Laurence Bontemps

Do iodinated fatty acids undergo a nonspecific deiodination in the myocardium

The intracellular and subcellular distribution of 16-(123I)-iodo-9-hexadecenoic acid were studied in isolated rat hearts, perfused with or without glucose. At various time intervals after injection, cardiac lipids were extracted and the activity was determined for all fractions and all lipid calsses. The total cardiac activity was maximal within 1 min postinjection and most of the activity was in the aqueous phase. The presence of glucose in the perfusion medium induced an increase of total cardiac and organic fraction activities. In the latter fraction, activity was very low for FFA, but high for triglycerides (TG), and especially polar lipids. The presence of an exogenous substrate, led to a more active esterification of fatty acids. Coronary effluent analysis showed, in the hydrophilic phase, a lower activity spike in the presence than in the absence of glucose. In the mitochondrial fraction most activity occurred in the organic phase, especially as polar lipids. In the nonmitochondrial fraction, activity was much higher in the aqueous phase. At 90 s postinjection of 1-14C-palmitic acid, over 80% of the myocardial activity was found in the hydrophilic fraction, which indicates, as for the iodo-fatty acid (IFA), an immediate and important oxidation, especially without glucose. These data seem to prove that IFA is taken up by the myocardial cell, subsequently enters the mitochondria and, without an early deiodination, is oxidized with iodide release. Changes in IFA metabolism, consecutive to modifications of glucose concetration in the perfusion medium can be observed by external detection of the myocardial activity curve. ω-Iodinated fatty acids do not undergo a nonspecific deiodination and are therefore well suited for an external study of myocardial metabolism.

Quantification of Ventricular Resynchronization Reserve by Radionuclide Phase Analysis in Heart Failure Patients: A Prospective Long-Term Study

Background—Phase analysis, developed to assess dyssynchrony from ECG-gated radionuclide ventriculography, has shown promising results. We hypothesized that quantifying the cardiac resynchronization reserve, that is, the extent of response to cardiac resynchronization therapy (CRT), by radionuclide imaging could potentially identify patients who are best suited for CRT. Methods and Results—Seventy-four patients ages 64.8±10.1 years were prospectively studied from July 2004 to July 2006, of whom 62.2% and 37.8%, respectively, were in New York Heart Association class 3 and 4. Mean QRS width was 173±25 ms. ECG-gated radionuclide ventriculography to quantify interventricular and intraventricular dyssynchrony was performed at baseline with and without CRT and at the 3-month follow-up visit. Amino-terminal-pro-brain natriuretic peptide (NT-pro-BNP) levels were also determined at baseline and at 3 months. During a mean follow-up of 10.1±7.6 months, there were 37 (50%) clinical events that defined the nonresponder group, including cardiac death or readmission for worsening heart failure. In multivariate Cox model analysis, higher NT-pro-BNP blood levels were associated with a significant increase in the risk for event (hazard ratio=1.085 for a 100 pg/L increase in NT-pro-BNP; 95% confidence interval, 1.014 to 1.161). Each 10° elevation in intraventricular dyssynchrony was associated with a decrease in the risk of events (hazard ratio=0.456, 95% confidence interval, 0.304 to 0.683). Receiver operating characteristic curve analysis demonstrated that an interventricular dyssynchrony cutoff value of 25.5° for intraventricular synchrony yielded 91.4% sensitivity and 84.4% specificity for predicting a good response to CRT. Conclusions—The quantification of interventricular dyssynchrony with radionuclide phase analysis suggests that early postimplantation interventricular dyssynchrony may provide identification of CRT responders.

In vivo measurement of myocardial oxidative metabolism and blood flow does not show changes in cancer patients undergoing doxorubicin therapy

Purpose: The aim was to investigate in patients receiving doxorubicin whether any alteration in myocardial oxidative metabolism or blood flow as assessed by positron emission tomography (PET) could be observed either after the first dose of the drug, or during its chronic administration. Methods: Six female non-heart-failure cancer patients treated with doxorubicin were included in a longitudinal study. Resting radionuclide cineangiography and PET scanning with carbon-11 acetate were performed the day before the initiation of doxorubicin treatment at a dosage of 50 mg/m2 every 3 weeks, and 3 weeks after the cumulative administration of 300 mg/m2 (chronic toxicity). In addition, PET was performed 24 h after the first administration of doxorubicin (evaluation of acute toxicity). Myocardial oxidative metabolism and blood flow were assessed by PET (acute and chronic toxicity), and left ventricular ejection fraction was measured by radionuclide angiography (chronic toxicity). Results: Using PET for both acute and chronic toxicity evaluations, no significant effect of doxorubicin was observed either on the flux through the tricarboxylic acid (TCA) cycle or on myocardial blood flow. However, systolic left ventricular function showed a small but significant impairment after the administration of 300 mg/m2 of doxorubicin. Conclusions: Other hypotheses should be explored to better explain the predominant mechanisms of the cardiotoxicity of anthracyclines in humans.

Kinetics of iodomethylated hexadecanoic acid metabolism in the rat myocardium: influence of the number and the position of methyl radicals

The methyl-branched fatty acids, if radioiodine labelled in alpha position, are potentially adapted to a selective study of FA myocardial uptake. To determine the position and the number of methyl radicals that are necessary to obtain a maximal uptake and a minimal degradation, we measured time-activity evolution of isolated and perfused rat hearts after an injection of iodinated fatty acids which are mono- or dimethylated in alpha or beta position. Except for dimethyl fatty acid, the uptake is similar for all fatty acids studied to that of the straight chain analogue; beta mono- or dimethyl fatty acids seem best adapted to a study of the uptake because alpha monomethyl fatty acids undergo a metabolic degradation and alpha mono- and dimethyl fatty acids induce ventricular fibrillations.

Mathematical model of the metabolism of 123I-16-iodo-9-hexadecenoic acid in an isolated rat heart. Validation by comparison with experimental measurements

The aim of the present study was to demonstrate that it is possible to estimate the intracellular metabolism of a fatty acid labelled with iodine using external radioactivity measurements. 123I-16-iodo-9-hexadecenoic acid (IHA) was injected close to the coronary arteries of isolated rat hearts perfused according to the Langendorff technique. The time course of the cardiac radioactivity was measured using an INa crystal coupled to an analyser. The obtained curves were analysed using a four-compartment mathematical model, with the compartments corresponding to the vascular-IHA (O), intramyocardial free-IHA (1), esterified-IHA (2) and iodide (3) pools. Curve analysis using this model demonstrated that, as compared to substrate-free perfusion, the presence of glucose (11 mM) increased IHA storage and decreased its oxidation. These changes were enhanced by the presence of insulin. A comparison of these results with measurements of the radioactivity levels within the various cellular fractions validated our proposed mathematical model. Thus, using only a mathematical analysis of a cardiac time-activity curve, it is possible to obtain quantitative information about IHA distribution in the different intracellular metabolic pathways. This technique is potentially useful for the study of metabolic effects of ischaemia or anoxia, as well as for the study of the influence of various substrates or drugs on IHA metabolism in isolated rat hearts.

Two-year assessment by exercise Thallium scintigraphy of myocardial revascularization using bilateral internal mammary and gastroepiploic arteries

OBJECTIVE To assess the blood flow supply offered to the myocardium by surgical revascularization using bilateral internal mammary (IMAs) and gastroepiploic (GEA) arteries. METHODS Two-year assessment by exercise thallium myocardial scintigraphy without medical treatment was performed in 122 patients (mean age 61 +/- 9 years) who underwent coronary artery bypass grafting (CABG) with exclusive use of IMAs and GEA. Usually, the right IMA was used to bypass the left anterior descending coronary artery, and the left IMA to bypass the diagonal and the marginal arteries as a sequential graft if required. The GEA was used to bypass the right coronary artery (RCA) in 50 patients and its posterior branches in 72 patients. RESULTS During maximal or submaximal exercise stress testing, 119 patients (98%) were asymptomatic and 26 patients (21%) exhibited moderate ischemic ECG modifications which were correlated (P < 0.01) with incomplete revascularization and with the use of GEA to bypass the RCA. A third of patients had moderate ischemic thallium defects on exercise reversible after redistribution (anterior, 10; lateral, 2; inferior, 28). Silent residual myocardial ischemia detected by thallium scintigraphy was correlated (P < 0.001) with ECG modifications and incomplete revascularization; and inferior thallium defects were more frequent when GEA bypassed the RCA (P < 0.05). However, 26% of patients had residual ischemia despite a complete revascularization, and in at least 18% of cases for GEA and 8% for right IMA, arterial graft blood flow was insufficient at maximum exercise level and caused silent residual myocardial ischemia detected by thallium scintigraphy. CONCLUSIONS Myocardial revascularization using bilateral IMAs and GEA offers a satisfactory myocardial perfusion in the majority of cases; however silent residual myocardial ischemia was detected in a third of patients and was related to incomplete revascularization and to insufficient blood flow supply probably due to small diameter of the arterial grafts.

Theoretical model for myocardial functional characterization: Application to a group of patients evaluated before and after surgical revascularization

BackgroundThe functional improvements resulting from coronary revascularization (CABG) in patients with depressed ventricular function may be described by the use of a model combining global or local quantification of myocardial perfusion, viability, and contraction. An illustration of this model, with data provided by conventional radionuclide studies as they are performed routinely in many centers, is presented and the limitations of this approach for predicting the results of CABG are discussed.Methods and ResultsThe model is based on three independent variables, which can be approximated in this preliminary study by parameters derived from standard stress and redistribution/reinjection thallium-201 single-photon emission computed tomography (SPECT) acquisitions with quantification of the tracer uptake defects and from a planar gated blood pool left ventricular ejection fraction (LVEF) measurement: Perfusion is assumed to correspond to 100-stress defect (in percentage), viability is 100-redistribution/reinjection defect, and contraction is 100(LVEF/70), assuming that a normal 70% LVEF corresponds to 100% contraction. In a group of 30 patients prospectively evaluated with this protocol and included in the study on the basis of a pre-CABG LVEF <40%, a significant improvement in LVEF was demonstrated (28.2%±8.5% before CABG vs 35.8%±7.3% after CABG), which is accompanied by a significant decrease of the stress thallium defects (34.8%±13.8% vs 25.6%±10.6%), whereas the average (but not the individual) redistribution/reinjection defects remain almost stable (27.7%±10.9% vs 25.7%±10.1%). As reported in the three-dimensional model, pre-CABG and post-CABG representative points clearly demonstrate the functional improvements for the main variables, but there is a large spectrum of responses to revascularization. It appears that the border between reversible and nonreversible thallium defects does not match the limit between ischemic myocardium (with no contraction alteration and therefore without contraction improvement potential) and hibernating myocardium, which is able to recover mechanical function and therefore is responsible for the improvement of global LVEF.ConclusionsThallium SPECT is far from ideal for use as an independent characterization of perfusion and viability because hibernating myocardium may be present in both the fixed and reversible parts of thallium defects. Prediction of functional recovery is conditioned by an accurate identification of viable but underperfused and noncontracting myocardium. In the future, with the use of adequate study protocols that are able to measure viability without interference of perfusion and perfusion independent of viability, the proposed model may be able to characterize regional function as a cluster of representative points for each territory and to delineate areas of the theoretical volume corresponding to a potentially recoverable situation.

A new experimental model for studies of drug actions on myocardial metabolism. Application to a study of the influence of POCA

In order to study myocardial metabolism by external detection, quantitative information on the metabolism of a gamma-emitting iodinated fatty acid (IHA) was obtained from time-activity curves of radioactivity in different compartments. A 4-compartment mathematical model was then developed; compartments 0, 1, 2, and 3 correspond respectively to vascular IHA, intracellular IHA, esterified forms, and iodide resulting from mitochondrial oxidation of IHA. We applied this model to a study of the influence of an inhibitor of fatty acid oxidation, POCA (2-[5(4 chlorophenyl) pentyl]-oxirane-2-carboxylate). Isolated rat hearts were perfused for 20 min with Krebs liquid containing increasing concentrations of POCA. IHA was then injected as a bolus at the entrance of the coronary network. The level of cardiac radioactivity was recorded for 30 min and the division into the 4 compartments was simulated at different concentrations of POCA. The drug appeared to increase the myocardial retention of IHA and slow down the speed of degradation and storage; the variations were dose-dependent. These results correspond to those obtained by intracellular analysis. The proposed method, which is reliable and sensitive, is an interesting experiment for pharmacological studies of cardiac metabolism.

Technetium-99m teboroxime scintigraphy

In order to evaluate the clinical value of a new myocardial perfusion tracer, a series of 30 patients (25 male, 5 female, mean age 56 years) referred for thallium 201 stress/redistribution scintigraphy has been studied using stress/rest (n = 7) or rest/stress (n = 23) protocols with technetium 99m teboroxime (Cardiotec SQUIBB). In all cases coronary artery disease was known or highly probable, with a history of myocardial infarction in 18 cases. Medical treatment was not discontinued at the time of stress testing, and coronary angiography was available in 27 patients. Exercise tests for both tracers were carried out on a bicycle ergometer during the same day, and the levels of exercise achieved for the 201Tl study were very similar to those achieved for 99mTc-teboroxime. Studies performed in three planar projections were evaluated using a model with four territories septal and anterior assumed to correspond to the left anterior descending artery, lateral and lateroposterior (left circonflex), inferior and posterior (right coronary artery) and apex. Classification of results was normal, ischaemic, infarcted and infarcted with ischaemia. On comparison with the 201Tl results, agreement was found in 86% (37/43) of normal regions and in 82% (63/77) of abnormal regions. Relative to documented coronary artery lesions (27 patients), sensitivity and specificity of 201Tl and 99mTc-teboroxime for exact correspondence between arteries and territories were respectively: 201Tl: sensitivity 64%, specificity 60%; 99mTc-teboroxime: sensitivity 62%, specificity 77%. These results, obtained in a given clinical context, indicate the ability of Cardiotec to evaluate myocardial perfusion with a significant saving in time, since the complete study duration (stress and rest) was: 201Tl, 4 h 35 min±21 min; 99mTc-teboroxime, 1 h 52 min ±29 min. Nevertheless, the high liver uptake was responsible for 68% of non-evauble inferior segments and the limited acquisition time makes the applicability of SPET questionable.

Quantification of Ventricular Resynchronization Reserve by Radionuclide Phase Analysis in Heart Failure PatientsClinical Perspective

Background—Phase analysis, developed to assess dyssynchrony from ECG-gated radionuclide ventriculography, has shown promising results. We hypothesized that quantifying the cardiac resynchronization reserve, that is, the extent of response to cardiac resynchronization therapy (CRT), by radionuclide imaging could potentially identify patients who are best suited for CRT. Methods and Results—Seventy-four patients ages 64.8±10.1 years were prospectively studied from July 2004 to July 2006, of whom 62.2% and 37.8%, respectively, were in New York Heart Association class 3 and 4. Mean QRS width was 173±25 ms. ECG-gated radionuclide ventriculography to quantify interventricular and intraventricular dyssynchrony was performed at baseline with and without CRT and at the 3-month follow-up visit. Amino-terminal-pro-brain natriuretic peptide (NT-pro-BNP) levels were also determined at baseline and at 3 months. During a mean follow-up of 10.1±7.6 months, there were 37 (50%) clinical events that defined the nonresponder group, including cardiac death or readmission for worsening heart failure. In multivariate Cox model analysis, higher NT-pro-BNP blood levels were associated with a significant increase in the risk for event (hazard ratio=1.085 for a 100 pg/L increase in NT-pro-BNP; 95% confidence interval, 1.014 to 1.161). Each 10° elevation in intraventricular dyssynchrony was associated with a decrease in the risk of events (hazard ratio=0.456, 95% confidence interval, 0.304 to 0.683). Receiver operating characteristic curve analysis demonstrated that an interventricular dyssynchrony cutoff value of 25.5° for intraventricular synchrony yielded 91.4% sensitivity and 84.4% specificity for predicting a good response to CRT. Conclusions—The quantification of interventricular dyssynchrony with radionuclide phase analysis suggests that early postimplantation interventricular dyssynchrony may provide identification of CRT responders.