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J Am Coll Cardiol, 2000; 35:1867-1873
© 2000 by the American College of Cardiology Foundation
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CLINICAL STUDIES

Myocardial perfusion and sympathetic innervation in patients with hypertrophic cardiomyopathy

Sheng-Ting Li, MD, PhD*, Cees J. Tack, MD{dagger}, Lameh Fananapazir, MD{ddagger} and David S. Goldstein, MD, PhD*

* Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892 USA
{dagger} Department of Internal Medicine, University Hospital, Nijmegen, The Netherlands
{ddagger} Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892 USA

Manuscript received February 16, 1999; revised manuscript received December 16, 1999, accepted February 9, 2000.

Reprint requests and correspondence: Dr. Sheng-Ting Li, National Institutes of Health, Building 10, Room 6N252, 10 Center Drive, MSC-1620, Bethesda, Maryland 20892-1620
lisht{at}box-1.nih.gov


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES

This study assessed left ventricular myocardial perfusion and sympathetic innervation and function in hypertrophied and nonhypertrophied myocardial regions of patients with hypertrophic cardiomyopathy (HCM).

BACKGROUND

Patients with HCM often have clinical findings consistent with increased cardiac sympathetic outflow. Little is known about the status of sympathetic innervation specifically in hypertrophic regions.

METHODS

We conducted positron emission tomographic (PET) scanning using the perfusion imaging agent 13N-ammonia (13NH3) and the sympathoneuronal imaging agent 6-[18F]-fluorodopamine (18F-FDA) in 8 patients with HCM and 15 normal volunteers. Positron emission tomographic data corrected for attenuation and the partial volume effect were analyzed using the region-of-interest technique.

RESULTS

Myocardial 13NH3-derived radioactivity was similar in hypertrophied and nonhypertrophied regions of patients with HCM and in normal volunteers. At all time points, the 18F:13N ratio was lower in hypertrophied than in nonhypertrophied regions of HCM patients and in the septum of normal volunteers (p = 0.001). Trends in 18F-FDA-derived radioactivity over time were normal in both hypertrophied and nonhypertrophied myocardium.

CONCLUSIONS

The results are consistent with decreased neuronal uptake of catecholamines in hypertrophied but not in nonhypertrophied myocardium of patients with HCM. Other aspects of cardiac sympathoneural function seem normal. Decreased neuronal uptake could reflect local relative hypoinnervation, decreased numbers of neuronal uptake sites, or metabolic limitations on cell membrane transport. By enhancing norepinephrine delivery to adrenoceptors for a given amount of sympathetic nerve traffic, decreased neuronal uptake can explain major clinical features of HCM.

Abbreviations and Acronyms
  13NH3 = 13N-ammonia
  18F-FDA = 6-[18F]-fluorodopamine
  HCM = hypertrophic cardiomyopathy
  PET = positron emission tomography
  ROI = region of interest

Hypertrophic cardiomyopathy (HCM) is a genetic disease inherited as an autosomal dominant trait and characterized by left ventricular hypertrophy in the absence of other causes for increased cardiac mass (1–5). The disease results from missense mutations of genes encoding sarcomeric proteins such as beta-myosin heavy chain, essential and regulatory light chain of myosin, alpha-tropomyosin, cardiac troponin T or I, or cardiac myosin binding protein C (6–11).

Clinical features of HCM, such as chest pain, progression of left ventricular hypertrophy, myocardial hypercontractility, propensity to ventricular arrhythmias and sudden death, and the beneficial effect of beta-adrenoceptor blockers, suggest increased cardiac sympathetic outflow and, consequently, increased delivery of the sympathetic neurotransmitter, norepinephrine, to myocardial adrenoceptors (3–5,12,13). Norepinephrine not only elicits vasoconstriction, increases myocardial oxygen consumption, and increases the rate of spontaneous depolarization of myocardial cells acutely, but also acts as a hypertrophic factor in cardiovascular smooth muscle cells (14–17).

Any of several abnormalities of cardiac sympathetic innervation or function can increase norepinephrine delivery to adrenoceptors. The most straightforward is an increase in the rate of local sympathetic nerve traffic, which increases release of norepinephrine from the nerve terminals. Although a previous study reported an increased appearance rate of norepinephrine in plasma in the great cardiac vein (cardiac norepinephrine spillover) in patients with HCM (18), the increase was relatively small, and, as noted below, increased cardiac sympathetic traffic alone cannot account for some other neurochemical findings.

Decreased neuronal reuptake of norepinephrine (Uptake-1), the main means for terminating the actions of norepinephrine in the human heart (19), also increases delivery of norepinephrine to adrenoceptors (20). Consistent with this mechanism, patients with HCM have a decreased fractional extraction of 3H-norepinephrine and a decreased arteriovenous increment in plasma levels of dihydroxyphenylglycol, the main neuronal metabolite of norepinephrine, compared with control patients (18).

Studies of cardiac kinetics of 3H-norepinephrine and its metabolites cannot provide information about possible abnormalities of sympathetic innervation or function specifically in hypertrophied regions. Investigators (21,22) have reported decreased 123I-meta-iodozylganidine-derived (123I-MIBG-derived) radioactivity in the hypertrophied regions of patients with HCM, and Schafers et al. (23) reported reduced 11C-hydroxyephedrine-derived radioactivity. These findings are consistent with locally decreased Uptake-1 activity; however, other abnormalities of cardiac sympathetic function can produce the same results.

Positron emission tomographic (PET) scanning after injection of 6-[18F]-fluorodopamine (18F-FDA), a newly developed catecholamine that acts as a false adrenergic neurotransmitter (Fig. 1), can visualize cardiac sympathetic innervation and function (24–29). Sympathetic nerve terminals rapidly take up circulating 18F-FDA and sequester it extensively in axoplasmic vesicles (24,30). The heart:blood ratio of 18F-FDA is 2:1 at 5 min and 9:1 at 180 min after injection (27).



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  		Figure 1 The structure (A) and fate of 6-[18F]-fluorodopamine (B).

 
Alterations in specific aspects of sympathetic neuroeffector function, including Uptake-1 activity, vesicular transport and storage of monoamines, oxidative deamination, and postganglionic sympathetic nerve traffic, produce characteristic changes in curves relating 18F-FDA–derived myocardial radioactivity to time (time-activity curves, TACs). Treatment with desipramine, which blocks Uptake-1, or 6-hydroxydopamine, which destroys sympathetic nerve terminals, decreases cardiac uptake of 18F-FDA (25,27,31). Reserpine, which blocks vesicular transport of axoplasmic monoamines, does not affect myocardial uptake of 18F-FDA but markedly decreases retention of 18F-FDA (25). Increased sympathetic activity, induced by exercise or sublingual nitroglycerin, increases the rate of loss of 18F-FDA–derived myocardial radioactivity (32), whereas ganglion blockade with trimethaphan prolongs the loss of 18F-FDA–derived myocardial radioactivity (25,27).

This study used 18F-FDA PET scanning to evaluate whether patients with HCM have alterations in sympathetic innervation or function in the hypertrophied regions that might predispose to a hyperadrenergic state. We also used the perfusion imaging agent 13N-ammonia (13NH3) (33) to adjust 18F-FDA concentrations for possible regional differences in delivery by the bloodstream (18F:13N ratio).


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Subjects.   Both 18F-FDA and 13NH3 were administered and thoracic PET scanning performed in 15 healthy adult volunteers (11 men and 4 women, aged 54 ± 22 years) and 8 patients with HCM (6 men and 2 women, aged 42 ± 18 years). All the volunteers had normal medical history, physical examination, electrocardiogram (ECG), and laboratory (blood and urine) tests. Of the 8 HCM patients, asymmetric septal hypertrophy was present in 5 (2 with hypertrophy of the apex as well), whereas hypertrophy was more diffuse in 3 patients, so that there were 8 hypertrophied and 5 nonhypertrophied regions. Caffeine-containing beverages, cigarettes, and alcohol were proscribed for at least 24 h before PET scanning.

The study protocol was approved by the Clinical Research Subpanel of the National Institute of Neurological Disorders and Stroke (NINDS). Each subject gave written informed consent.

PET scanning.   Three-dimensional PET studies were performed on an AdvanceTM whole-body scanner (General Electric, Milwaukee, Wisconsin). An 8-min transmission scan, using rotating 68Ge/68Ga pin sources, was obtained for attenuation correction and for confirming the location of the heart, before the 13NH3 and 18F-FDA PET scans. Immediately after the first transmission scan, myocardial perfusion was assessed by PET imaging (35 contiguous transaxial slices 4.25 mm apart) for 20 min after a 1-min IV infusion of 5 mCi of 13NH3.

For sympathoneuronal imaging, after the second transmission scan, PET images (35 contiguous transaxial slices 4.25 mm apart) were acquired after IV infusion of 18F-FDA (synthesized as described previously) (27) at a constant rate for 3 min after, beginning at least 1 h after 13NH3 administration. A series of PET scans (5 frames x 1 min, 5 x 5 min, 4 x 15 min, and 3 x 30 min, total 3 h) was acquired.

Data analysis.   The 18F-FDA data were reconstructed after correction for attenuation and for physical decay of 18F. Cardiac images were analyzed as described previously (27). Briefly, circular regions of interest (ROIs) approximately half the ventricular wall thickness were placed on images of the septum, lateral wall, and left ventricular chamber using time-averaged pictures of a single slice. Left ventricular radioactivity was averaged from two ROIs each in the left ventricular free wall and septum. Time-activity curves relating myocardial radioactivity with time were constructed from the dynamic PET data and compared between the HCM and control groups.

Static 13NH3 PET images were reconstructed after analogous correction for attenuation and physical decay of 13N and analyzed using the same ROI technique.

Radioactivity concentrations were standardized by correcting for the dose of radioactive drug per unit body mass of the subject and expressed as nCi · kg/cc · mCi.

Because infused 18F-FDA is delivered by the bloodstream, the amount of 18F-FDA–derived radioactivity depends on regional perfusion. To correct 18F-FDA–derived radioactivity for regional perfusion, the ratio of 18F-FDA–derived radioactivity to 13NH3-derived radioactivity (18F:13N) was calculated in the same ROIs.

Correction for partial volume effect.   Because of asymmetric septal hypertrophy, increased septal myocardial concentrations of 18F and 13N might reflect a partial volume effect. To correct for this effect, thicknesses of the left ventricualr free wall and septum were measured by echocardiography, and recovered coefficient functions for the GE AdvanceTM PET scanner were calculated and applied by blurring in-plane data with a two-dimensional Gaussian filter (34,35).

Statistics.   All data were expressed as means ± SEM. The HCM and normal volunteer groups were compared using between–within analyses of variance (2-factor repeated-measures analysis of variance [ANOVA]), the between factor being diagnosis and the within factor being time (StatView SE+GraphicsTM, Abacus Concepts, Berkeley, California). A factorial ANOVA was used to assess effects of blood flow and diagnostic group on myocardial 18F-FDA–derived radioactivity.

Bi-exponential equations of best fit were calculated using a "peeling" approach to describe the relationships between myocardial radioactivity and time in each subject. The equation for the mono-exponential line of best fit for the late phase, including the y-intercept (yo) and apparent rate constant (k), was determined for the last four scanning intervals (midpoints 97.5 min to 165 min after administration of 18F-FDA; Cricket Software, Malvern, Pennsylvania). Differences between the estimated and empirical values were calculated and graphed, and the mono-exponential line of best fit for the early phase was determined, beginning with the peak value of 18F-FDA–derived radioactivity. Values for yo and k for the early phase were than calculated.

Values for yo and k for 18F-FDA–derived radioactivity, with and without adjustment for perfusion, were compared to those in the normal volunteers, using independent-means t-tests. Statistical significance was defined by a p value less than 0.05.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
After administration of 18F-FDA or 13NH3, the left ventricular myocardium was visualized clearly in all subjects (Fig. 2). The myocardial distribution of both tracers was more heterogeneous in patients with HCM than in normal volunteers.



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  		Figure 2 Thoracic positron emission tomographic scans depicting (left) myocardial 13N-ammonia–derived radioactivity, (middle) 6-[18F]-fluorodopamine–derived radioactivity, and (right) the ratio of 18F:13N in (top) a normal volunteer and (bottom) a patient with hypertrophic cardiomyopathy, after IV injection of 5 mCi 13N-ammonia and then 1 mCi 6-[18F]-fluorodopamine. Sep = septum; Lat = lateral wall; Ap = apex; LV = left ventricle.

 
Mean left ventricular myocardial radioactivity.   Values for time-averaged 13NH3-derived radioactivity in left ventricular myocardium as a whole were similar in patients with HCM (7137 ± 506 nCi · kg/cc · mCi) and in normal volunteers (7293.4 ± 409 nCi · kg/cc · mCi; Fig. 3).



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  		Figure 3 13NH3-Derived radioactivity in patients with hypertrophic cardiomyopathy and normal volunteers. HCM = average myocardial radioactivity of patients with hypertrophic cardiomyopathy (n = 8); HY = radioactivity in hypertrophied regions of patients with HCM (n = 8); NH = radioactivity in nonhypertrophied regions of patients with HCM (n = 5); NL = average radioactivity in left ventricular myocardium of normal volunteers (n = 15); NF = radioactivity in left ventricular free wall of normal volunteers (n = 15); NS = radioactivity in septum of normal volunteers (n = 15).

 
The mean concentration of 18F-FDA–derived radioactivity in left ventricular myocardium increased to a peak at 5 to 8 min after initiation of the 3-min infusion in both subject groups (8499 ± 722 nCi · kg/cc · mCi in HCM patients, 10,263 ± 673 nCi · kg/cc · mCi in normal volunteers). The 18F-FDA–derived radioactivity thereafter declined bi-exponentially. In both the early and late phases of the decline, the groups did not differ in mean values for k or yo (Table 1).


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  		Table 1 Kinetic Parameters for 6-[18F]-Fluorodopamine–Derived Radioactivity in Normal Volunteers and in Patients With Hypertrophic Cardiomyopathy

 
There was a significant time-dependent decline of 18F-FDA–derived radioactivity (F = 134.2, p = 0.0001). Patients with HCM had a lower mean ratio of 18F:13N than did the normal volunteers (F = 11.1, p = 0.0039), and the trend in 18F:13N differed significantly between the groups (F = 2.39, p = 0.0085; Fig. 4, upper part). The peak value also occurred significantly earlier in the HCM patients (5.1 min vs. 8.0 min; Fig. 4, lower part).



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  		Figure 4 Mean values (±SEM) for the ratio of 18F:13N in septum or average of left ventricular myocardium of normal volunteers (n = 15) and in hypertrophied (n = 8) and nonhypertrophied regions (n = 5) of patients with hypertrophic cardiomyopathy, after injection of 13N-ammonia and then 6-[18F]-fluorodopamine.

 
Hypertrophied versus nonhypertrophied regions in patients with HCM.   After correction for the partial volume effect, mean 13NH3-derived radioactivity in hypertrophied regions did not differ from that in nonhypertrophied regions (Fig. 3).

Peak 18F-FDA–derived radioactivity (9457 ± 1074 nCi · kg/cc · mCi in hypertrophied regions, 9436 ± 1084 nCi · kg/cc · mCi in nonhypertrophied regions) and mean values for k or yo (Table 1) did not differ between hypertrophied and nonhypertrophied regions in patients with HCM.

Hypertrophied regions in patients with HCM versus controls.   After correction for the partial volume effect, 13NH3-derived radioactivity in hypertrophied regions of patients with HCM (7767 ± 680 nCi · kg/cc · mCi) did not differ significantly from that in the left ventricular myocardium of normal volunteers (7428 ± 413 nCi · kg/cc · mCi; Fig. 3).

Neither mean peak 18F-FDA–derived radioactivity nor 13NH3-derived radioactivity (6694 ± 425 nCi · kg/cc · mCi) in nonhypertrophied regions of patients with HCM differed from the corresponding values in normal volunteers.

Perfusion-adjusted 18F-FDA–derived radioactivity.   In the hypertrophic regions of patients with HCM, the mean ratio of 18F:13N was significantly less than that in normal volunteers (F = 15.7, p = 0.001). The 18F-FDA–derived radioactivity declined in a time-dependent manner (F = 137.4, p = 0.0001), and the groups differed significantly in the trends of 18F:13N (F = 3.20, p = 0.0005). The ratio of peak 18F-FDA–derived radioactivity to 13NH3-derived radioactivity was also significantly lower in hypertrophied than in nonhypertrophied regions of HCM patients (t = 2.13) or in normal volunteers (t = 3.87, p = 0.0005; Fig. 4). Among the five patients with asymmetric septal hypertrophy, the mean ratio of septal 18F:13N was also significantly less than that in normal volunteers (F = 13.4, p = 0.0023). The 18F-FDA–derived radioactivity declined in a time-dependent manner (F = 115.8, p = 0.0001), and the groups differed significantly in the trends of 18F:13N (F = 3.27, p = 0.0005).

Peak 18F-FDA–derived radioactivity correlated positively with 13NH3-derived radioactivity across subjects (Fig. 5). For a given amount of 13NH3-derived radioactivity, patients with HCM had lower values for peak 18F-FDA–derived radioactivity in the hypertrophied than nonhypertrophied regions (F = 12.7, p = 0.0044) and myocardium of normal volunteers (F = 16.2, p = 0.0006). The relationship between 18F-FDA–derived radioactivity and 13NH3-derived radioactivity did not vary as a function of the diagnostic group or hypertrophied status. For a given amount of 13NH3-derived radioactivity, peak 18F-FDA–derived radioactivity in nonhypertrophied regions of patients with HCM was similar to that in normal volunteers.



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  		Figure 5 Relationship between peak 18F-FDA–derived radioactivity and 13NH3-derived radioactivity in hypertrophied and nonhypertrophied regions of 7 patients with HCM (another 1 outlier deleted) and in left ventricular myocardium of 15 normal volunteers.

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
The main finding of the present study was in patients with HCM, ratios of 18F-FDA–derived radioactivity to 13NH3-derived radioactivity in hypertrophied regions were significantly smaller than those in nonhypertrophied regions or in left ventricular myocardium of normal volunteers. As explained below, these findings indicate decreased neuronal uptake of 18F-FDA by cardiac sympathetic nerve terminals for a given amount of delivery by blood perfusion in the hypertrophied regions.

Cardiac sympathetic function in hypertrophied regions.   Shapes of curves relating myocardial 18F-FDA–derived radioactivity with time in patients with HCM did not differ from those in normal volunteers, even after adjustment for perfusion. Thus, the decrease in perfusion-adjusted 18F-FDA–derived radioactivity did not result from accelerated loss of 18F-FDA–derived radioactivity after neuronal uptake of the tracer, as would occur with decreased efficiency of the vesicular monoamine transporter (25) or with increased regional sympathetic nerve traffic (32).

The present results confirm and extend those from other studies using different sympathoneural and perfusion imaging agents, indicating decreased Uptake-1 activity in myocardium of patients with HCM. Shimizu et al. (22) reported reduced 123I-MIBG–derived radioactivity in hypertrophied regions of patients with HCM who had a conduction disturbance or decrease in or disappearance of a negative T wave during 12 months of serial electrocardiography, compared with patients who had an increase in or appearance of a negative T wave; however, the study did not include a control group and did not consider possible regional differences in perfusion.

In addition, Nakajima et al. (36) noted reduced 123I-MIBG–derived radioactivity for a given amount of 201Tl uptake in hypertrophied regions of patients with septal thicknesses exceeding 16 mm, compared to patients with septal thicknesses less than 16 mm; this study also did not include a control group. Schäfers et al. (23) found a decreased cardiac volume of distribution of 11C-hydroxyephedrine in patients with HCM compared with values in control subjects, consistent with decreased neuronal uptake; however, that study did not examine possible regional localization of the abnormality within the myocardium. Ungerer et al. (21) reported a close correlation between 11C-hydroxephedrine uptake and tissue norepinephrine content in cardiomyopathic human heart; however, the patients all had dilated, not hypertrophic, cardiomyopathy.

Decreased 18F-FDA uptake in hypertrophied regions in patients with HCM could reflect relative sympathetic hypo-innervation, such as by "dilution" of nerve terminals by hypertrophied myocardial cells and interstitial fibrosis (4). Because myocardial uptake and retention of 18F-FDA requires the energy-dependent Uptake-1 process (25), and because patients with HCM can have impaired oxidative and glucose metabolism in hypertrophied regions (37,38), locally decreased uptake of 18F-FDA might also result from local metabolic changes. Although decreased neuronal uptake could also result from increased effective arteriovenous shunting, related to decreased arteriolar density (39), this would not have decreased the 18F:13N ratio.

Myocardial perfusion in hypertrophied regions.   Available published reports about regional myocardial blood flow and perfusion in patients with HCM have been remarkably inconsistent. Investigators (36) reported increased regional uptake of 201Tl in the hypertrophied septa of patients with HCM. Camici et al. (40) found more 13NH3-derived radioactivity in the hypertrophied septum than in the nonhypertrophied free wall, although the difference from corresponding values in control subjects was not significant. In contrast, Ishiwata et al. (37) and Tadamura et al. (38) reported reduced 11C-acetate–derived radioactivity, which is a measure of myocardial perfusion (41), and Grover-McKay et al. (34) and Nienaber et al. (42) reported reduced 13NH3-derived radioactivity in the hypertrophied regions. Hypertrophied regions have normal uptake of 15O-water (42–44).

Some of these differences may have arisen from lack of correction for the partial volume effect in hypertrophied myocardial regions. In the present study, after correction for the partial volume effect, 13NH3-derived radioactivity in hypertrophied regions was approximately normal.

Cardiac sympathetic innervation and myocardial perfusion in nonhypertrophied regions.   Both 18F-FDA–derived and 13NH3-derived radioactivity levels were normal in nonhypertrophied regions of patients with HCM, and trends in perfusion-adjusted 18F-FDA–derived radioactivity were similar in patients with HCM and in normal volunteers. These findings indicate normal postganglionic nerve traffic to functionally intact sympathetic nerve terminals in the nonhypertrophied regions.

In summary, decreased perfusion-adjusted 18F-FDA–derived radioactivity appears to reflect decreased neuronal uptake (Uptake-1) by sympathetic nerves in hypertrophied but not in nonhypertrophied regions of patients with HCM. Because of the importance of Uptake-1 for terminating the actions of catecholamines in the human heart (19), decreased Uptake-1 activity would be expected to augment delivery of locally released and circulating catecholamines to adrenoceptors in the hypertrophied myocardium during sympathetic or adrenomedullary activation. This in turn could contribute to hypercontractility, susceptibility to ventricular arrhythmias, reduced coronary vasodilator reserve, and progressive hypertrophy in HCM.


   Acknowledgments
 
The authors acknowledge Pat Woltz, RN, and Dotti Tripodi, RN, for their assistance in patient care, and helpful suggestions by Dr. Stephen L. Bacharach and Dr. Irwin J. Kopin.


   References
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