Article

Supine low-frequency power of heart rate variability reflects baroreflex function, not cardiac sympathetic innervation*

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Cardiac sympathetic neuroimaging

For cardiac sympathetic neuroimaging the subject was positioned supine, feet-first in a GE Advance scanner (General Electric, Milwaukee, WI), with the thorax in the gantry. After positioning the patient with the thorax in the scanner and transmission scanning for attenuation correction, 6-[18F]fluorodopamine (usual dose 1 mCi, specific activity 1.0 to 4.0 Ci/mmole, in about 10 mL normal saline) was infused intravenously at a constant rate for 3 min, and dynamic scanning data were obtained for thoracic radioactivity, with the midpoint of the scanning interval at 7.5 min after injection of the tracer (data collection interval between 5 and 10 min). Cardiac sympathetic denervation was defined by low concentrations of 6-[18F] fluorodopamine-derived radioactivity in the interventricular septum (< 5,000 nCi-kg/cc-mCi) or left ventricular free wall (< 4,000 nCi-kg/cc-mCi) corresponding to about 2 SD below the normal means.

Cardiac norepinephrine spillover

Subgroups of subjects (3 PD + NOH, 3 MSA, 3 PAF, 5 normal volunteers) underwent right heart catheterization for measurement of cardiac norepinephrine spillover. 3H-Norepinephrine was infused intravenously, and arterial and coronary sinus blood was sampled and coronary sinus blood flow was measured by thermodilution for measurements of cardiac norepinephrine spillover as described previously.18 In some subjects, yohimbine was infused during cardiac catheterization. Patients with chronic autonomic failure received the doses described above; normal volunteers and patients with chronic orthostatic intolerance received twice the doses described above.

Data analysis

Statistical analyses were performed using StatView version 5.0.1. (SAS Institute, Cary, NC). Mean values in the baseline condition for the several subject groups were compared using single-factor ANOVA. Responses to drugs were analyzed by dependent-means t tests. Differences in response to pharmacologic tests among subject groups were compared using repeated measures analyses of variance. Relationships between individual hemodynamic values were assessed by linear regression and calculation of Pearson correlation coefficients. Post-hoc testing consisted of the Fisher PLSD test. Multiple regression analysis was done on the individual data, with the log of LF power as the dependent measure and the log of baroreflex slope and septal 6-[18F] fluorodopamine-derived radioactivity as independent measures. Mean values were expressed ± SEM.

RESULTS

Baseline

Across the 7 subject groups (N = 98), LF power was unrelated to subject group (F = 1.2). When individual subjects were stratified in terms of cardiac sympathetic denervation or innervation, based on concentrations of 6-[18F]fluorodopamine-derived radioactivity more than 2 SD below the normal mean, then LF power was lower in the Denervated group (mean 221 ± 55 msec2/Hz, N = 34) than in the Innervated group (516 ± 93 msec2/Hz, N = 64, F = 4.8, P = 0.03). LF power normalized for total power, HF normalized for total power, and the ratio of LF:HF were not related to 6-[18F]fluorodopamine-derived radioactivity.

When subjects were stratified in terms of BRS, then LF power was lower in the Low BRS group (223 ± 105 msec2/Hz, N = 46) than in the Normal BRS group (617 ± 97 msec2/Hz, N = 25, F = 6.1, P = 0.02). The Low BRS group did not differ from the Normal BRS group in normalized LF power (F = 0.8).

Figure 1. Mean (± SEM) values for the log of low-frequency power of heart rate variability in subject groups with innervated (Innerv) or denervated (Denerv) hearts, as indicated by low 6-[18F] fluorodopamine-derived radioactivity, and normal (Nl) or low baroreflex-cardiovagal slope (BRS), as indicated by slope ≤3 msec/mm Hg during the Valsalva maneuver. ***Significant difference, P < 0.001.

When individual subjects were stratified into 4 groups, based on both cardiac 6-[18F]fluorodopamine-derived radioactivity (Innervated or Denervated) and on baroreflex-cardiovagal slope (Normal BRS or Low BRS), then both LF power and the log of LF power varied highly significantly as a function of subject group (F = 9.5, P < 0.0001; F = 4.6, P = 0.0004). The Denervated-Low BRS group had lower LF power than did the Denervated-Normal BRS group (P = 0.05), and the Innervated-Low BRS group had lower LF power than did the Innervated-Normal BRS group (P < 0.0001). When level of baroreflex function was taken into account, the Innervated and Denervated groups did not differ in LF power (Figure 1).
Values for HF power also varied with subject group when individual subjects were stratified in terms of both cardiac sympathetic innervation and BRS (F = 4.9, P = 0.004; Table 2). The Innervated-Low BRS group had lower HF power than did the Innervated-Normal BRS group (P = 0.003); however, the Denervated-Low BRS group did not differ from the Denervated-Normal BRS group in HF power. Normalization of LF and HF power for total power, and the ratio of low-to-high frequency did not reveal additional group differences (Table 2). In particular, the LF:HF ratio did not vary with the subject group (F = 0.6).

Figure 2. Mean (± SEM) values for (A) low-frequency power of heart rate variability and (B) cardiac norepinephrine spillover during right heart catheterization in subject groups with innervated (Innerv) or denervated (Denerv) hearts, as indicated by low 6-[18F]fluorodopaminederived radioactivity, and normal (Nl) or low baroreflex-cardiovagal slope (BRS), as indicated by slope ≤3 msec/mm Hg during the Valsalva maneuver. *Significant difference, P < 0.05. **Significant difference, P < 0.01.

Analysis of data from subjects during cardiac catheterization showed that LF power varied as a function of subject group (F = 5.3, P = 0.03, Figure 2). The Innervated-Low BRS group had lower LF power than did the Innervated-Normal BRS group (P = 0.04), whereas the Denervated-Low BRS and Innervated-Low BRS groups did not differ in LF power. As expected, the Denervated-Low BRS group had lower cardiac norepinephrine spillover than the Innervated-Low BRS group.

Figure 3. Individual values for the log of low-frequency (LF) power as a function of (A) septal 6-[18F]fluorodopamine-derived radioactivity and (B) the log of baroreflex-cardiovagal slope.

Individual values for LF power were positively correlated with BRS. When values for both variables were log-transformed, the log of LF power correlated positively with the log of BRS slope (r = 0.72, P < 0.0001, Figure 3). Individual values for the log of LF power were also correlated with the magnitude of decrease in systolic pressure during performance of the Valsalva maneuver (r = −0.60, P < 0.0001) and with the orthostatic change in systolic pressure (r = 0.58, P < 0.0001). In contrast, the log of LF power was unrelated to the septal myocardial concentration of 6-[18F]fluorodopamine-derived radioactivity, the plasma norepinephrine concentration, or cardiac norepinephrine spillover.

From multiple regression analysis for the log of LF power as the dependent measure and the log of baroreflex slope and septal 6-[18F]fluorodopamine-derived radioactivity as independent measures, the regression coefficient for the log of baroreflex slope was 0.92 (P < 0.0001), whereas the regression coefficient for 6-[18F] fluorodopamine-derived radioactivity was 3 ×10−6.

At baseline, the log of HF power correlated positively with the log of LF power (r = 0.77, P < 0.0001). HF power varied with the subject group (F = 4.9, P = 0.004). As with LF power, HF power was greater in the Innervated-Normal BRS than in the Innervated-Low BRS (P = 0.001, Table 2). As expected, the log of HF power correlated positively with the log of BRS (r = 0.60, P < 0.0001). The log of HF power also correlated negatively with the magnitude of decrease in systolic pressure during the Valsalva maneuver (r = −0.24, P = 0.02) and positively with the orthostatic change in systolic pressure (r = 0.40, P = 0.004).

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