Impaired Myocardial Sympathetic Innervation Is Associated with Diastolic Dysfunction in Heart Failure with Preserved Ejection Fraction: 11C-Hydroxyephedrine PET Study

Tadao Aikawa; Masanao Naya; Masahiko Obara; Osamu Manabe; Yuuki Tomiyama; Keiichi Magota; Satoshi Yamada; Chietsugu Katoh; Nagara Tamaki; Hiroyuki Tsutsui

doi:10.2967/jnumed.116.178558

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FIGURE 1.
Participant flowchart and diastolic dysfunction grading of HFpEF patients. DT = deceleration time; LA = left atrial.
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FIGURE 2.
Representative images of ¹¹C-HED PET (A and C) and Doppler echocardiography (B and D) in 2 HFpEF patients (patient 1 with hypertensive heart disease and grade 1 diastolic dysfunction [A and B]). In patient 2 with cardiac amyloidosis and grade 2 diastolic dysfunction (C and D), the polar map of ¹¹C-HED RI (C) shows more extensive impairment of myocardial sympathetic innervation than that of patient 1 (A). Red arrowheads indicate E wave, and yellow arrowheads indicate e′.
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FIGURE 3.
Scatterplots of global RI (A) and CVRI (B) for comparison among the 3 groups. Horizontal lines indicate mean value.
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FIGURE 4.
Scatterplots of global RI (A) and CVRI (B) for comparison between the 2 HFpEF groups with nonischemic heart disease (n = 28). Horizontal lines indicate mean value.
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FIGURE 5.
Scatterplots demonstrate association of LVEF (A and B) and LV mass index (C and D) with global RI and CVRI in study subjects. CI = confidence interval.

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TABLE 1

Clinical Characteristics of Study Subjects (n = 53)

		HFpEF
Characteristic	Control (n = 12)	DD_0–1 (n = 22)	DD_2–3 (n = 19)	P
Age (y)	64 ± 12	65 ± 14	63 ± 16	0.94
Sex				0.20
Male	5	13	14
Female	7	9	5
BMI (kg/m²)	23.4 ± 4.1	24.3 ± 5.0	24.0 ± 4.2	0.87
NYHA functional class (I/II/III)		6/13/3	0/11/8	<0.02
Hypertension	10 (83%)	17 (77%)	8 (42%)	0.02
Diabetes	0 (0%)	10 (45%)^†	5 (26%)	0.02
Hyperlipidemia	7 (58%)	15 (68%)	11 (58%)	0.76
Atrial fibrillation	0 (0%)	8 (36%)	7 (37%)	0.047
Coronary artery disease	0 (0%)	6 (27%)	7 (37%)	0.06
Prior myocardial infarction	0 (0%)	6 (27%)	7 (37%)	0.06
Heart failure etiologies				0.03
Ischemic cardiomyopathy		5 (23%)	7 (37%)
Hypertrophic cardiomyopathy		5 (23%)	4 (21%)
Hypertensive heart disease		6 (27%)	1 (5%)
Dilated cardiomyopathy		0 (0%)	5 (26%)
Other		6 (27%)	2 (11%)
Blood data
Hemoglobin (g/dL)	13.0 ± 1.6	12.9 ± 1.9	13.5 ± 1.5	0.46
Creatinine (mg/dL)	0.65 (0.57–0.92)	0.81 (0.66–0.99)	0.87 (0.70–1.13)	0.12
Estimated glomerular filtration rate (mL/min/1.73 m²)	75.6 ± 19.4	66.3 ± 17.2	67.7 ± 33.2	0.56
B-type natriuretic peptide (pg/mL)	11.5 (8.5–19.0)	97.0 (25.2–223.3)^*	78.8 (34.1–242.0)^*	<0.001
Norepinephrine (pg/mL)	426 ± 177	367 ± 216	371 ± 199	0.70
Troponin T (ng/mL)	0.004 (0.003–0.009)	0.016 (0.009–0.045)^*	0.038 (0.014–0.058)^*	<0.001
Medication
ACE-Is or ARBs	5 (42%)	20 (91%)^*	13 (68%)	0.009
β-blockers	1 (8%)	14 (64%)^*	18 (95%)^*^‡	<0.001
Aldosterone antagonists	2 (17%)	1 (5%)	5 (26%)	0.15
Diuretics	1 (8%)	7 (32%)	9 (47%)	0.08
Calcium-channel blockers	7 (58%)	10 (45%)	6 (32%)	0.33
Statins	4 (33%)	12 (55%)	10 (53%)	0.46
Warfarin	0 (0%)	2 (9%)	5 (26%)	0.08
DOACs	0 (0%)	6 (27%)	3 (16%)	0.13
SHFM mean life expectancy (y)		10.6 ± 4.9	9.7 ± 3.3	0.50

↵* P < 0.01 vs. control.
↵† P < 0.05 vs. control.
↵‡ P < 0.05 vs. DD_0–1.
BMI = body mass index; NYHA = New York Heart Association; ACE-Is = angiotensin-converting enzyme inhibitors; ARBs = angiotensin II receptor blockers; DOACs = direct oral anticoagulants.
Data are mean ± SD; n, with percentages in parentheses; or median, with interquartile ranges in parentheses.

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TABLE 2

Hemodynamics and Echocardiographic Findings

		HFpEF
Parameter	Control (n = 12)	DD_0–1 (n = 22)	DD_2–3 (n = 19)	P
Systolic blood pressure (mm Hg)	121 ± 16	109 ± 22	107 ± 21	0.18
Diastolic blood pressure (mm Hg)	67 ± 10	61 ± 12	62 ± 12	0.29
Heart rate (bpm)	58 ± 7	58 ± 11	57 ± 10	0.96
LVEF (%)	67 (64–69)	51 (43–57)^*	45 (42–58)^*	<0.001
LV end-diastolic diameter (mm)	46 ± 4	51 ± 8	52 ± 9	0.07
LV end-systolic diameter (mm)	28 ± 2	37 ± 10^†	41 ± 10^*	0.002
Left atrial end-systolic diameter (mm)	37 (33–39)	42 (39–49)^†	43 (34–46)	0.03
LV mass index (g/m²)	75 ± 11	123 ± 36^*	133 ± 33^*	<0.001
Left atrial volume index (mL/m²)	33 (31–38)	42 (35–53)	43 (31–59)	0.10
E/A	0.79 (0.67–0.98)	0.61 (0.55–0.77)	1.02 (0.85–1.43)^‡	0.002
E wave deceleration time (ms)	216 (195–242)	219 (184–242)	182 (167–294)	0.69
Septal e′ (cm/s)	7.2 ± 2.4	6.0 ± 2.4	4.7 ± 1.3^*	0.009
Lateral e′ (cm/s)	8.8 ± 1.8	8.9 ± 3.9	6.9 ± 2.0	0.07
E/e′	8.7 (7.9–9.2)	9.2 (8.0–11.1)	13.0 (10.0–16.3)^*^‡	<0.001

↵* P < 0.01 vs. control.
↵† P < 0.05 vs. control.
↵‡ P < 0.01 vs. DD_0–1.
LV = left ventricular; E/A = peak velocity of early-diastolic mitral flow (E) to peak atrial velocity (A) ratio; E/e′ = E to mean early diastolic annular velocity (e′) ratio.
Data are mean ± SD; n, with percentages in parentheses; or median, with interquartile range in parentheses.

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TABLE 3

PET Imaging Results

		HFpEF
Parameter	Control (n = 12)	DD_0–1 (n = 22)	DD_2–3 (n = 19)	P
Global RI (min⁻¹)	0.123 ± 0.028	0.092 ± 0.024^*	0.075 ± 0.018^*^†	<0.001
Regional RI (min⁻¹)
Anterior	0.124 ± 0.028	0.097 ± 0.028^‡	0.078 ± 0.019^*^†	<0.001
Septal	0.128 ± 0.030	0.099 ± 0.025^*	0.085 ± 0.024^*	<0.001
Inferior	0.119 ± 0.029	0.087 ± 0.022^*	0.069 ± 0.019^*^†	<0.001
Lateral	0.119 ± 0.027	0.087 ± 0.027^*	0.067 ± 0.016^*^†	<0.001
CVRI (%)	7.9 ± 1.6	14.1 ± 4.7^*	18.4 ± 7.7^*^†	<0.001
¹¹C-hydroxyephedrine influx rate (mL⋅g⁻¹⋅min⁻¹)	0.302 ± 0.053	0.231 ± 0.065^*	0.189 ± 0.053^*	<0.001

↵* P < 0.01 vs. control.
↵† P < 0.05 vs. DD_0–1.
↵‡ P < 0.05 vs. control.
Data are mean ± SD.

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TABLE 4

Logistic Regression Analysis to Identify Clinical Factors Contributing to Presence of DD_2–3 in HFpEF Patients

	Univariate		Multivariate model 1		Multivariate model 2
Factor	OR	P	OR	P	OR	P
Age (per 10 y)	0.92 (0.59–1.43)	0.72	–	–	–	–
Sex (male)	1.94 (0.53–7.77)	0.32	–	–	–	–
BMI (kg/m²)	0.99 (0.86–1.13)	0.88	–	–	–	–
Hypertension	0.21 (0.05–0.79)	0.02	0.29 (0.06–1.37)	0.12	0.18 (0.03–0.98)	0.048
Diabetes	0.43 (0.11–1.56)	0.20	–	–	–	–
Coronary artery disease	1.56 (0.41–6.03)	0.51	–	–	3.41 (0.59–25.2)	0.17
Atrial fibrillation	1.02 (0.28–3.68)	0.97	–	–	–	–
B-type natriuretic peptide (per 100 pg/mL)	1.19 (0.87–1.81)	0.29	–	–	–	–
SHFM mean life expectancy (y)	0.95 (0.81–1.10)	0.49	–	–	–	–
LVEF (per 5%)	0.76 (0.51–1.08)	0.13	1.04 (0.60–1.83)	0.89	1.08 (0.60–2.05)	0.80
LV mass index (per 10 g/m²)	1.08 (0.90–1.32)	0.39	–	–	–	–
Global RI (per 0.01 min⁻¹)	0.64 (0.41–0.90)	0.008	0.66 (0.38–0.99)	0.044	0.62 (0.33–0.98)	0.042
CVRI (per 5%)	1.76 (1.06–3.20)	0.03	1.88 (1.01–3.95)	0.046	1.79 (0.94–3.88)	0.08

OR = odds ratio; model 1 = including LVEF and stepwise-selected variables; model 2 = including coronary artery disease, LVEF, and stepwise-selected variables; BMI = body mass index.
Data in parentheses are 95% confidence intervals.