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Nuclear Molecular Imaging of the Failing Heart: Evaluation of Cardiac Sympathetic Nerve Activity and Mitochondrial Function in Patients with Cardiomyopathy

Nuclear imaging of failing myocardium is targeting the impaired part related to several processes of myocardial metabolism or work. Myocardium mainly utilizes fatty acid or glucose for ATP production in mitochondria. Intracellular calcium handling, which needs an amount of ATPs, induces myocardial contraction and relaxation, and is regulated with beta adrenal-stimulation. In the failing myocardium, any of these parts related to the myocardial work are variedly impaired, and could be the imaging target. Despite recent advancement of heart failure treatment, the patients with heart failure remain in high morbidity and mortality. For appropriate managements or prediction of prognosis in patients with heart failure, it is important to evaluate the mechanism of the failing myocardium. In this article, we focus on the usefulness of the 2 radionuclide imaging in evaluating sympathetic nerve function using myocardial 123 I-MIBG scintigraphy and mitochondrial function using myocardial 99m Tc-sestamibi SPECT in the patients with cardiomyopathy.

relaxation at physical or pharmacological stress (10,11) could cause heart failure. Accordingly, detailed evaluation of the myocardial properties in failing heart is important for appropriate treatments or the prediction of the prognosis in the patients with heart failure, using non-invasive imaging modalities, such as echocardiography, nuclear imaging, magnetic resonance image (MRI), or computed tomography (CT) (12)(13)(14).
In this article we focus on the clinical usefulness of the 2 radionuclide molecular imaging in evaluating myocardial mitochondrial function which produce myocardial energy source of ATPs using 99m Tc-sestamibi, and the sympathetic nerve function which regulates the myocardial intracellular calcium handling in myocardial contraction and relaxation using 123 I-MIBG in patients with non-ischemic cardiomyopathy.

Sympathetic nerve functional imaging with 123 I-MIBG
Myocardial imaging with 123 I-MIBG, the analogue of norepinephrine (NE), could visualize the activity and the innervation of adrenal sympathetic nervous system in the heart, and is widely used for evaluation of the patients with heart failure (6,15). Increased sympathetic nervous activity or denervation are seen in heart failure patients, and could be imaged with myocardial 123 I-MIBG image (16). Several reports have shown the clinical usefulness of 123 I-MIBG for prediction of major cardiac events, including heart failure hospitalization or cardiac death (17)(18)(19)(20), discharge of implantable cardioverter defibrillator (21), or evaluation of the effectiveness of betablockade (22)(23)(24)(25)(26), renin-angiotensin-aldosterone system inhibitor (27)(28)(29), and nicorandil (30,31) in patients with heart failure. And, a multi-center study of ADMIRE-HF (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure) trial was conducted (32), and meta-analysis of Japanese-single cohort was also performed (33) Fig. 1 and 2). These parameters were also associated with mRNA expressions of the proteins related to calcium handling or beta-adrenal signaling. And we also demonstrated that 123 I-MIBG parameters are associated with impaired myocardial functional reserve during atrial pacing tachycardia in 30 HCM patients (42). In these studies, we showed that myocardial 123 I-MIBG imaging parameters could predict abnormal myocardial functional reserve related to the impairment of calcium handling or beta adrenal signaling in non-ischemic cardiomyopathy patients.

Tc-Sestamibi
Myocardial mitochondria produce about 30 kg/day of ATPs as a myocardial energy source (43). Intra-mitochondrial membrane potential is strongly negative charged of -161±7 mV in normal myocyte (44). When cardiomyocytes are damaged by myocardial ischemia or other causes, the mitochondrial membrane potential is increasing (45). 99m Tcsestamibi, which is generally used as the tracer of SPECT-MPI, is a mono-positive ion, and usually retained within the mitochondria by the strong negative membrane potential (46).
However in the damaged myocyte with increased mitochondrial membrane potential, 99m Tc-sestamibi is washed out from myocyte (47).
It is reported that mitochondria in large clusters varied in size and shape with few myofibrils in myocardial tissue of DCM patients (48). Also, it is reported that mitochondrial damages were seen in several other heart diseases (43 Tc-seatamibi was associated with myocardial A, B. Relationship between 99m Tc-sestamibi washout rate (WR) and hemodynamic changes from baseline to peak dobutamine stress. A. A significant inverse correlation was observed between 99m Tc-sestamibi WR and % changes in LV dP/dtmax from baseline to peak (15μg/kg/min) dobutamine stress. B. A significant inverse correlation was observed between 99m Tc-sestamibi WR and % changes in T1/2 from baseline to peak (15μg/kg/min) dobutamine stress. C-F. Comparison of mitochondrial mRNA expression between the 2 Groups. α-KGDH (C), NDUFV3 (D), and COX5B (E) were significantly lower in Group B (WR of 99m Tc-sestamibi ≤24.3%) than in Group A (WR of 99m Tc-sestamibi >24.3%). The normal value of 99m Tc-sestamibi washout rate of the age-matched control group (10 subject; 9 men; age: 56±9 years) was 11±5%. Representative Case of group A (Left). A 66-year-old man shows no global increased 99m Tc-sestamibi WR (19.4%). An increased washout was observed in the small anteroseptal area (red arrows) on SPECT image. The %LV dP/dtmax was favorably increased. Electron microscopy revealed a relatively preserved mitochondrial configuration as well as a small amount of glycogen accumulations (green arrows) and lipid droplets (yellow arrows).
Representative case of group B (Right). A 45-year-old woman exhibited an increased MIBI WR (28.3%). An increased washout was observed in the anteroseptal to the inferoseptal wall. The %LV dP/dtmax showed a subtle increase in response to dobutamine. Electron microscopy reveals many damaged mitochondria (blue arrows) and glycogen accumulations (green arrows). (From ref. (59) reprinted with permission.) Calcium influx through cell membrane calcium channel induces calcium-induced calcium release from sarcoplasmic reticulum (SR) through ryanosine receptor (RyR). Then, intra-cellular calcium binding to the actin filament induces the sliding of the actinmyosin filament, resulting in myocardial contraction. Calcium dissociation from actin filament causes myocardial relaxation, and calcium is retaken up to SR through sarcoplasmic reticulum calcium ATPase (SERCA2a), regulated by phospholamban (PL). Intracellular calcium concentration is regulated with a calcium pump out through natrium calcium exchanger or plasma membrane calcium ATPase. Beta adrenal stimulus activates phosphokinase A, which makes for phosphorylation of calcium channel, RyR, PL, and the calcium handling cycle is activated. Each process consumes an amount of ATP, and the lack of ATP would have a harmful effect on calcium handling and reduced cardiac function.

Conclusions
The myocardial imaging with 99m Tc-sestamibi and 123 I-MIBG could visualize myocardial mitochondrial or sympathetic nervous function, that is closely related to myocardial work at the molecular level. These radionuclide imaging contribute to make for a profound understanding of the essential mechanism of pathogenesis of the failing myocardium.