Frontiers in Myocardia

Myocardial perfusion imaging can be used to diagnose and make a risk stratification of the patients with coronary artery disease. Recognizing normal subjects as definitely normal is one of the critical factors in daily practice. This article describes myocardial perfusion imaging, including technical points especially in IQ-SPECT system and a new technology, semiconductor camera.

Recent advances in gated stress myocardial perfusion imaging (MPI) have facilitated the clinical use for assessment of inducible ischemia, viability and cardiac event risks in patients with known or suspected coronary artery disease (CAD). This is because gated MPI enables simultaneous quantitative analysis of regional and global myocardial perfusion and function and because cardiac functional information improves diagnostic efficacies of conventional clinical and myocardial perfusion data in the risk-stratification of CAD patients, more definitively clarifying into a low- or high-risk category. Gated stress MPI can be also applied for early identification of patients with suspected or known CAD at a high-risk for future manifestation of heart failure (HF), for differentiation of HF etiology and for improvement in riskstratification of HF patients. In addition to clinical risks, left ventricular mechanical dyssynchrony assessed by gated MPI can be a novel powerful prognostic marker in HF patients. Thus, ECG-gating approach in stress and/or resting MPI study can contribute to better risk-stratification and to appropriate selection of prophylactic or therapeutic strategy, including optimal drugs or electrical device treatment, in a cost-effective manner in suspected or known cardiac patients.

After the Surgical Treatment for Ischemic Heart Failure (STICH) trial was introduced, it is controversial whether myocardial viability assessment is necessary or not. Myocardial viability assessment has been regarded as an essential element to select candidates for revascularization who will benefit from revascularization. However, viability determination failed to identify the patients with a differential survival benefit from CABG as compared with medical therapy alone from the sub-study of STICH trial. F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) assisted management for patients with severe left ventricular (LV) dysfunction and suspected coronary artery disease (CAD) also failed to demonstrate a significant reduction in cardiac events compared with standard care (PARR-2 study). However, a significant benefit was observed when there was adherence to PET analysis is limited to PET recommendations. Like this, when the negative report is interpreted carefully, viability assessment can assign the right patients for the right treatment. To assess viability, concomitant myocardial jeopardy is essential to evaluate. Endpoints for viability assessment were regional/global functional recovery, symptom relief, exercise capacity improvement, reduction of re-hospitalization rate, and prevention of LV remodeling after revascularization. Some beneficial effects can be obtained in patients with ischemic LV dysfunction in the presence of viability even if functional recovery was not demonstrated. The importance of viability assessment and the similarities and differences of imaging modalities are discussed in this chapter.

Cardiac single photon emission computed tomography (SPECT) / computed tomography (CT) has been introduced to provide anatomical information on such as coronary calcification combined with functional information of myocardial perfusion imaging. Fusion imaging provides accurate co-registration of coronary stenosis and perfusion abnormalities, and allows identification of reduced coronary flow reserve. This chapter shows an overview of relevant literature including clinical value in SPECT/CT.

With the increasing availability of positron emission tomography (PET) myocardial perfusion imaging (MPI), PET MPI and the absolute quantification of myocardial blood flow (MBF) have become popular in clinical settings [1]. PET MPI shows higher diagnostic accuracy than that of single-photon emission computed tomography (SPECT) and shows predictive value for cardiac events [2, 3]. Quantitative MBF assessment also provides important additional diagnostic or prognostic information over that attained through conventional visual assessment [4]. The success of MBF quantification using PET/computed tomography (CT) has increased demand for this quantitative diagnostic approach to be more accessible. In this regard, MBF quantification approaches have been developed using several other diagnostic imaging modalities including SPECT, dynamic CT perfusion imaging, and cardiac magnetic resonance (CMR). In the United States (US), the Food and Drug Administration (FDA) has approved 13N-ammonia (13N-NH3) and 82rubidium (82Rb) for clinical use [5]. The Japanese Ministry of Health, Labour and Welfare (JMHLW) approved 13N-NH3 PET MPI for diagnosis of coronary artery disease (CAD) in March 2012 but has not approved other PET MPI tracers [6, 7]. Since 13N-NH3 PET MPI will be addressed elsewhere in this e-book, this review will address the clinical aspects of PET/CT MPI using other PET flow tracers.

Rapid technological advance has brought many myocardial perfusion imaging (MPI) modalities other than myocardial single-photon emission computed tomography (SPECT) imaging. Cardiac magnetic resonance (CMR) and cardiac computer tomography (CCT) myocardial imaging give us more precise imaging with an improved special resolution which can depict subendocardial ischemia. As for CMR, T2 weighted imaging demonstrated edematous region without enhancement. Recent advances in CMR of parametric mapping technique now permit the visualization and quantification of the tissue characteristics and also give us the opportunity to guess disease process. On the other hand, SPECT fusion imaging with a coronary artery from CCT or CMR also gives us useful territorial information of coronary artery disease. In this chapter, recent advances and status of CMR and CCT imaging surrounding SPECT MPI are described.

A number of radiolabeled fatty acids have been developed to assess myocardial fatty acid metabolism. Radioactive fatty acid analogues are classified into PET and SPECT tracers; carbon-11 is the most common isotope for PET, while iodine- 123 is typically used in SPECT. The main approaches for the development in fatty acid tracers include shift from PET tracers to SPECT tracers, iodine stabilization, and prolonged retention of tracers in the myocardium. 15-(p-iodophenyl)-3-(R, S)-methyl pentadecanoic acid (BMIPP), an iodine-123 labeled branched-chain fatty acid analogue, has been widely available for routine clinical SPECT in Japan, and provides useful information on abnormal fatty acid metabolism in ischemic heart disease as well as nonischemic cardiomyopathy. This agent plays a crucial role in the diagnosis of these diseases, and the prediction of therapeutic effect and prognosis. Reduced BMIPP uptake than perfusion is often observed in ischemic heart disease such as myocardial infarction and angina pectoris. This mismatched uptake may reflect ischemic but viable myocardium, and is associated with stunned or hibernating myocardium. In addition, BMIPP can serve as a memory marker of transient myocardial ischemia because BMIPP abnormality may persist even after perfusion recovery following ischemia. On the other hand, heart-to-mediastinum (H/M) ratio is commonly used as an index of BMIPP uptake in nonischemic cardiomyopathy. This topic will overview basic principles and clinical applications of fatty acid metabolic imaging.

Impairments in the myocardial metabolism of fatty acids occurs not only as a result of ischemic insults, but also with any type of myocardial damage, such as radiation injuries and genetic alterations. Changes in myocardial metabolism persist after these events. BMIPP (I-123-labeled beta-methyl-p-iode-phenyl-pentadecanoic acid) is a unique radiopharmaceutical with the ability to image changes in myocardial fatty acid metabolism. Therefore, BMIPP has been widely used in the diagnosis and risk stratification of ischemic heart diseases, cardiomyopathies, and other disease conditions in Japan since its introduction to the commercial market in 1993. The main clinical target is the detection of severe ischemia and a damaged myocardium due to acute and chronic coronary artery diseases without a stress test. A recent study on BMIPP in a population of hemodialysis patients revealed that it also has potential as an important tool for managing and triaging patients with a poor prognosis in this specific population group. Furthermore, it is useful for differential diagnoses and prognostic assessments of cardiomyopathies, such as hypertrophic, dilated, and Takotsubo cardiomyopathies. The clinical utility of BMIPP has recently expanded to radiation injuries, chronic thromboembolism pulmonary hypertension (CTEPH), triglyceride deposit cardiomyovasculopathy (TGCV), and mitochondrial cardiomyopathy. The proper use of BMIPP provides important information that cannot be obtained using myocardial perfusion imaging (MPI). BMIPP; more than meets the MPI.

Heart failure has become a worldwide pandemic, with high morbidity and mortality, and also high costs. While better therapies are improving outcomes, many of the treatments are invasive and expensive, particularly cardiac implantable electronic devices (CIEDs). As the effectiveness of many pharmacologic therapies are attributed to their addressing the neurohormonal pathophysiology underlying heart failure, one would expect that using CIEDs based on neurohormonal parameters would provide more effective use of them. An important component of the neurohormonal system is cardiac adrenergic innervation that can be imaged with single photon radiotracers such as iodine-123 metaiodobenzylguanidine (¹²³I-mIBG) and analogous positron emission (PET) tracers such as carbon-11-metahydroxyephedrine (11C-HED). Adrenergic imaging has consistently been shown to effectively risk stratify patients with heart failure with reduced ejection fraction (HFrEF), and it does so independently of, and in many cases better than, customarily used parameters. In addition, adrenergic imaging has been shown to effectively and independently stratify HFrEF patients in terms of the risk of a lethal ventricular arrhythmic event. For therapeutic guidance, while adrenergic imaging is unlikely to influence institution of guidelines directed pharmacologic treatments, there is much evidence of a potential to help guide use of CIEDs such as biventricular pacemakers for cardiac resynchronization therapy (CRT), ventricular assist devices for end-stage HFrEF (LVAD), and implantable cardioverter defibrillators (ICDs). In particular, ¹²³I-mIBG imaging parameters appear to follow a patient’s clinical response to CRT and perhaps could better identify which patients are more likely to benefit. ¹²³I-mIBG imaging parameters, by identifying when pharmacologic therapy is failing, could show earlier in the disease course when LVAD would be beneficial, and then later help determine when or if patients who already have the device have achieved reverse ventricular remodeling sufficient to consider LVAD explantation. Finally, evidence indicates that adrenergic imaging should be able to more effectively guide use of ICDs than current recommendations that are based largely on ejection fraction, with imaging especially able to identify patients who are very unlikely to benefit from this device that has underappreciated morbidities. In addition, with regard to addressing ventricular arrhythmias, there are studies reporting benefits of adrenergic imaging for guidance of invasive electrophysiological therapeutic procedures. Thus, while CIEDs have provided tremendous benefit to people with advanced heart failure, with technologic advances continuously occurring, radionuclide adrenergic imaging shows much promise in more effectively guiding use of these devices.

Although the guidelines of the Japanese Circulation Society recommend Iodine-123 meta-iodobenzylguanidine (123I-MIBG) myocardial scintigraphy in patients with heart failure, this scintigraphy can be applied to evaluate cardiac sympathetic activity in hypertrophic cardiomyopathy (HCM) and takotsubo syndrome (TTS). Increased cardiac sympathetic activity in HCM is associated with the various clinical features, the advancement of disease stage, and the prognosis. However, it has not been fully studied whether this neurotransmitter imaging function as a monitor of the therapeutic effect in HCM. 123I-MIBG myocardial scintigraphy has been taken an important role to explore the underlying pathophysiological mechanism in TTS. TTS is a novel cardiac syndrome involving acute onset of ST-segment elevation on electrocardiography, mimicking acute myocardial infarction without coronary artery flow limitation. Although over 25- years have passed since the first description, the details of the underlying pathophysiology are still unclear. Of great interest now is whether it could be utilized to stratify the cardiac risk in patients with TTS using 23I-MIBG myocardial scintigraphy. In this chapter, we focus on the clinical value of 123I-MIBG myocardial scintigraphy in these patients.

A heart is controlled by sympathetic and parasympathetic nerve system. The synapse mediator of sympathetic nerve ending is norepinephrine, and the mediator of parasympathetic nerve ending is acetylcholine. In the case of heart failure, infarction or various heart diseases, the abnormality of cardiac sympathetic nerve appears. Iodine- 123 metaiodobenzylguanidine (¹²³I-MIBG) is widely used for radiopharmaceutical in the world. ¹²³I-MIBG is proven as a specific radiolabeled tracer of sympathetic innervation heart because of high accumulation ratio compared with normal sympathetic nerve heart. The material is taken up in a sympathetic nerve ending and stored in synapse granular vesicles like uptake-mechanism of norepinephrine. Cardiovascular diseases have a relation with activity of the sympathetic cardiac nerves. To evaluate cardiac sympathetic activity, ¹²³I-MIBG scintigraphy is commonly used. ¹²³I-MIBG scintigraphy is performed at 10 to 15 minutes (early image) and 3 to 4 hours (delayed image) after intravenous injection. Cardiac ¹²³I-MIBG uptake is commonly assessed by viewing the planar images. ¹²³I-MIBG SPECT has been used to evaluate regional denervation and for better quantification of the size and severity of innervation abnormalities. Therefore, ¹²³I-MIBG scintigraphy is very useful and widely available nuclear imaging method for assessing myocardial sympathetic innervation.

The heart-to-mediastinum ratio (HMR) in planar images has been used for the evaluation of cardiac ¹²³I-meta-iodobenzylguanidine (MIBG) uptake. However, the HMR values are influenced by both collimators and the cardiac and mediastinal regions of interests (ROI). Two technical developments in semi-automated ROI setting software and a calibration method for HMR values were described in this article.

Arteriosclerosis is a chronic disease and is related to infectious contributing factors. A hybrid SPECT/CT system may provide subclinical information of atherosclerosis noninvasively. The combined diagnosis of coronary artery calcification and myocardial perfusion imaging can be effectively used for the patients’ monitoring and aggressive risk factor modification as well as optimal medical therapy. FDG PET/CT was employed to evaluate the inflammation of the vessels. This article aims at providing an updated overview about diagnosis of atherosclerosis by nuclear cardiology technique.

Takotsubo syndrome is characterized by a transient reversible left ventricular dysfunction. Takotsubo syndrome has been associated with different neurological conditions. The heart-to-mediastinum ratio of MIBG was decreased and acute washout rate was increased in the acute phase of Takotsubo syndrome extended abnormal findings of ¹²³I-BMIPP. Such information by cardiac metabolism imaging can be used as an important tool for detecting myocardial injury and diagnosing disease. This article aims at providing an updated overview about diagnosis of Takotsubo syndrome by nuclear cardiology technique.

The recent development of noninvasive radionuclide and hybrid imaging systems may promote preclinical cardiovascular research. Molecular imaging advances beyond the traditional imaging paradigm of detecting morphological contrasts and aims to explore the physiological and pathological molecular processes at cellular and subcellular levels within intact living subjects. Molecular imaging typically uses targeted tracers that bind specific molecular targets with high affinity. Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) provide distinct advantages over morphological imaging modalities regarding the detection of signals on a molecular level. Monitoring of small rodent animal models of cardiac diseases utilizing noninvasive imaging is a unique approach and is essential to further understand the dynamic processes of diseases. Here, we review the applications of SPECT and PET in small animal research.