• Case report
• Coronary artery disease
• Energy metabolism
• NH3-PET
• Regenerative medicine
• Tc-99m MIBI scintigraphy

• 99mTc-labeled tracer
• Cardiac sarcoidosis
• FDG PET
• SPECT
• Washout

• [18F]‐fluorodeoxyglucose
• [99mTc]‐sestamibi
• cardiomyopathy
• imaging
• myocardial infarction
• positron emission tomography

• R41 HL140919 NHLBI NIH HHS
• National Heart, Lung, and Blood Institute

• Atrophy
• Diabetes
• Exercise intolerance
• HFrEF
• Mitochondrial dysfunction

• Exercise intolerance
• HFrEF
• Mitochondrial dysfunction
• OPA1
• Sex

• cardiac function
• protonophore
• substrate uptake

Sudden unexpected death in epilepsy (SUDEP) is the major cause of death in those patients suffering from refractory epilepsy (RE), with a 24-fold higher risk relative to the normal population. SUDEP risk increases with seizure frequency and/or seizure-duration as in RE and Status Epilepticus (SE). P-glycoprotein (P-gp), the product of the multidrug resistant ABCB1-MDR-1 gene, is a detoxifying pump that extrudes drugs out of the cells and can confer pharmacoresistance to the expressing cells. Neurons and cardiomyocytes normally do not express P-gp, however, it is overexpressed in the brain of patients or in experimental models of RE and SE. P-gp was also detected after brain or cardiac hypoxia. We have previously demonstrated that repetitive pentylenetetrazole (PTZ)-induced seizures increase P-gp expression in the brain, which is associated with membrane depolarization in the hippocampus, and in the heart, which is associated with fatal SE. SE can produce hypoxic-ischemic altered cardiac rhythm (HIACR) and severe arrhythmias, and both are related with SUDEP. Here, we investigate whether SE induces the expression of hypoxia-inducible transcription factor (HIF)-1α and P-gp in cardiomyocytes, which is associated with altered heart rhythm, and if these changes are related with the spontaneous death rate. SE was induced in Wistar rats once a week for 3 weeks, by lithium-pilocarpine-paradigm. Electrocardiograms, HIF-1α, and P-gp expression in cardiomyocytes, were evaluated in basal conditions and 72 h after SE. All spontaneous deaths occurred 48 h after each SE was registered. We observed that repeated SE induced HIF-1α and P-gp expression in cardiomyocytes, electrocardiographic (ECG) changes, and a high rate of spontaneous death. Our results suggest that the highly accumulated burden of convulsive stress results in a hypoxic heart insult, where P-gp expression may play a depolarizing role in cardiomyocyte membranes and in the development of the ECG changes, such as QT interval prolongation, that could be related with SUDEP. We postulate that this mechanism could explain, in part, the higher SUDEP risk in patients with RE or SE.

• HIF-1α
• P-glycoprotein
• QT prolongation
• SUDEP
• Status Epilepticus
• cardiomyocytes
• hypoxia

The present study aimed to discuss the role of mitochondrion in cardiac function and disease. The mitochondrion plays a fundamental role in cellular processes ranging from metabolism to apoptosis. The mitochondrial-targeted molecular imaging could potentially illustrate changes in global and regional cardiac dysfunction. The collective changes that occur in mitochondrial-targeted molecular imaging probes have been widely explored and developed. As probes currently used in the preclinical setting still have a lot of shortcomings, the development of myocardial metabolic activity, viability, perfusion, and blood flow molecular imaging probes holds great potential for accurately evaluating the myocardial viability and functional reserve. The advantages of molecular imaging provide a perspective on investigating the mitochondrial function of the myocardium in vivo noninvasively and quantitatively. The molecular imaging tracers of single-photon emission computed tomography and positron emission tomography could give more detailed information on myocardial metabolism and restoration. In this study, series mitochondrial-targeted ^99mTc-, ¹²³I-, and ¹⁸F-labeled tracers displayed broad applications because they could provide a direct link between mitochondrial dysfunction and cardiac disease.

Previous studies showed that autoantibodies (M₂-AA) against the second extracellular loop of M₂ muscarinic receptor (M₂AChR-el2) from dilated cardiomyopathy (DCM) serum could induce DCM-like morphological changes in mice hearts. However, the effects of M₂-AA on the cardiac function during the process of DCM and the potential mechanisms are not fully known. The present study was designed to dynamically observe the cardiac function, mitochondrial changes, and M₂ receptor binding characteristics in rats long-term stimulated with M₂-AA in vivo.

M₂-AA-positive model was established by actively immunizing healthy male Wistar rats with synthetic M₂AChR-el2 peptide for 18 months. Meanwhile, vehicle group rats were administrated with physiological saline. The change of mitochondrial membrane potential (ΔΨm) was detected by radionuclide imaging. The ultrastructure of mitochondria was observed under electron microscopy. The M₂ receptor binding characteristics were determined by radioactive ligand binding assay.

After immunization for 12 months, compared with vehicle group, M₂AChR-el2-immunized rats showed decreased myocardial contractility and cardiac diastolic function evidenced by declined maximal rate of rise of ventricular pressure and increased left ventricular end-diastolic pressure, respectively. Additionally, mitochondrial swelling and vacuolation were observed. At 18 months, M₂AChR-el2-immunized rats manifested significant decreased cardiac systolic and diastolic function and pathological changes such as enlargement of right ventricular cavity and wall thinning; and the mitochondrial damage was aggravated. Furthermore, the M₂ receptor maximum binding capacity (B_max) of the M₂AChR-el2-immunized rats significantly decreased, while the M₂ receptor dissociation constant (K_d) was increased.

Our study suggested that long-term stimulation with M₂-AA leaded to the ventricular dilatation and gradual deterioration of cardiac dysfunction. Mitochondrial damage and the down-regulation of M₂ receptor density and affinity may be involved in the process.

• Animals
• Autoantibodies/immunology
• Cardiomyopathy, Dilated/immunology
• Cardiomyopathy, Dilated/metabolism
• Cardiomyopathy, Dilated/pathology
• Cardiomyopathy, Dilated/physiopathology
• Heart/physiopathology
• Humans
• Male
• Membrane Potential, Mitochondrial
• Mitochondria/immunology
• Mitochondria/metabolism
• Mitochondria/pathology
• Myocardium/immunology
• Myocardium/metabolism
• Myocardium/pathology
• Rats, Wistar
• Receptor, Muscarinic M2/analysis
• Receptor, Muscarinic M2/immunology
• Receptor, Muscarinic M2/metabolism

• Heart failure
• Mitochondrial function
• Peripheral muscle
• Tc-MIBI

• Arrhythmia management
• Arrhythmia mechanisms
• Diabetic cardiomyopathy
• Mitochondrial DNA mutation
• Mitochondrial cardiomyopathy
• Mitochondrial syndrome

• Arrhythmias, Cardiac
• Cardiomyopathies
• DNA, Mitochondrial/genetics
• Humans
• Mitochondrial Diseases
• Mutation

Hepatic mitochondrial dysfunction has been implicated in pathological conditions leading to non-alcoholic steatohepatitis (NASH). Technetium-99 m-2-methoxyisobutyl-isonitrile (^99mTc-MIBI), a lipophilic cationic myocardial perfusion agent, is retained in the mitochondria depending on membrane potential. The aim of this study was to investigate the feasibility of ^99mTc-MIBI for evaluating the hepatic mitochondrial dysfunction induced by methionine-choline-deficient (MCD) diet in mice.

Male C57Black6J/jcl mice were fed a MCD diet for up to 4 weeks. SPECT scan (N =6) with ^99mTc-MIBI was performed at 2 and 4 weeks after MCD diet. Mice were imaged with small-animal SPECT/CT under isoflurane anesthesia. Radioactivity concentrations of the liver were measured, and the time of maximum (T_max) and the elimination half-life (T_1/2) were evaluated. After SPECT scan, liver histopathology was analyzed to evaluate steatosis and inflammation. Non-alcoholic fatty liver disease (NAFLD) activity score was obtained from the histological score of hepatic steatosis and inflammation. Blood biochemistry and hepatic ATP content were also measured (N =5 to 6).

Plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were significantly elevated at 2 and 4 weeks after MCD diet. A decrease in hepatic ATP content was also observed in MCD-fed mice. ^99mTc-MIBI SPECT imaging clearly showed the decrease of hepatic ^99mTc-MIBI retention in MCD-fed mice compared to control mice. T_1/2 after ^99mTc-MIBI injection was significantly decreased in the liver of MCD-fed mice (control, MCD 2 weeks, and MCD 4 weeks, T_1/2 = 57.6, 37.6, and 19.8 min, respectively), although no change in T_max was observed in MCD-fed mice. SPECT data and histological score showed that the negative correlation (r = −0.74, p <0.05) between T_1/2 and NAFLD activity score was significant.

Hepatic ^99mTc-MIBI elimination was increased with increase in NAFLD activity score (NAS) in mice fed MCD diet for 2 and 4 weeks. These results suggest that ^99mTc-MIBI SPECT imaging might be useful for detecting hepatic mitochondrial dysfunction induced by steatosis and inflammation such as NAFLD or NASH.

The recent development of cardiac magnetic resonance (CMR) techniques has allowed detailed analyses of cardiac function and tissue characterization with high spatial resolution. We review characteristic CMR features in ischemic and non-ischemic cardiomyopathies (ICM and NICM), especially in terms of the location and distribution of late gadolinium enhancement (LGE). CMR in ICM shows segmental wall motion abnormalities or wall thinning in a particular coronary arterial territory, and the subendocardial or transmural LGE. LGE in NICM generally does not correspond to any particular coronary artery distribution and is located mostly in the mid-wall to subepicardial layer. The analysis of LGE distribution is valuable to differentiate NICM with diffusely impaired systolic function, including dilated cardiomyopathy, end-stage hypertrophic cardiomyopathy (HCM), cardiac sarcoidosis, and myocarditis, and those with diffuse left ventricular (LV) hypertrophy including HCM, cardiac amyloidosis and Anderson-Fabry disease. A transient low signal intensity LGE in regions of severe LV dysfunction is a particular feature of stress cardiomyopathy. In arrhythmogenic right ventricular cardiomyopathy/dysplasia, an enhancement of right ventricular (RV) wall with functional and morphological changes of RV becomes apparent. Finally, the analyses of LGE distribution have potentials to predict cardiac outcomes and response to treatments.

• Cardiomyopathy
• Cardiac magnetic resonance
• Late gadolinium enhancement
• Cardiac function
• Clinical features
• Prognosis

• Biological Transport
• Case-Control Studies
• Coronary Angiography
• Coronary Artery Disease/diagnostic imaging
• Coronary Artery Disease/metabolism
• Coronary Artery Disease/physiopathology
• Coronary Circulation
• Female
• Humans
• Male
• Middle Aged
• Myocardium/metabolism
• Perfusion
• Radionuclide Imaging
• Rest
• Technetium Tc 99m Sestamibi/metabolism

Autophagy is important in cells for removing damaged organelles, such as mitochondria. Insufficient autophagy plays a critical role in tissue injury and organ dysfunction under a variety of pathological conditions. However, the role of autophagy in nonlethal traumatic cardiac damage remains unclear. The aims of the present study were to investigate whether nonlethal mechanical trauma may result in the change of cardiomyocyte autophagy, and if so, to determine whether the changed myocardial autophagy may contribute to delayed cardiac dysfunction. Male adult rats were subjected to nonlethal traumatic injury, and cardiomyocyte autophagy, cardiac mitochondrial function, and cardiac function in isolated perfused hearts were detected. Direct mechanical traumatic injury was not observed in the heart within 24 h after trauma. However, cardiomyocyte autophagy gradually decreased and reached a minimal level 6 h after trauma. Cardiac mitochondrial dysfunction was observed by cardiac radionuclide imaging 6 h after trauma, and cardiac dysfunction was observed 24 h after trauma in the isolated perfused heart. These were reversed when autophagy was induced by administration of the autophagy inducer rapamycin 30 min before trauma. Our present study demonstrated for the first time that nonlethal traumatic injury caused decreased autophagy, and decreased autophagy may contribute to post-traumatic organ dysfunction. Though our study has some limitations, it strongly suggests that cardiac damage induced by nonlethal mechanical trauma can be detected by noninvasive radionuclide imaging, and induction of autophagy may be a novel strategy for reducing posttrauma multiple organ failure.

• Animals
• Apoptosis
• Apoptosis Regulatory Proteins/genetics
• Apoptosis Regulatory Proteins/metabolism
• Autophagy
• Beclin-1
• Gene Expression
• Heart Injuries/diagnostic imaging
• Heart Injuries/metabolism
• Heart Injuries/pathology
• Heart Injuries/physiopathology
• Male
• Microtubule-Associated Proteins/genetics
• Microtubule-Associated Proteins/metabolism
• Mitochondria/drug effects
• Mitochondria/metabolism
• Mitochondria/pathology
• Myocardium/metabolism
• Myocardium/pathology
• Myocytes, Cardiac/drug effects
• Myocytes, Cardiac/metabolism
• Myocytes, Cardiac/pathology
• Organ Culture Techniques
• Perfusion
• Radionuclide Imaging
• Rats
• Rats, Wistar
• Sirolimus/pharmacology
• Time Factors

• Earthquake
• Heart failure
• Japan
• Stress

Mitochondria play an important role in energy production for the cell. The proper function of a myocardial cell largely depends on the functional capacity of the mitochondria. Therefore it is necessary to establish a novel and reliable method for a non-invasive assessment of mitochondrial function and metabolism in humans. Although originally designed for evaluating myocardial perfusion, ^99mTc-MIBI can be also used to evaluate cardiac mitochondrial function. In a clinical study on ischemic heart disease, reverse redistribution of ^99mTc-MIBI was evident after direct percutaneous transluminal coronary angioplasty. The presence of increased washout of ^99mTc-MIBI was associated with the infarct-related artery and preserved left ventricular function. In non-ischemic cardiomyopathy, an increased washout rate of ^99mTc-MIBI, which correlated inversely with left ventricular ejection fraction, was observed in patients with congestive heart failure. Increased ^99mTc-MIBI washout was also observed in mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and in doxorubicin-induced cardiomyopathy. Noninvasive assessment of cardiac mitochondrial function could be greatly beneficial in monitoring possible cardiotoxic drug use and in the evaluation of cardiac damage in clinical medicine.

• 99mTc-MIBI
• cardiomyopathy
• heart failure
• ischemic heart disease
• mitochondria

This study was designed to clarify the significance of washout rate (WR) determined from ^99mTc-sestamibi myocardial scintigraphic images and the levels of cardiac enzymes in patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI).

A total of 56 consecutive patients with AMI (mean age 65.8±8.5 years), who underwent PCI on admission, were included. Cardiac enzyme, the MB isoenzyme of creatinine kinase (CK-MB), was measured every 3 h after admission. Two weeks after the onset of AMI, ^99mTc-sestamibi myocardial scintigraphy was performed at early (30 min) and delayed (4 h) phases after tracer injection. The heart-to-mediastinum ratio (H/M) and WR were calculated from the planar images.

PCI was performed at 9.4±6.0 h after the onset of AMI. In 26 patients the culprit lesion was located in the right coronary artery and in 24 patients it was located in the left anterior descending coronary artery. The peak CK-MB was 274.1±169.4 IU/L (13.5±3.9 h). The early and delayed H/Ms and WR of ^99mTc-sestamibi were 2.74±0.58, 3.00±0.70, and 58.8±10.0%, respectively. The delayed H/M was significantly correlated with the peak CK-MB (r=−0.37, p=0.005). The WR of ^99mTc-sestamibi was also significantly correlated with the peak CK-MB (r=−0.34, p=0.012).

These results suggest that the WR determined from ^99mTc-sestamibi myocardial scintigraphic images reflects the extent of myocardial damage in AMI patients.

• Diastolic function
• Metaiodobenzylguanidine
• Prognosis
• Quantitative gated single photon emission computed tomography
• β-methyl-p-iodophenyl-pentadecanoic acid

• Female
• Heart Failure/complications
• Heart Failure/diagnostic imaging
• Heart Failure/genetics
• Humans
• Hypertrophy, Left Ventricular/complications
• Hypertrophy, Left Ventricular/diagnostic imaging
• Hypertrophy, Left Ventricular/genetics
• Middle Aged
• Mitochondrial Diseases/complications
• Mitochondrial Diseases/diagnostic imaging
• Mitochondrial Diseases/genetics
• Pericardial Effusion/complications
• Pericardial Effusion/diagnostic imaging
• Pericardial Effusion/genetics
• Radionuclide Imaging
• Radiopharmaceuticals
• Technetium Tc 99m Sestamibi

• Animals
• Electron Transport Complex IV/metabolism
• Male
• Muscle, Skeletal/metabolism
• Myocardium/metabolism
• Physical Conditioning, Animal/physiology
• Radiopharmaceuticals
• Rats
• Rats, Wistar
• Technetium Tc 99m Sestamibi