration induced by baroreflex response, consequently increasing total peripheral resistance.

Phase IV is more dependent on cardiac adrenergic tone than on systemic peripheral resistance¹⁸ and therefore reflects cardiac sympathetic function. PRT reflects the adrenergic component of baroreflex function, accompanied by muscle sympathetic neural activation with norepinephrine release and binding to α-adrenergic receptors, resulting in vasoconstriction and BP recovery.²⁴ The significant relation of cardiac ¹²³I-MIBG uptake to only phase IV on the VM suggested that cardiac ¹²³I-MIBG uptake reflects cardiac adrenergic function, but not cardiovagal parasympathetic or α-adrenergic vasomotor functions.

It was reported that MIBG myocardial uptake is sometimes impaired in PD even in the absence of abnormal findings on autonomic testing, suggesting that MIBG myocardial scintigraphy is more sensitive than standard autonomic testing for the early detection of silent autonomic dysfunction.²⁵ We previously reported that patients with PD, especially those with early stage disease, have relatively preserved α-adrenergic vasomotor and cardiac parasympathetic functions.¹⁵ Cardiovascular dysautonomia in PD is first expressed as cardiac sympathetic dysfunction, followed by vasomotor and cardiac parasympathetic impairment.¹⁵ Autonomic dysfunction in PD may differ between the parasympathetic and sympathetic nervous systems, as well as between the heart and blood vessels.

In patients with DLB, cardiovascular autonomic function was considered to be more severely and extensively impaired than in patients with PD,^26,27 and the reduction in cardiac ¹²³I-MIBG uptake was more pronounced in patients with DLB than in those with PD.^27,28 In our study, patients with DLB or PDD had markedly impaired cardiac ¹²³I-MIBG uptakes and lower indices of cardiovascular autonomic activity on the VM and HUT testing as compared with patients with PD. These findings suggested that patients with PDD or DLB had impaired cardiac ¹²³I-MIBG uptake in parallel with reduced cardiovascular autonomic function. However, the impairment of cardiac ¹²³I-MIBG uptake in LDB correlated only with the transient BP overshoot in phase IV on the VM and was not related to other cardiovascular parameters. This fact indicated that cardiac ¹²³I-I MIBG uptake was impaired in association with cardiac sympathetic failure in LBD.

In MSA, autonomic dysfunction is generally more severe than in PD.^29,30,31 However, cardiac ¹²³I-MIBG uptake in MSA was higher than that in PD, although it was slightly lower than the control value. Our previous study also demonstrated that cardiac ¹²³I-MIBG uptakes were higher in MSA than in PD, although the decreases in transient BP overshoot in phase IV on the VM were similar in PD and MSA.¹⁶ We therefore assumed that cardiac sympathetic failure in MSA was not associated with cardiac ¹²³I-MIBG uptake. These findings suggest that sympathetic cardiac dysfunction in MSA is caused by central or preganglionic lesions and not by postganglionic efferent lesions, although postsynaptic denervation has been attributed to the slightly reduced cardiac ¹²³I-MIBG uptakes in MSA.³²