Myocardial Fatty Acid Metabolism Research Articles

Recent developments in 99mTc and 123I-radiopharmaceuticals for SPECT imaging

Availability of 123I of high radionuclidic purity has encouraged the development of 123I-based radiopharmaceuticals for the assessment of myocardial fatty acid metabolism, myocardial neuronal activity, and for receptor and antibody imaging. Advances in the chemistry of technetium have resulted in the development of novel agents for myocardial and cerebral perfusion and renal function studies. Monoclonal antibodies labeled with 99mTc show promise for imaging neoplastic lesions, myocardial infarcts, and thrombus localization. Recent developments in 123I and 99mTc agents for myocardial and brain imaging studies are discussed.

Standardized non-invasive assessment of myocardial free fatty acid kinetics by means of 15-(para-iodo-phenyl) pentadecanoic acid (123I-pPPA)scintigraphy: I. Method

Two simple mathematical functions have been applied for estimating myocardial perfusion and fatty acid metabolism from planar, dynamic 123I-para-phenylpentadecanoic acid (123I-pPPA) studies. The first one uses a modified gamma function and the latter one a biexponential fit. The reciprocal of mean transit time is assumed to represent myocardial blood flow and the fast phase (size and half-time) of the biexponential fit primarily accounts for beta oxidation of 123I-pPPA.

The Influence of Lactate and Dipyridamole on Myocardial Fatty Acid Metabolism in Man, Traced with 123l-17-lodo-heptadecanoic Acid

Changes in myocardial metabolism can be detected externally by registration of time-activity curves after administration of radioiodinated fatty acids. In this scintigraphic study the influence of lactate on fatty acid metabolism was investigated in the normal human myocardium, traced with 123I-17-iodoheptadecanoic acid (123I-17-HDA). In patients (paired, n = 7) lactate loading decreased the uptake of 123I-17-HDA significantly from 27 (control: 22-36) to 20 counts/min/pixel (16-31; p less than 0.05 Wilcoxon). The half-time value increased to more than 60 min (n = 5), oxidation decreased from 61 to 42%. Coronary vasodilatation, a well-known side effect of lactate loading, was studied separately in a dipyridamole study (paired, n = 6). Coronary vasodilatation did not influence the parameters of the time-activity curve. These results suggest that changes in plasma lactate level as occurring, among other effects, during exercise will influence the parameters of dynamic 123I-17-HDA scintigraphy of the heart.

Effect of short-term fasting on [123I] iodohexadecenoic acid metabolism in the isolated perfused rat heart. Validation of mathematical model by comparison with experimental measurements

In order to study metabolic modifications induced by short term fasting and their consequences on the uptake and intracellular fate of fatty acids iodine labelled in omega position, rats undergo a 36h fasting. Hearts are perfused in a Langendorff system with a glucose (11 mM) perfusion medium; [123I] hexadecenoic acid (IHA) is injected as a bolus. A comparison between time-activity curves p.i. demonstrates a much faster activity decrease for the hearts fasted animals. The intracellular analysis shows that short fasting did not significantly increase the myocardial uptake of fatty acids, but decreased the storage and increased the degradation of the fatty acids taken up. Mathematical analysis of the myocardial time-activity curves obtained by external detection provided results comparable to those of intracellular analysis. The coefficients of correlation between the values of the aqueous phases, organic phases and free fatty acids measured by intracellular analysis and calculated with the compartmental model are consistently higher than 0.97. Consequently, this experimental model combined with mathematical analysis of the time-course of myocardial radioactivity after 123IHA administration appears to be very promising method for studying the effects of drugs or variations of energy substrate availability on myocardial fatty-acid metabolism.

Newly developed myocardial imaging by using single photon emission computed tomography (SPECT).

Thallium myocardial imaging is a useful technique to evaluate myocardial perfusion and myocardial viability in ischemic heart disease. However, myocardial imaging using single photon emission computed tomography (SPECT) and gamma-emitting radiopharmaceuticals has been recently developed for more precise evaluation of myocardial infarction and ischemia. The present study evaluates animal experiments and the clinical applications of these new myocardial imaging techniques. Areas considered on 1) myocardial necrosis assessed using 111In-antimyosin, 2) myocardial fatty acid metabolism assessed using 123I-beta-methyl-iodophenyl pentadecanoic acid (BMIPP) and 3) myocardial sympathetic neural activity assessed using 123I-metaiodobenzyl guanidine (MIBG). Dual energy SPECT using these new agents and thallium gives precise characterization of the myocardial tissue in the infarcted and ischemic area.

Regional rates of myocardial fatty acid metabolism: comparison with coronary angiography and ventriculography

In 50 patients, 1 mCi 123I phenylpentadecanoic acid (IPPA) was injected at peak ergometric stress and 1500 frames were acquired (1 frame/s) with a high count rate gamma camera. Parametric images of rates of decrease and increase for different time intervals after stress were compared with coronary angiography and LV ventriculography, separately evaluating the 3 main coronary territories: 18/150 territories supplied by normal coronaries presented rather homogeneous regional clearing rates, whereas a gradual decrease in clearing rates towards the end of the territory (frequently with peripheral defects) was seen in all 87/150 territories with significant coronary narrowing. In local correspondence to clearing defects, initial IPPA accumulations could be observed with later onset of clearing between 10 and 25 min. 44/150 territories presented abnormal clearing rates, mostly with a patchy pattern, with normal coronary anatomy, but all except one had LV dysfunction and a clinical diagnosis of cardiomyopathy, diabetes mellitus or hypertensive disease. Twenty four of the 41 patients with CAD had, in correspondence to a prior myocardial infarction, minimum or missing metabolic activity frequently in circumscribed zones, partly separated by bridges of still viable tissue with preserved but reduced clearing rates.

New Radionuclide Agents for Cardiac Imaging: Description and Application

The introduction of three new radiopharmaceuticals into clinical research and practice has broadened the potential applications and scope of nuclear cardiology examinations. Technetium-99m labeled isonitrile perfusion agents have excellent imaging characteristics allowing the accurate identification of coronary artery disease. Simultaneous assessments of ventricular function are possible with these agents. Iodine-123 phenylpentadecanoic acid myocardial scintigraphy permits assessments of myocardial perfusion and fatty acid metabolism, and permits investigations of myocardial metabolism with conventional imaging equipment. Iodine-123 meta-iodobenzyl-guanidine serves as an indicator of the functional integrity of the sympathetic nervous system and permits evaluations of the effects of various disease states on catecholamine handling by the heart.

Fatty acid myocardial imaging using 123I-?-methyl-iodophenyl pentadecanoic acid (BMIPP): comparison of myocardial perfusion and fatty acid utilization in canine myocardial infarction (Occlusion and reperfusion model)

To evaluate the relationship between myocardial perfusion and fatty acid metabolism in canine myocardial infarction, 16 dogs were studied using thallium and 123I-beta-methyl-iodophenyl pentadecanoic acid (BMIPP). Eight dogs (group A) had left anterior coronary arterial occlusion (6 h ligation), 6 dogs (group B) had reperfusion (3 h ligation and 1 h reperfusion) and 2 dogs served as the normal control. Myocardial imaging with BMIPP was excellent, owing to its higher uptake and longer retention in myocardium and rapid blood disappearance in addition to diminished liver and lung uptake. The mean half time value which was generated from the BMIPP myocardial washout curve, was significantly larger in the reperfused myocardium. The gamma camera imaging showed uncoupling of BMIPP and thallium (BMIPP uptake greater than thallium uptake) in five dogs in group B. On the other hand, all dogs in group A had a persistent defect in BMIPP and thallium uptake. Our findings indicate that the combination of BMIPP and thallium for myocardial imaging supply different information about the zone of infarction and ischemia, which may be useful for the assessment of myocardial viability.

Abnormal myocardial fatty acid metabolism in dilated cardiomyopathy detected by iodine-123 phenylpentadecanoic acid and tomographic imaging

The radioiodinated synthetic fatty acid iodine-123 Phenylpentadecanoic acid (IPPA) has proven useful in the identification of regional abnormalities of cardiac metabolism in patients with myocardial ischemia. The present study was performed to test the hypothesis that the myocardial distribution and turnover of fatty acids, assessed noninvasively with IPPA, are altered in patients with cardiomyopathy. Nine normal volunteers and 19 patients with dilated cardiomyopathy of various etiologies underwent cardiac imaging with single-photon emission computed tomography (SPECT) after intravenous injection of IPPA. Apical short-axis and basal short-axis sections were reconstructed and quantitatively analyzed for relative IPPA activity distribution and washout. Patients with congestive cardiomyopathy demonstrated significantly greater heterogeneity of IPPA uptake than normal subjects (maximal percent variation of activity 27 ± 11 vs 18 ± 4, p < 0.01). They also demonstrated a more rapid percent washout rate than control subjects (24 ± 8 vs 17 ± 6 for the apical short-axis section, p < 0.05; 26 ± 7 vs 18 ± 5 for the basal short-axis section, p < 0.01). These abnormalities of fatty acid distribution and turnover were independent of the etiology of the cardiomyopathy. The degree of heterogeneity of IPPA uptake was significantly related to the patients' New York Heart Association functional class (r = 0.64, p < 0.01). Thus, compared with normal myocardium, the myocardium of patients with congestive cardiomyopathy demonstrates a more heterogeneous distribution of fatty acid uptake, which parallels the clinical severity of the disease. Furthermore, patients with congestive cardiomyopathy demonstrate a more rapid myocardial clearance of the labeled fatty acid, as assessed with SPECT imaging.

Cardiac nuclear medicine: positron emission tomography in clinical medicine.

Positron-emission tomography (PET) and radioactively labelled substrates permit metabolic studies to be carried out in vivo and in situ with few if any limitations regarding the choice of substrates as long as they can be tagged with positron-emitting radionuclides, especially those like 11C and 13N. With respect to cardiology, 13N-ammonia and 82Rb are helpful in the examination of myocardial perfusion. The evaluation of myocardial glucose and fatty acid metabolism with 18F-deoxyglucose (FDG) and 11C-palmitate has proved to be clinically useful. Thus, myocardial ischemia and hypoxia, infarct size, the transmural extent of the infarction and tissue viability after it can all be examined as can pathological biochemistry in patients with primary or secondary cardiomyopathies. Single-photon-emitting labelled substances such as 123I-labelled fatty acid analogues also provide information equivalent to that which can be gathered by PET for clinical use. Thus, one major task of PET is the validation of methods and the transformation of these methods to single-photon-emitting radiotracers for broad clinical application, in situations where the expense of PET cannot at present be justified.

Pacing and the Non-Invasive Evaluation of Myocardial Fatty Acid Metabolism by Means of 17-123I-Heptadecanoic Acid Scintigraphy

The extent of myocardial non-esterified fatty acid (NEFA) oxidation depends among other things on exogeneous NEFA supply and energy demand. In 6 patients with a multi-programmable pacemaker scintigraphy with 17-123Iodo-heptadecanoic acid (17-123I-HDA) was performed to investigate NEFA metabolism at two levels: at a control level (basal heart rate 69 +/- 6) and at increased pace frequency (104 +/- 5). In both situations the derived time-activity curves, measured during a period of 75 min, were fitted with a monoexponential plus a constant curve: A(t) = A(0).exp (-t In2/T1/2) + C. The half-time value, the uptake measured as the peak activity and the relative size of the oxidation pool were determined. The median of the half-time value did not change: 24 min (range 19-31) in the control heart rate study and 22 min (19-27) during the increased pace frequency study. The median of the uptake increased significantly from 33 cpm/pixel/2 mCi/100 kg (23-34) to 40 cpm/pixel/2 mCi/100 kg (35-42; p less than 0.05 Wilcoxon). The median of the relative size of the oxidation pool increased from 57% (52-62) to 69% (63-71; p less than 0.05). We conclude that during pacing the augmented need for NEFA resulted in a demonstrable increase in uptake and oxidation of 17-123I-HDA. This result suggests that radioiodinated NEFA may be a valuable tool to quantify noninvasively the level of the myocardial NEFA metabolism in the human heart.

Metabolism of palmitate in isolated working hearts from spontaneously diabetic "BB" Wistar rats.

Myocardial fatty acid metabolism was studied in spontaneously-diabetic "BB" Wistar rats. The study involved 4 groups: control Wistar rats, nondiabetic littermates of "BB" Wistar rats, insulin-treated diabetic "BB" rats, and diabetic "BB" rats in which insulin treatment was removed 24 hours prior to study (uncontrolled diabetes). Hearts were perfused for 30 minutes as isolated working hearts in perfusate containing 1.2 mM (1-14C)-palmitate bound to 3% albumin, and 11 mM glucose. Palmitate oxidative rates, calculated as micromoles palmitate oxidized per gram dry weight per minute, were significantly decreased in both diabetic groups (0.447 +/- 0.043 and 0.528 +/- 0.038 in uncontrolled diabetic and treated diabetic versus 0.584 +/- 0.032 and 0.629 +/- 0.033 in nondiabetic littermate and control rats, respectively). This decrease was accompanied, however, by a significant decrease in the heart rate of these 2 groups when compared with control or nondiabetic animals. If the decreased heart function in the diabetic animals was accounted for, no decrease in palmitate oxidative rates occurred, suggesting that fatty acid oxidative metabolism is not impaired in the diabetic myocardium. In the uncontrolled diabetic rats, an increased rate of palmitate incorporation into myocardial triglycerides was seen compared with treated diabetic, nondiabetic littermates, and control rats (8.5 +/- 0.3 mumol/g dry wt/30 min versus 4.8 +/- 0.3, 5.9 +/- 0.7, and 5.7 +/- 0.3, respectively). Myocardial levels of coenzyme A were elevated in the uncontrolled diabetic rats compared with all other groups (647 +/- 25 nmol/g dry wt versus 484 +/- 27, 508 +/- 56, and 534 +/- 9, in treated diabetic, nondiabetic, and control rats, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Canine biventricular performance during acute progressive pulmonary microembolization: Regional myocardial perfusion and fatty acid uptake

The cardiac output during acute pulmonary artery hypertension (PAH) may be compromised by right ventricular (RV) outflow obstruction, myocardial ischemia, or adverse ventricular interactions. To study the relative contributions of these mechanisms to impaired biventricular function during PAH, we injected 75 to 105-μm glass beads into the pulmonary vasculature of 11 dogs and correlated the hemodynamic alterations with changes in biventricular function. Biventricular ejection fractions and interventricular septal motion were evaluated by gated blood pool angiocardiograms. Regional myocardial blood flow (n = 8 dogs) was measured with microspheres, and regional myocardial fatty acid metabolism during PAH (n = 8 dogs) was assessed by measuring the regional myocardial extraction of the radioiodinated fatty acid analog, 15-(p-iodophenyl)-3-methylpentadecanoic acid (3m-PIP/PDA). Following microembolization, the mean pulmonary artery pressure increased from 14 ± 1 to 48 ± 2 mm Hg ( P < .001) and cardiac output decreased from 3.5 ± 0.3 to 2.6 ± 0.3 1 /min ( P < .05). Right ventricular volume increased and RV ejection fraction decreased progressively. Abnormal septal motion during PAH occurred in 5 of 11 dogs and was associated with decreased LV diastolic compliance. Right ventricular myocardial blood flow remained increased during PAH while the regional extraction of 3m-PIP/PDA was uniform throughout the heart. These findings suggest that during moderate PAH the canine cardiac output is limited by RV outflow obstruction and decreased LV diastolic compliance rather than by ischemia.

Effect of isoproterenol on the metabolism of myocardial fatty acids

The effect of beta-adrenergic stimulation on myocardial fatty acid metabolism was studied in the anesthetized open-chest dog. Isoproterenol (1 microgram/kg/min) was infused; and samples of arterial blood and of left ventricular wall were taken at the 5th min for the determination of the following variables: in arterial blood: lactate and serial free fatty acids (FFA); in myocardial tissue: creatine phosphate (CP), ATP, lactate, carnitine, acylcarnitine, glycerol, and the fatty acid content of each of phospholipids (PL), cholesterol esters (CE), triglycerides (TG), diglycerides (DG), monoglycerides (MG), and FFA. A capillary gas chromatography was used for fatty acid assay. Isoproterenol decreased the content of creatine phosphate but not of ATP. Lactate increased in both arterial blood and myocardial tissue. The five-fold increase in arterial FFA (P less than 0.001) was accompanied with a significant increase in FFA serum/tissue ratio. Free carnitine decreased and acylcarnitine increased. Triglycerides content (which is expressed in terms of its total fatty acid content) was considerably reduced by beta-stimulation in comparison with control group (2694 +/- 689 vs. 7518 +/- 833 nmol/g wet wt, P less than 0.001), and tissue glycerol increased (P less than 0.01). The decrease in total MG content was significant, but not that of DG, nor that of CE. Total PL content did not change. The most marked individual changes (except in PL) were observed on monounsaturated fatty acids, 18: 1 omega 9, 18: 1 omega 7, and 16: 1 cis. The significant changes of monounsaturated/saturated and of 16:1 cis/16:1 trans ratios, in arterial FFA and tissue TG, suggested modifications in the distribution of fatty acids.(ABSTRACT TRUNCATED AT 250 WORDS)

Fatty Acid Metabolism in Symptomatic Patients with Mitral Valve Prolapse but without Coronary Artery Disease - Comparison with 201 Tl Myocardial Perfusion Scintigraphy

Using 123I-omega-heptadecanoic acid (HDA) and 201Tl, respectively, myocardial fatty acid metabolism and perfusion were studied in 51 symptomatic patients with mitral valve prolapse (MVP) as diagnosed by ventriculography, and no evidence of coronary artery disease. Twelve subjects with normal coronary arteries and normal ventriculogram served as a control group for the evaluation of elimination kinetics of HDA. In the control group, the mean elimination half-life was 26.1 +/- 3.6 min, whereas the patients with MVP had a mean value of 25.0 +/- 6.4 min. In patients with MVP, a high incidence concerning abnormalities of accumulation and/or elimination of HDA occurred, namely accumulation defects in 31% and both prolonged and shortened elimination half-lives in 16% and 29%, respectively. Myocardial perfusion scintigraphy using 201Tl showed abnormalities in 76%. Correlations were found between decreased uptake of HDA and prolonged elimination half-life as well as defects by 201Tl, presumably due to ischemia based on small-vessel disease or abnormalities of cellular metabolism.

Lipoprotein lipase activity in ischaemic and anoxic myocardium.

Myocardial lipoprotein lipase (LPL) activity during ischaemia has not been fully understood, although it plays an important role in regulating myocardial fatty acid metabolism. In this experiment, the effects of ischaemia (Experiment A) and anoxia (Experiment B) on two distinct fractions of LPL, i.e. functional and nonfunctional forms were investigated in isolated, perfused rat heart. In Experiment A, hearts were perfused by Neely-Morgan working heart mode with Krebs Henseleit bicarbonate (KHB) buffer (95% O2:5% CO2), then whole heart ischaemia was induced by using a one-way aortic valve, simultaneously switching to the same buffer but containing heparin (5 mu/ml) for 20 min. In Experiment B, the hearts were perfused by Langendorff method with KHB buffer (95% O2:5% CO2) and the buffer was switched to KHB (95% N2:5% CO2) containing heparin for 20 min. Coronary effluent was collected at 5 min intervals and used for the measurement of functional LPL activities using 3H-glyceryltrioleate. The hearts were quickly frozen at the end of perfusion and homogenized. The suspension was used for the measurement of non-functional LPL activities. In Experiment A, functional LPL activities in ischaemia were significantly lower than in the aerobic condition. On the contrary, the nonfunctional LPL activity in ischaemia was significantly higher than in the aerobic condition. In Experiment B these values were also significantly lower than in the aerobic condition. However, there was no significant difference in non-functional LPL activity between the anoxia and aerobic condition. These results indicate that there is a conversion defect from the precursor of LPL to the functional form of LPL in ischaemia, whereas disturbed LPL synthesis might be involved in anoxic myocardium.

Myocardial fatty acid metabolism after acute ethanol consumption

This study was undertaken to assess the effect of ethanol ingestion on myocardial fatty acid metabolism in man. Nine individuals with informed consent and with a habitual ethanol consumption of approximately 40 g per day, but without any clinical signs of heart and metabolic disease, were examined after i.v. injection of omega-123I-heptadecanoic acid (IHA). Eight days later, these individuals were similarly examined after 2 h of continuous ingestion of a body weight dependent amount of ethanol, which was calculated to produce a blood level of 100 mg per 100 ml (1%). Then the subjects had been asked to reduce their ethanol consumption rigorously for 15 months. Subsequently after 2 weeks of abstinence a follow-up investigation without ethanol loading was carried out. The investigations were performed with an Anger scintillation camera in LAO-45 degrees projection. The measurement period was 40 min. Tracer accumulation and regional elimination half-times of IHA were analysed. In all patients, acute ethanol loading produced significant changes in pattern of accumulation and/or regional elimination half-times. Ethanol-induced alterations in segmental accumulation did not appear to be predictably correlated with changes in segmental elimination half-times. After rigorous reduction of ethanol consumption followed by 2 weeks of abstinence a normalization of the tracer uptake was observed; the distribution pattern was almost homogeneous. Also the regional elimination half-times became normal. The data demonstrate the significant effects of both chronic ethanol consumption and particularly acute ethanol loading on myocardial fatty acid metabolism and the reversibility of the effects.

Myocardial fatty acid metabolism after acute ethanol consumption

HÖCK, A.1; NOTOHAMIPRODJO, G.2; SPOHR, G.; KAISER, K. P.; FREUNDLIEB, C.1; VYSKA, K.2; SHREEVE, W. W.3; SCHWEITZER, H.4; FEINENDEGEN, L. E.Author Information

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.

Dynamic 123I-HDA myocardial scintigraphy after aortocoronary bypass grafting.

In an attempt to evaluate the dynamics of fatty acid metabolism after aortocoronary bypass grafting (ACBG), ten patients were investigated after ACBG by 123I-HDA myocardial scintigraphy. Tracer kinetics were followed for 90 min and compared to those of 36 nongrafted patients with different underlying heart diseases, including healthy volunteers. Regional analysis and monoexponential curve fitting were used to evaluate t1/2 (half-life of the early period of tracer elimination); biexponential curve analysis was used to calculate Ca/Cb, the ratio of a fast and a slow component of tracer elimination. Rest and stress MUGA-RNV served as discriminating parameters to discern between patient groups with normal and abnormal ventricular function. Group I (normal controls) encompassed ten patients with normal ventricular function, including three after ACBG, and group II seven patients after ACBG and with abnormal ventricular function. Group III had coronary artery disease (CAD) documented by angiography, and group IV by prior myocardial infarction (MI). Group V included patients with cardiomyopathy (CMP). Regional analysis of group II revealed no significant differences to control regions (Gr I) for t1/2 or Ca/Cb, but showed for Ca/Cb a nonsignificant shift toward group III values. However, group II differed significantly from group III and V. Three patients with normal ventricular function after ACBG showed elimination values that were all well within the range of completely normal individuals. Thus our data support the assumption that a normal function is indicative of a normal metabolism. Following myocardial fatty acid metabolism during rest might be a helpful noninvasive tool for etiologic differentiation of disturbed ventricular function.