Progress in nuclear cardiology: new imaging beyond perfusion and function

The rapid development of nuclear medicine instruments and the widespread availability of new radiopharmaceutical agents has created a new era of nuclear cardiology. This review will introduce new techniques beyond perfusion and function that have recently become available in Japan. Tc-99m perfusion imaging agents provide excellent myocardial perfusion images that may enhance diagnostic accuracy in the study of coronary artery disease. In addition, greater photon flux from the tracer permits simultaneous assessment of regional perfusion and function with the use of first-pass angiography or ECG-gated acquisition. In addition, Tc-99m perfusion agents are available for acute patients in emergency departments. When the tracer is administrated at both the acute and subacute phases of myocardial infarction, perfusion SPECT imaging permits accurate estimates of areas at risk and salvaged myocardium. Nuclear cardiology has progressed toward biochemical imaging in vivo. Positron emission tomography (PET) enables metabolic assessment in vivo. Preserved FDG uptake indicates ischemic but viable myocardium that is likely to improve regional dysfunction after revascularization. While FDG-PET is available only in a limited number of facilities, FDG-SPECT using ultrahigh energy collimators and branched fatty acid analog I-123 BMIPP SPECT offer potential for metabolic imaging in routine clinical settings. Less uptake of BMIPP than thallium is often observed in the ischemic myocardium and hypertrophic cardiomyopathy. Such a perfusion-metabolic mismatch as that in FDG-PET seems to be similarly observed in BMIPP SPECT. Severe ischemia is identified as reduced BMIPP uptake at rest despite normal or normalized perfusion, suggesting a significant role of BMIPP in ischemic memory imaging. I-123 MIBG uptake in the myocardium reflects adrenergic neuronal function in vivo. In the study of coronary artery disease, neuronal denervation is often observed around the infarcted myocardium and post-ischemic region as well. More importantly, reduced MIBG uptake in these patients can assess the severity of congestive heart failure. In addition, the improvement in MIBG can be seen in relation to improved patient condition following medical treatment. These new techniques will provide insights into new pathological states in ischemic heart disease and a variety of myocardial disorders. Nuclear cardiology plays an important role in selecting optimal treatments for these patients.     

Human pharmacokinetics and radiopharmacological studies of the myocardial perfusion agent: technetium (2-carbomethoxy-2-isocyano-propane)6+.

The myocardial perfusion agent technetium (2-carbomethoxy-2-isocyano-propane)6+ (99mTc-CPI) is unique from other cationic technetium isonitrile complexes in that it exhibits moderate washout from the heart and rapid hepatobiliary clearance in animal models and human volunteers. Dynamic imaging and HPLC analysis were performed in humans and guinea pigs to outline the pharmacological basis of its pharmacokinetics. Enzymatic hydrolysis of the terminal ester groups in blood was found to occur at a moderate rate producing new species that have been shown not to accumulate in heart tissue. However, after extraction by the heart, liver or kidneys, the 99mTc-CPI complex undergoes metabolism at a much slower rate than observed in the blood. Differences in hydrolysis rate and products obtained indicate separate mechanisms of hydrolysis occurring in blood and other organs. It is proposed that the heart washout occurring after hydrolysis produces a neutral compound which is no longer retained by the negative cytosolic and mitochondrial membrane potentials in myocardial tissue.     

Effect of mitochondrial and plasma membrane potentials on accumulation of hexakis (2-methoxyisobutylisonitrile) technetium(I) in cultured mouse fibroblasts

Hexakis(2-methoxyisobutylisonitrile) technetium(I) (Tc-MIBI) is representative of a class of 99mTc-based lipophilic cationic myocardial perfusion imaging agents. To test the hypothesis that the mechanism of cellular uptake may involve distribution across biologic membranes in response to membrane potential, Tc-MIBI net uptake and retention were determined in cultured mouse BALB/c 3T3, NIH 3T3, and v-src transformed NIH 3T3 fibroblasts as well as in cultured chick embryo heart cells. Isovolumic depolarization of plasma membrane potentials with 130 mM K 20 mM Cl buffer decreased Tc-MIBI net cell uptake in all preparations. In BALB/c 3T3 cells, depolarizing mitochondrial membrane potential with valinomycin in high K buffer or with the protonophore CCCP inhibited net uptake and retention of Tc-MIBI while hyperpolarizing mitochondrial and plasma membrane potentials with the K+/H+ exchanger nigericin increased Tc-MIBI net uptake. These results indicated that net cellular uptake and retention of Tc-MIBI in fibroblasts were determined by both mitochondrial and plasma membrane potentials; the gamma-emitting properties of Tc-MIBI may therefore raise the possibility of monitoring membrane potential in vivo.     

Evaluation of novel cationic (99m)Tc-nitrido complexes as radiopharmaceuticals for heart imaging: improving liver clearance with crown ether groups

This report describes the evaluation of a series of novel cationic (99m)Tc-nitrido complexes, [(99m)TcN(DTC)(PNP)]+ (DTC = crown ether-containing dithiocarbamates; PNP = bisphosphine), as potential radiotracers for myocardial perfusion imaging. Synthesis of cationic (99m)Tc-nitrido complexes was accomplished in two steps according to literature methods. Biodistribution studies were performed in rats. Planar images of Sprague-Dawley rats administered with 15+/-2 MBq of cationic (99m)Tc radiotracer were obtained using a PhoGama large field-of-view Anger camera. Samples from both urine and feces were analyzed by a reversed-phase radio-HPLC method. Results from biodistribution studies showed that most of the cationic (99m)Tc-nitrido complexes have a high initial heart uptake with a long myocardial retention. They also show a rapid clearance from the liver and lungs. Cationic complexes [(99m)TcN(L2)(L6)]+ and [(99m)TcN(L4)(L6)]+ show heart/liver ratios four to five times better than that of (99m)Tc-sestamibi due to their much faster liver clearance. Their heart uptake and heart/liver ratio are comparable to that of (99m)TcN-DBODC5 within the experimental error. These findings have been confirmed by the results from imaging studies. Radio-HPLC analysis of urine and feces samples indicated that there was very little metabolism of cationic (99m)Tc-nitrido complexes in rats under anesthesia. The key finding of this study is that lipophilicity remains the most important factor affecting both heart uptake and target-to-background (T/B) ratios. Crown ethers are very useful functional groups to improve the liver clearance of cationic (99m)Tc-nitrido complexes. It is the combination of the appropriate DTCs and bisphosphines that results in cationic (99m)Tc-nitrido complexes with high heart uptake and fast clearance from the liver at the same time. The fast liver clearance of [(99m)TcN(L2)(L6)]+ and [(99m)TcN(L4)(L6)]+ suggests that they might be used to obtain clinically useful images as early as 30 min postinjection. [(99m)TcN(L2)(L6)]+ and [(99m)TcN(L4)(L6)]+ are very promising candidates for further evaluation in more extensive preclinical animal models.     

In vivo cardiac 1H-MRS in the mouse.

The mouse is the predominant animal model to study the effect of gene manipulations. Imaging techniques to define functional effects on the heart caused by genomic alterations are becoming increasingly routine in mice, yet methods for in vivo investigation of metabolic phenotypes in the mouse heart are lacking. In this work, cardiac 1H-MRS was developed and applied in mouse hearts in vivo using a single-voxel technique (PRESS). In normal C57Bl/6J mice, stability and reproducibility achieved by dedicated cardiac and respiratory gating was demonstrated by measuring amplitude and zero-order phase changes of the unsuppressed water signal. Various cardiac metabolites, such as creatine, taurine, carnitine, or intramyocardial lipids were successfully detected and quantified relative to the total water content in voxels as small as 2 microl, positioned in the interventricular septum. The method was applied to a murine model of guanidinoacetate N-methyltransferase (GAMT) deficiency, which is characterized by substantially decreased myocardial creatine levels. Creatine deficiency was confirmed noninvasively in myocardium of anesthetized GAMT-/- mice. This is the first study to report the application of cardiac 1H-MRS in mice in vivo.     

Use of 11C-triphenylmethylphosphonium for the evaluation of membrane potential in the heart by positron-emission tomography

The membrane potential in cells can be estimated by electrophysiological techniques and biomedical methods using lipophilic cations labelled with 14C. However, these techniques cannot be applied to the human heart. In this study a lipophilic cation, triphenylmethylphosphonium (TPMP), was labelled with carbon-11 with the purpose of investigating its suitability for the estimation of membrane potential in vivo. A biodistribution study in mice and rats showed significant uptake of the cation in the heart a few minutes after IV injection which remained constant for 60 min. In vivo study by positron-emission tomography showed that after IV injection of 11C-TPMP in the dog, activity rose almost immediately in the myocardium and then remained constant for 60 min. A rapid injection of KCl (greater than 40 mg/kg) 20 min after injection of 11C-TPMP led to an instantaneous fall in myocardial 11C-TPMP concentration. Membrane potential (delta psi), calculated from the TPMP distribution ratio between intracellular and plasma water space by the Nernst equation, was estimated at -148.1 +/- 6.0 mV for the dog heart. This value reflected both cell membrane potential and mitochondrial membrane potential and, thus, the energy state of the myocardial cells.     

Clinical application of 99mTc-SQ30,217 myocardial imaging--a study of pharmacokinetics and imaging time

99mTc-SQ30217 555 MBq (15 mCi) was intravenously injected to 6 healthy subjects to study its safety, pharmacokinetics and the imaging time. Neither side effects nor abnormalities in physical findings, hemato-biochemical tests, urinary test, etc. caused by this agent were observed in any case and its safety was suggested. Radiation dose estimates over the entire body was 4.88 mGy/1,110 MBq (0.488 rad) and that over the major organs was less than 10 mGy and they were within the allowable ranges. 99mTc-SQ30217 showed biphasic disappearance curve in blood with the half-life of alpha-phase 0.02 hour and that of beta-phase 10.14 hours. 99mTc-SQ30217 was considered to show characteristic pharmacokinetics in that the myocardial accumulation was high in an early stage of the administration, but it rapidly decreased. Both heart to liver ratio and heart to lung ratio were high within 10 minutes, but they decreased after 15 minutes. As a result of SPECT imaging of 4 patients with ischemic cardiac disease, the images obtained with 99mTc-SQ30217 at an early period after the administration was as good as those with 201Tl and the appearance of defects in the images with both agents was similar. 99mTc-SQ30217 was considered to be sufficiently useful as a 99mTc-labelled agent for myocardial blood flow.     

正电子核素心肌代谢显像剂的研究进展

心肌细胞利用葡萄糖、脂肪酸、乳酸及酮体等多种底物产生能量,以维持自身的正常舒缩功能。心肌细胞能量代谢的异常改变与多种心脏疾病相关,如心肌缺血和心力衰竭等。放射性核素显像作为一种无创性功能检查方法,能够用于心肌细胞代谢状况的评价。放射性核素心肌代谢显像剂是由放射性核素标记的心肌代谢底物及其类似物,在临床上分为氧代谢显像剂...     

Comparative myocardial uptake characteristics of hexakis (alkylisonitrile) technetium(I) complexes. Effect of lipophilicity

Hexakis (alkylisonitrile) technetium(I) complexes are a new class of cationic, lipophilic myocardial perfusion imaging agents. To further evaluate the effect of lipophilicity on myocardial uptake characteristics, the authors systematically synthesized and tested Tc-isonitrile complexes of varying lipophilicity in both cellular and whole animal systems. In chick heart cells in monolayer culture, cellular plateau level uptake in general correlated with lipophilicity of the complexes (determined by reverse phase high performance liquid chromatography) (r = .71) as well as with scintigraphic intensity of imaged rabbit hearts (r = .91). Exceptions to this trend indicated that additional factors such as size of the complex and form of the terminal alkyl chain branching also may have influenced uptake. The data indicated that neither the lipophilic properties nor the cation charge alone were sufficient to predict myocardial uptake. In addition, intravenous injection of complexes into rabbits showed optimal myocardial images with agents of intermediate lipophilicity. Results indicated that, following intravenous administration, complexes of low lipophilicity yielded suboptimal myocardial images because of low heart cell uptake, whereas complexes of high lipophilicity yielded poor relative myocardial visualization because of excessive binding to additional organs and compartments.     

New Ga derivatives of the H2dedpa scaffold with improved clearance and persistent heart uptake

Recent advances in positron emission tomography (PET)/computed tomography have fueled the development of new PET-isotope-based agents for myocardial perfusion imaging. (68)Ga, a generator-produced PET isotope, is an attractive radionuclide for developing a (68)Ga-based cardiac imaging agent. We have synthesized seven new chelate systems based on our previously reported 1,2-[{6-(carboxylato-)pyridin-2-yl}methylamino]ethane (H(2)dedpa) scaffold. These ligands form lipophilic, cationic complexes upon coordination of (67/68)Ga(III) under mild, direct labeling conditions within 10 min at room temperature. The corresponding cold complexes were also synthesized, and the solid-state structure of one of the complexes, [Ga(19)][ClO(4)], was determined. All compounds were investigated for in vitro stability against transferrin, and log P values were determined. In vivo biodistribution studies in mice showed that four of the seven investigated complexes provided greatly improved blood, lung and kidney clearance compared to previously reported derivatives. Two complexes with log P>1.1 exhibited persistent heart uptake over the course of 2 h above 1% ID/g.     

Kinetic characterization of a novel cationic <Superscript>99m</Superscript>Tc(I)-tricarbonyl complex, <Superscript>99m</Superscript>Tc-15C5-PNP,for myocardial perfusion imaging

Background  

Intense liver uptake of ^99mTc-sestamibi (MIBI) often interferes with visualization of myocardial perfusion in the inferior wall of the left ventricle. To develop improved myocardial perfusion agents, crown ether-containing dithiocarbamates and bisphosphines have been introduced in recent years. This study was designed to investigate the myocardial imaging properties and in vivo kinetics of a cationic ^99mTc(I)-tricarbonyl complex, ^99mTc-15C5-PNP, in comparison with MIBI.     

Contrast-enhanced magnetic resonance imaging in the assessment of myocardial infarction and viability

Contrast-enhanced magnetic resonance imaging (MRI) can be used to visualize the transmural extent of myocardial infarction with high spatial resolution. The aim of this review is to provide an overview of the use of contrast-enhanced MRI for characterization of ischemic myocardial injury in comparison to other imaging methods and its relevance in clinical syndromes related to coronary artery disease. Infarcted myocardium appears hyperenhanced compared with normal myocardium when imaged by a delayed-enhancement MRI technique with the use of an inversion-prepared T₁-weighted sequence after injection of gadolinium chelates, such as gadolinium-diethylenetriamine pentaacetic acid. Experimental and clinical studies indicate that the extent of delayed enhancement is reproducible and closely correlates with the size of myocardial necrosis or infarct scar as determined by established in vitro and in vivo methods. Furthermore, MRI appears to be more sensitive than other imaging methods in detecting small subendocardial infarctions. The transmural extent of delayed enhancement potentially predicts functional outcome after revascularization in acute myocardial infarction and chronic ischemic heart disease, indicating that it can accurately discriminate between infarction and dysfunctional but viable myocardium. Further experience from clinical trials is needed to understand the association of delayed enhancement with clinical outcomes. Financial assistance was provided by EC-FP6-project DiMl (LSHB-CT-2005-512146) and Finnish Foundation for Cardiovascular Research.     

Technetium mixed-ligand complexes containing bidentate phosphines and monodentate thiol ligands. Preparation,in vitro data and detection of a certain heart affinity

TcO₄⁻ is reduced by a mixture of phosphine and thiol ligands to yield cationic complexes in which both ligands are coordinated. Polar and lipophilic properties of the products can easily be controlled by variation of either of the ligands. The yields are always high. Potential heart affinity of the compounds was screened by means of the isolated perfused rat heart. Some of the complexes show significant heart uptake and good retention in the myocardial tissue.     

Gadolinium phosphonates as MR imaging contrast agents: Physiologic effects in rabbit hearts

The hemodynamic effects of the diphosphonate terminus of a new infarct-avid magnetic resonance (MR) imaging agent, gadolinium-DTPA (diethylenetriamine-pentaacetic acid) HPDP (1-hydroxo-3-aminopropane-1,1-diphosphonate), and HEDP (hydroxyethyl-1,1-diphosphonate) (a simple diphosphonate terminus model) have been evaluated at MR imaging doses in both isolated and intact rabbit hearts. Rapid injections of the sodium salt of the diphosphonates reversibly depressed left ventricular developed pressure and its first derivative (dP/df) but did not affect the in vivo heart rate. Hemodynamic depression was prevented by the co-administration of two equivalents of calcium ion per diphosphonate terminus in the isolated heart and by either slow infusion or co-administration of one equivalent of calcium ion per diphosphonate terminus in the in vivo heart. Therefore, if these agents are to be used in MR imaging of acute myocardial infarction, appropriate measures should be taken to prevent negative inotropic effects.     

Use of 11C-triphenylmethylphosphonium for the evaluation of membrane potential in the heart by positron-emission tomography

The membrane potential in cells can be estimated by electrophysiological techniques and biomedical methods using lipophilic cations labelled with ¹⁴C. However, these techniques cannot be applied to the human heart. In this study a lipophilic cation, triphenylmethylphosphonium (TPMP), was labelled with carbon-11 with the purpose of investigating its suitability for the estimation of membrane potential in vivo. A biodistribution study in mice and rats showed significant uptake of the cation in the heart a few minutes after IV injection which remained constant for 60 min. In vivo study by positron-emission tomography showed that after IV injection of ¹¹C-TPMP in the dog, activity rose almost immediately in the myocardium and then remained constant for 60 min. A rapid injection of KCl (>40 mg/kg) 20 min after injection of ¹¹C-TPMP led to an instantaneous fall in myocardial ¹¹C-TPMP concentration. Membrane potential (), calculated from the TPMP distribution ratio between intracellular and plasma water space by the Nernst equation, was estimated at-148.1±6.0 mV for the dog heart. This value reflected both cell membrane potential and mitochondrial membrane potential and thus, the energy state of the myocardial cells.     

Cardiac 17O MRI: Toward direct quantification of myocardial oxygen consumption

A new ¹⁷O‐labeled blood contrast agent was injected intravenously in control dogs. Electrocardiogram (ECG)‐triggered myocardial T₁ρ imaging was performed to obtain spin‐locking T₁ρ‐weighted myocardial signals for the detection of resultant metabolite H₂¹⁷O water in the heart. Bolus and slow injection methods of various doses of the ¹⁷O‐labeled and ¹⁶O‐labeled agents were carried out in order to evaluate the sensitivity of this method and determine the optimal injection method. Bolus injection provided approximately 1% signal reduction, whereas slow injection with larger amount of agent yielded 11.9 ± 0.6% signal reduction. Myocardial oxygen consumption rate was determined by a technique to quantify cerebral oxygenation consumption rate previously developed in ¹⁷O brain studies. With either injection method, myocardial oxygen consumption rate at rest was 5.0 – 5.6 μmol/g/min. Therefore, it appears feasible to detect metabolically generated HO water in vivo in the heart, using the ¹⁷O‐labeled blood tracer. Myocardial oxygen consumption rate can then be quantified in vivo, which may open new doors for the assessment of myocardial metabolism. Magn Reson Med 63:1442–1447, 2010. © 2010 Wiley‐Liss, Inc.     

Reduction of the influence of the liver uptake to the myocardial uptake on technetium-99m myocardial SPECT; usefulness and problems of a mask processing method]

The aim of this study is to evaluate the usefulness of a mask processing method for obtaining the true myocardial tracer distribution by eliminating the influence of the liver uptake to the myocardial uptake on myocardial SPECT images by using technetium-99m (99mTc) blood flow agents. A SPECT imaging was performed with a two-head SPECT system (GCA-7200A/DI) in both phantom and clinical studies. The mask processing method was applied to the reconstructed and projection images. The phantom consisted of heart, lung, liver and spine. A defect was located in the inferior wall of the left ventricle and other parts of the heart and liver were filled with 99mTc solution. For clinical study 10 patients with difficulty in the interpretation of the inferior wall were selected for the evaluation of usefulness of the mask method. In the phantom study, the mask processing method applied to the reconstructed images was able to remove the overlapped liver from the heart, but was not able to remove the influence of the liver uptake to the myocardial uptake. Nevertheless, the mask processing method applied to the projection images successfully eliminated not only the overlapped liver but also the influence of the liver uptake to the myocardial uptake. In the clinical study, the liver uptake could be removed from the uptake in the inferior wall in 8 of 10 patients with the mask processing methods. In 2 patients, the overlapped liver uptake could not be eliminated from the uptake in the inferior wall because the distance between the liver and heart was too short. The mask processing method applied to the projection images was thought to be superior to that applied to the reconstruction images in both phantom and clinical studies. The mask processing method, especially applied to the projection images, seems to be useful for the elimination of the liver uptake from the inferior wall of the myocardium on myocardial SPECT images using 99mTc blood flow agents.     

Thallium-201: non-invasive determination of the regional distribution of cardiac output

Sapirstein (1) employed cationic radiopotassium to determine the fractional distribution of cardiac output to several organs. Thallium-201 can substitute for radiopotassium in myocardial imaging, and was evaluated in the present studies to determine the distribution of cardiac output in the anesthetized dog in comparison with tracer microspheres, both under control circumstances and following the infusion of norepinephrine in a dose sufficient to raise the blood pressure 20 mm Hg above control levels. The concentrations of thallium-201 and microspheres were similar in the heart, kidney, thyroid, and skeletal muscle in both control and norepinephrine-treated animals (r=0.93). Thallium concentration in the liver and lung exceeded that of microspheres, however, and probably is not related solely to the regional distribution of arterial perfusion. These data suggest that in the heart, kidney, thyroid, and skeletal muscle, thallium-201 distribution reflects the fractional distribution of cardiac output.     

Myocardial imaging with radiolabeled free fatty acids: Applications and limitations

The assessment of myocardial fatty acid metabolism using radiolabeled substrates has recently become a new diagnostic modality in noninvasive cardiology. The development of metabolic tracers has been made possible largely due to a combined increase in the understanding of myocardial biochemistry and in nuclear-medicine technology. Initially, imaging and the exploration of myocardial metabolism appeared to be the exclusive domain of positron-emission tomography. However, investigators have been successful in applying radioiodine-labeled fatty acids that can be monitored using conventional gamma cameras. These metabolic substrates can be used not only for imaging purposes, but also for the evaluation of regional metabolic clearance rates, which may serve as a parameter for myocardial fatty acid metabolism. Although the initial results have been promising, the analysis and interpretation of clearance curves appears to be rather complicated and may produce a lot of unanswered questions. A great deal remains to be done due to the complex biological behavior of the tracers employed and the difficulties encountered in quantitatively delineating the distribution of radioactivity in the beating heart in vivo. Therefore, closer integration of myocardial biochemistry and the metabolic imaging technique seems to be necessary for enhancing our knowledge of myocardial fatty acid metabolism and to make metabolic imaging clinically useful.

     

In vivo “hot spot” MR imaging of neural stem cells using fluorinated nanoparticles

To optimize ¹⁹F MR tracking of stem cells, we compared cellular internalization of cationic and anionic perfluoro‐15‐crown‐5‐ether (PFCE) nanoparticles using cell culture plates with different surface coatings. The viability and proliferation of anionic and cationic PFCE‐labeled neural stem cells (NSCs) did not differ from unlabeled cells. Cationic PFCE nanoparticles (¹⁹F T1/T2 = 580/536 ms at 9.4 Tesla) were superior to anionic particles for intracellular fluorination. Best results were obtained with modified polystyrene culture dishes coated with both carboxylic and amino groups rather than conventional carboxyl‐coated dishes. After injecting PFCE‐labeled NSCs into the striatum of mouse brain, cells were readily identified in vivo by ¹⁹F MRI without changes in signal or viability over a 2‐week period after grafting. These results demonstrate that neural stem cells can be efficiently fluorinated with cationic PFCE nanoparticles without using transfection agents and visualized in vivo over prolonged periods with an MR sensitivity of approximately 140 pmol of PFCE/cell. Magn Reson Med 60:1506–1511, 2008. © 2008 Wiley‐Liss, Inc.