Myocardial Fatty Acid Metabolism Research Articles

Insulin resistance and impaired myocardial fatty acid metabolism in dialysis patients with normal coronary arteries

We investigated whether insulin resistance is associated with impaired cardiac fatty acid metabolism in maintenance hemodialysis patients without coronary artery disease. We studied 55 nondiabetic (63+/-11 years old) and 51 diabetic (61+/-10 years old) hemodialysis patients with normal coronary arteries, using single-photon emission computed tomography (SPECT) with an iodinated fatty acid analogue, iodine-123-beta-methyl iodophenyl-pentadecanoic acid ((123)I-BMIPP), to evaluate cardiac fatty acid metabolism. SPECT imaging was graded regionally from 0 (normal) to 4 (absence of tracer) to calculate a summed score for 17 left ventricular segments. Insulin resistance was determined using the homeostasis model assessment index of insulin resistance (HOMA-IR). HOMA-IR correlated with summed BMIPP score in nondiabetic and diabetic patients. Stepwise multiple regression analysis showed that HOMA-IR was independently associated with BMIPP summed score in nondiabetic (beta=0.774, t=9.218, P=0.0001) and diabetic patients (beta=0.792, t=9.079, P=0.0001). Left ventricular ejection fraction was lower in nondiabetic subjects with BMIPP summed score of at least 6 plus HOMA-IR of at least 4 than in others with lower values for both assessments (53.1+/-13.8%, n=20 vs 67.7+/-9.1%, n=23, P=0.0002); this was also true in diabetic subjects (50.9+/-15.2%, n=24 vs 71.0+/-13.6%, n=11, P=0.0007). Association between insulin resistance and impaired cardiac fatty acid metabolism may contribute to left ventricular dysfunction in patients with maintenance hemodialysis without coronary diseases.

Increased Myocardial Fatty Acid Metabolism in Patients With Type 1 Diabetes Mellitus

The purpose of this study was to determine if myocardial fatty acid utilization (MFAU) and myocardial fatty acid oxidation (MFAO) are increased in diabetic patients. Experimental models of diabetes mellitus demonstrate that MFAU and MFAO are increased, and that this dependence on myocardial fatty acid metabolism may be detrimental to cardiac function. Whether similar metabolic changes occur in humans with diabetes mellitus is unclear. Eleven healthy non-diabetic control patients (5 women, ages 25 +/- 5 years) and 11 otherwise healthy patients with type 1 diabetes mellitus (T1DM) (8 women, ages 36 +/- 10 years, HbA1c 8.4 +/- 1.9%) underwent positron emission tomography for the determination of myocardial blood flow (MBF); myocardial oxygen consumption (MVO2); myocardial glucose utilization (MGU); and MFAU, MFAO, and %MFAO. Plasma lactate, insulin, and MBF levels were similar between the two groups. However, plasma glucose (5.71 +/- 0.98 mumol/ml vs. 5.28 +/- 0.65 mumol/ml, p = 0.04), free fatty acid levels (0.60 +/- 0.24 mumol/ml vs. 0.19 +/- 0.07 mumol/ml, p < 0.0001), and MVO2 (6.64 +/- 2.21 vs. 4.51 +/- 1.39 mumol/g/min, p = 0.007) levels were higher in the T1DM subjects. Furthermore, compared with control patients, T1DM subjects exhibited higher MFAU (213 +/- 135 nmol/g/min vs. 57 +/- 28 nmol/g/min, p = 0.0004), MFAO (206 +/- 131 nmol/g/min s. 50 +/- 26 nmol/g/min, p = 0.0002), and %MFAO (94 +/- 6% vs. 81 +/- 19%, respectively, p = 0.04). In contrast, MGU was lower in T1DM subjects than in controls (207 +/- 108 nmol/g/min vs. 403 +/- 191 nmol/g/min, p = 0.0008). Humans with diabetes mellitus exhibit increased MFAU and MFAO and reduced MGU consistent with observations obtained in experimental models of diabetes.

Serial Alterations and Prognostic Implications of Myocardial Perfusion and Fatty Acid Metabolism in Patients With Acute Myocardial Infarction

Impaired fatty acid metabolism the myocardial infarction (MI)-related area has prognostic value, but can alter over time. The aim of this study was to correlate alterations in myocardial fatty acid uptake and perfusion assessed by serial imaging with future outcomes in post-MI patients. Following 2 imaging procedures using 15-4-iodophenyl-3-(R,S)-methylpentadecanoic acid (BMIPP) and perfusion tracers at an 11-month interval, 97 patients with acute MI were followed up for 33 months with respect to the primary endpoints of death, non-fatal MI and heart failure. Regional tracer uptake was semi-quantified for both the MI-related and remote coronary territories. A large BMIPP defect relative to a perfusion defect appeared on MI-related coronary territories. Thirteen patients with cardiac events had a greater prevalence of large BMIPP and perfusion defect scores for the MI-related areas on the first scan, previous MI, diabetes mellitus, and worsening of perfusion tracer uptake in the MI-related area than those without cardiac events. Multivariate analysis identified worsening perfusion in the MI-related area on the second scan, a large BMIPP defect in the same area on the first scan and previous MI as significant predictors with chi-square values of 3.48, 6.41 and 6.84, respectively. A combination of 3 predictors significantly (p<0.05) increased the global chi-square value to 15.45 compared with each chi-square value. The size of the infarct-related risk area assessed by early cardiac BMIPP imaging and deterioration of perfusion tracer uptake in the compromised area for the first 12 months following acute MI are related to future cardiac events, indicating a rationale for identifying metabolically damaged but viable myocardium for further risk stratification of post-MI patients.

Early Positive Biomarker in Relation to Myocardial Necrosis and Impaired Fatty Acid Metabolism in Patients Presenting With Acute Chest Pain at an Emergency Room

Measurement of circulating biomarkers has enabled early diagnosis and risk assessment of acute coronary syndrome. This study sought diagnostic values of the first single-point data of biomarkers obtained soon after patient arrival by comparing with scintigraphically quantified myocardial injury in patients presenting with acute chest pain at an emergency room. Serial blood samples were taken soon after arrival in an emergency department in 74 patients with suspected acute coronary syndrome to quantify blood levels of troponin-T (TnT), heart-type fatty acid-binding protein (H-FABP), myocardial-bound creatine kinase (CK-MB), and myoglobin. Myocardial perfusion and metabolic defects were scintigraphically quantified. The first single-point data had high positive predictive values for detecting the defects (80-100%) but low negative predictive values (15-41%). CK-MB and TnT had higher specificities (73-100%) but significantly lower positive rates (22-27%) than the others (61-68%), resulting in greater sensitivities of H-FABP and myoglobin (75-80%) than those of CK-MB and TnT (29-35%). Among biomarkers, TnT peak concentrations most closely correlated with scintigraphic abnormalities. H-FABP can contribute to early detection of myocardial injury and TnT is most likely to correlate with injured myocardial mass. The differential features of biomarkers are complementary in patients with acute chest pain presenting at an emergency room.

Modulation of Myocardial Energetics

The traditional paradigm for heart failure management centered on mitigating the hemodynamic changes that occur in response to the failing heart. Subsequently, pharmacological modulation of neurohormonal activation and more recently cardiac resynchronization have been shown to reverse ventricular remodeling and to slow disease progression. Despite these advances in therapy, successful treatment of heart failure remains challenging, with rates of hospitalization in the United States exceeding 1 million per year and the annual number of heart failure–related deaths increasing steadily.1 Unfortunately, the history of drug development for heart failure has been marked by many disappointments, most notably the excess mortality associated with oral positive inotropes that were targeted at improving hemodynamics. In addition, more recent interventions aimed at interrupting endothelin and cytokine signaling or reducing oxidative stress have yet to fulfill hopes for novel biological therapies. Thus, new therapeutic strategies are needed to alter the natural history of the disease and to slow or reverse current epidemiological trends. The report by Lee and colleagues2 in this issue of Circulation points toward the promise of an alternative approach based on favorably influencing the efficiency of myocardial energetics, thereby increasing cardiac performance without depending on changes in oxygen consumption or improvement in hemodynamics. Article p 3280 The study of agents aimed at enhancing myocardial energy efficiency has focused principally on shifting myocardial substrate use toward more oxygen-efficient pathways.3 Although the complete oxidation of fatty acids to CO2 yields more adenosine triphosphate (ATP) per molecule of CO2 produced than does complete oxidation of glucose, a greater amount of oxygen is required to completely oxidize a fatty acid of equivalent carbon-chain length. Therefore, for a given amount of oxygen consumed, metabolism of glucose is more “oxygen efficient,” producing ≈15% more ATP (Figure).3,4 Production of ATP and consumption of …

Metabolic therapy for the diabetic patients with ischaemic heart disease

Diabetic patients with ischaemic heart disease have a greater amount of myocardial ischaemia, often silent, and an increased incidence of heart failure compared to nondiabetic patients. This is the result of altered myocardial metabolism and accelerated atherogenesis with involvement of peripheral coronary segments causing chronic hypoperfusion and diffuse hybernation. In patients with diabetes mellitus and myocardial ischaemia, the metabolic changes occurring as a consequence of the mismatch between blood supply and cardiac metabolic requirements are heightened by the diabetic metabolic changes. An important metabolic alteration of diabetes is the increase in free fatty acid concentrations and increased muscular and myocardial free fatty acid uptake and oxidation. This increased uptake and utilization of free fatty acid during stress and ischaemia is responsible for the increased susceptibility of the diabetic heart to myocardial ischaemia and to a greater decrease of myocardial performance for a given amount of ischaemia compared to nondiabetic hearts. Given the metabolic alterations of the diabetic heart at rest and during episodes of myocardial ischaemia, a therapeutic approach aimed at an improvement of cardiac metabolism through manipulations of the utilization of metabolic substrates should result in an improvement of myocardial ischaemia and of left ventricular function. Modulation of myocardial free fatty acid metabolism should be the key target for metabolic interventions in patients with coronary artery disease with and without diabetes. In diabetic patients, the effects of modulation of free fatty acid metabolism should be even greater than those observed in patients without diabetes. The inhibition of FFA oxidation with trimetazidine improves cardiac metabolism at rest, decreases cardiac ischaemia and therefore prevents the decline of left ventricular function due to chronic hypoperfusion and repetitive episodes of myocardial ischaemia. Because of its effect on cardiac metabolism at rest, its effects on myocardial ischaemia and left ventricular function trimetazidine should always be considered for the treatment of diabetic patients with ischaemic heart disease with or without left ventricular dysfunction.

Impact of hormone replacement on myocardial fatty acid metabolism: Potential role of estrogen

Estrogen increases fatty acid utilization and oxidation and may decrease glucose use in human skeletal muscle, whereas these effects are attenuated by progesterone. Whether these ovarian hormones exhibit similar effects on myocardial metabolism is unknown. Myocardial blood flow and oxygen consumption, as well as glucose and fatty acid metabolism, were examined retrospectively by use of positron emission tomography in 24 postmenopausal women receiving estrogen (n = 7), estrogen plus progesterone (n = 8), or no hormone replacement (n = 9) and in 22 age-matched men. Myocardial blood flow was higher in women regardless of hormone replacement status. Myocardial oxygen consumption was higher in women taking estrogen only when compared with men (7.3 +/- 1.6 micromol.g(-1).min(-1) vs 4.6 +/- 1.2 micromol.g(-1).min(-1), P < .001). Glucose utilization was not affected by gender or hormone replacement. Whereas fatty acid levels and the degree of myocardial fatty acid uptake were not distinguished by gender or hormone use, myocardial fatty acid utilization was higher in women taking estrogen when compared with men (259 +/- 68 nmol.g(-1).min(-1) vs 176 +/- 50 nmol.g(-1).min(-1), P = .01) and trended higher when compared with women not receiving hormonal therapy (185 +/- 46 nmol.g(-1).min(-1), P = .07) but was not different from that of women taking estrogen plus progesterone (205 +/- 58 nmol.g(-1).min(-1), P = not significant). In postmenopausal women, estrogen use is associated with increased myocardial fatty acid utilization. Thus, when the cardiac effects of hormone replacement therapy are being assessed, alterations in myocardial substrate metabolism should be considered.

Assessment of contractile response to dobutamine stress by means of ECG-gated myocardial SPECT: Comparison with myocardial perfusion and fatty acid metabolism

The present study assessed left ventricular performance during dobutamine stress measured using gated SPECT, and compared the results to myocardial perfusion and fatty acid metabolism. Thirty-six patients with myocardial infarction given (99m)Tc-sestamibi or (99m)Tc-tetrofosmin were examined by gated SPECT at rest and during dobutamine stress (4-20 microg x kg(-1) x min(-1)). After acquiring data at the highest dose, 201TlCl was injected and dual-isotope SPECT was performed to assess myocardial ischemia. Thirty of 36 patients also underwent myocardial SPECT with 123I-BMIPP. Regional wall motion changes during dobutamine infusion were determined from the gated SPECT data and classified as: (1) Improvement, (2) Worsening, (3) No change, and (4) Biphasic response. For myocardial segments of each infarct area, stress 201Tl, rest (99m)Tc and (123)I-BMIPP uptakes were graded on a five-point scoring system of defects from 0 (normal) to 4 (grossly defective). Rest 99mTc defect score index (DSI) in No change area was significantly higher than that in Biphasic area. The ADSI (stress 201Tl - rest (99m)Tc) in Biphasic area was significantly higher than those in Improvement and No change areas. The deltaDSI (BMIPP - (99m)Tc) in Worsening area tended to be higher than that in No Change area. Regional contractile response to dobutamine stress analyzed by gated SPECT showed that the response in-myocardial infarct areas could be classified by rest and stress myocardial perfusion and BMIPP accumulation.

Influence of substrate supply on cardiac efficiency, as measured by pressure-volume analysis in ex vivo mouse hearts

In the present study, we tested the reliability of measurements of pressure-volume area (PVA) and oxygen consumption (MVo(2)) in ex vivo mouse hearts, combining the use of a miniaturized conductance catheter and a fiber-optic oxygen sensor. Second, we tested whether we could reproduce the influence of increased myocardial fatty acid (FA) metabolism on cardiac efficiency in the isolated working mouse heart model, which has already been documented in large animal models. The hearts were perfused with crystalloid buffer containing 11 mM glucose and two different concentrations of FA bound to 3% BSA. The initial concentration was 0.3 +/- 0.1 mM, which was subsequently raised to 0.9 +/- 0.1 mM. End-systolic and end-diastolic pressure-volume relationships were assessed by temporarily occluding the preload line. Different steady-state PVA-MVo(2) relationships were obtained by changing the loading conditions (pre- and afterload) of the heart. There were no apparent changes in baseline cardiac performance or contractile efficiency (slope of the PVA-MVo(2) regression line) in response to the elevation of the perfusate FA concentration. However, all hearts (n = 8) showed an increase in the y-intercept of the PVA-MVo(2) regression line after elevation of the palmitate concentration, indicating an FA-induced increase in the unloaded MVo(2). Therefore, in the present model, unloaded MVo(2) is not independent of metabolic substrate. This is, to our knowledge, the first report of a PVA-MVo(2) relationship in ex vivo perfused murine hearts, using a pressure-volume catheter. The methodology can be an important tool for phenotypic assessment of the relationship among metabolism, contractile performance, and cardiac efficiency in various mouse models.

A selective angiotensin receptor antagonist, termisaltan, produced regression of left ventricular hypertrophy with the improvement of myocardial perfusion and fatty acid metabolism

A selective angiotensin receptor antagonist, termisaltan, produced regression of left ventricular hypertrophy with the improvement of myocardial perfusion and fatty acid metabolism

Spontaneous Anterograde Flow of the Infarct Artery Preserves Myocardial Perfusion and Fatty Acid Metabolism in Patients With Anterior Acute Myocardial Infarction

It remains unclear whether spontaneous anterograde flow preserves myocardial fatty acid metabolism in patients with acute myocardial infarction (AMI). The present study comprised 129 patients with a first anterior AMI in whom Thrombolysis in Myocardial Infarction (TIMI) 3 flow was obtained on the final angiogram: 28 patients with spontaneous anterograde flow and 101 patients with total occlusion on the initial angiogram. Thallium-201 (201Tl) and iodine-123-beta-methyl-p-iodophenyl penta-decanoic acid (123I-BMIPP) dual-isotope myocardial single-photon emission computed tomography (SPECT) was performed at 6.5+/-4.2 days after onset. The SPECT image was divided into 17 segments, and each segment was graded with scores between 0 and 4 (0, normal uptake; 4, defective). The sum of each score was defined as the total defect score (TDS). TDS values for 201Tl (9.0 +/-7.4 vs 16.8+/-12.2, p < 0.01) and 123I-BMIPP (19.3+/-11.6 vs 24.1 +/-10.4, p < 0.05) were significantly lower in patients with spontaneous anterograde flow than in those with total occlusion. These results suggest that spontaneous anterograde flow of the infarct artery preserves not only myocardial perfusion but also fatty acid metabolism in patients with AMI. 123I-BMIPP SPECT image may underestimate the area at risk especially in patients with spontaneous anterograde flow.

Haplotype analysis of carnitine transporters and left ventricular mass in human essential hypertension

The carnitine-associated alteration of myocardial fatty acid metabolism may be one of the molecular mechanisms underlying left ventricular hypertrophy (LVH) in essential hypertension. We tested the hypothesis that polymorphisms of the genes involved in carnitine transport, OCTN2, CPT1A, CPT1B, and CPT2, might be associated with LVH. Haplotype-based association analysis in an observational study. Outpatients from the Nephrology Division of the University Hospital. A total of 215 never-treated, middle-aged patients with mild essential hypertension. Relationships between left ventricular mass index (LVMI) (measured with m-mode echocardiography) and haplotype combinations for 13 common genetic variants selected from single nucleotide polymorphism database (dbSNPs). The SNPs were selected to cover the genomic region of the four loci, and a total of 23 haplotypes were identified: 8 for OCTN2 (H1 to H8), 8 for CPT1A (H9 to H16), 3 for CPT1B (H17 to H19), and 4 for CPT2 (H20 to H23). In a multilocus haplotype analysis, after adjusting for sex, age, systolic blood pressure, diastolic blood pressure, body mass index, and duration of hypertension, a significant effect on LVMI was seen for H13 (+8.9, P = .05), H14 (-5.63, P = .05), H15 (-18.79, P = .0006), H18 (-1.66, P = .03), and H22 (-3.42, P = .004). These significant haplotypes were respectively 3.7%, 1.6%, 1.6%, 39.3%, and 29.7% of the total population. These results identify the carnitine-transporter gene family as candidate modifiers of LVMI in human hypertension. The use of common SNPs to define informative haplotypes associated with the phenotype of interest is the starting point for progress toward identification of the trapped contributing SNP(s).

Scatter and cross-talk correction for one-day acquisition of123i-bmipp and99mtc-tetrofosmin myocardial spect

123I-15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) and 99mTc-tetrofosmin (TET) are widely used for evaluation of myocardial fatty acid metabolism and perfusion, respectively. ECG-gated TET SPECT is also used for evaluation of myocardial wall motion. These tests are often performed on the same day to minimize both the time required and inconvenience to patients and medical staff. However, as 123I and 99mTc have similar emission energies (159 keV and 140 keV, respectively), it is necessary to consider not only scattered photons, but also primary photons of each radionuclide detected in the wrong window (cross-talk). In this study, we developed and evaluated the effectiveness of a new scatter and cross-talk correction imaging protocol. Fourteen patients with ischemic heart disease or heart failure (8 men and 6 women with a mean age of 69.4 yr, ranging from 45 to 94 yr) were enrolled in this study. In the routine one-day acquisition protocol, BMIPP SPECT was performed in the morning, with TET SPECT performed 4 h later. An additional SPECT was performed just before injection of TET with the energy window for 99mTc. These data correspond to the scatter and cross-talk factor of the next TET SPECT. The correction was performed by subtraction of the scatter and cross-talk factor from TET SPECT. Data are presented as means +/- S.E. Statistical analyses were performed using Wilcoxon's matched-pairs signed-ranks test, and p < 0.05 was considered significant. The percentage of scatter and cross-talk relative to the corrected total count was 26.0 +/- 5.3%. EDV and ESV after correction were significantly greater than those before correction (p = 0.019 and 0.016, respectively). After correction, EF was smaller than that before correction, but the difference was not significant. Perfusion scores (17 segments per heart) were significantly lower after as compared with those before correction (p < 0.001). Scatter and cross-talk correction revealed significant differences in EDV, ESV, and perfusion scores. These observations indicate that scatter and cross-talk correction is required for one-day acquisition of 123I-BMIPP and 99mTc-tetrofosmin SPECT.

Interventricular conduction delay is associated with myocardial fatty acid metabolic abnormalities in dilated cardiomyopathy

Background: Interventricular conduction delay (IVCD) is an important prognostic indicator in dilated cardiomyopathy (DCM). Abnormalities in glucose metabolism are related to prolonged QRS duration in patients with severe heart failure, and improvement after resynchronization therapy is also reported. However, an association between IVCD and abnormal myocardial fatty acid metabolism has not been well understood in DCM patients. Methods: To investigate the association of the metabolic abnormalities with IVCD, I-123 beta-methyliodophenylpentadecanoic acid (BMIPP) and thallium-201 (Tl) single photon emission computed tomography (SPECT) were performed in 62 non-ischemic DCM patients. The uptake was scored visually from 0 (normal) to 3 (defect) in 17 segments of the left ventricle (LV), and a total defect score in all 17 segments was calculated. Results: Seventeen patients with prolonged QRS duration (<130 msec) showed greater LV end-diastolic diameter (70±13 versus 64±7mm, p=0.007) and lowere LV ejection fraction (25 ± 10 versus 31 ± 10%, p = 0.04) as compared with the other 44 without IVCD. The total defect score of BMIPP was greater in the patients with IVCD (22 ± 6 versus 16 ± 8, p = 0.009), although that of Tl was similar. Multiple logistic regression analysis for 10 clinical variables including scintigraphic parameters demonstrated a strong association of the BMIPP score with IVCD (odds ratio: 1.19/ 1 increase, p = 0.02). Conclusions: IVCD in DCM patients is strongly associated with myocardial fatty acid metabolic abnormalities.

A quantitative analysis of I-123 BMIPP uptake in the heart and surrounding tissues

Background: After an exercise-induced ischemia, recent studies have shown prolonged disturbances in myocardial fatty acid metabolism, termed “ischemic memory”, which can be successfully imaged by [ 123I] BMIPP at rest. A potential advantage of BMIPP is that it permits uncoupling of the treadmill stress from tracer injection. In this study, we determined the cardiac image quality of BMIPP by quantifying regional tracer uptake in the heart and surrounding tissues in coronal slices. The results were compared with thallium images obtained in the same patients. Methods: 13 pts with documented reversible thallium defects during exercise underwent subsequent rest BMIPP SPECT imaging within 30 hours of the thallium study. The mean thallium dose injected was 5.2 ± 0.4 mCi while the mean BMIPP dose injected was 3.6 ± 0.4 mCi. After BMIPP injection, two sets of SPECT images were acquired; a 10-minute acquisition obtained 10 minutes after BMIPP injection and a 20-minute acquisition obtained 35–60 minutes after injection. A circular region of interest (ROI) was drawn around the heart, which was then duplicated and repositioned over the lung, liver, and left upper quadrant bowel in coronal slices. Mean counts in each ROI were expressed as lung/heart, liver/heart, and bowel/heart region ratios for thallium, 10-minute BMIPP and 35–60 minute BMIPP images (table). Results: BMIPP images showed excellent cardiac tracer uptake by quantitative SPECT analysis without lung or abdominal visceral interference. The lung/heart and bowel/heart ratios were similar for thallium and BMIPP images. However, the liver/heart ratio was higher for BMIPP images than thallium. Conclusion: The cardiac imaging characteristics of BMIPP are excellent with greater tracer uptake in the heart than the surrounding tissues of lung, liver and bowel. Compared to thallium, BMIPP shows higher liver/heart but similar lung/heart and bowel/heart ratios. However, when the more favorable physical properties of I-123 are taken into consideration, [ 123I] BMIPP becomes an excellent “ischemic memory” cardiac agent. * lung/heart liver/heart bowel/heart BMIPP 10 minute .30 ± .03 .65 ± .18 .25 ± .09 BMIPP 35–60 minute .33 ± .06 .61 ± .15 .30 ± .10 thallium .23 ± .14 .22 ± .07 * .21 ± .06 * different from BMIPP (10 and 35–60 minute) p < 0.03.

Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women.

Obesity is a risk factor for impaired cardiac performance, particularly in women. Animal studies suggest that alterations in myocardial fatty acid metabolism and efficiency in obesity can cause decreased cardiac performance. In the present study, we tested the hypothesis that myocardial fatty acid metabolism and efficiency are abnormal in obese women. We studied 31 young women (body mass index [BMI] 19 to 52 kg/m2); 19 were obese (BMI >30 kg/m2). Myocardial oxygen consumption (MVO2) and fatty acid uptake (MFAUp), utilization (MFAU), and oxidation (MFAO) were quantified by positron emission tomography. Cardiac work was measured by echocardiography, and efficiency was calculated as work/MVO2. BMI correlated with MVO2 (r=0.58, P=0.0006), MFAUp (r=0.42, P<0.05), and efficiency (r=-0.40, P<0.05). Insulin resistance, quantified by the glucose area under the curve (AUC) during an oral glucose tolerance test, correlated with MFAUp (r=0.55, P<0.005), MFAU (r=0.62, P<0.001), and MFAO (r=0.58, P<0.005). A multivariate, stepwise regression analysis showed that BMI was the only independent predictor of MVO2 and efficiency (P=0.0005 and P<0.05, respectively). Glucose AUC was the only independent predictor of MFAUp, MFAU, and MFAO (P<0.05, <0.005, and <0.005, respectively). In young women, obesity is a significant predictor of increased MVO2 and decreased efficiency, and insulin resistance is a robust predictor of MFAUp, MFAU, and MFAO. This increase in fatty acid metabolism and decrease in efficiency is concordant with observations made in experimental models of obesity. These metabolic changes may play a role in the pathogenesis of decreased cardiac performance in obese women.

804-5 Impact of increased fatty acid delivery on myocardial fatty acid metabolism in Obese young women

804-5 Impact of increased fatty acid delivery on myocardial fatty acid metabolism in Obese young women

Fatty acid metabolism assessed by 125I-iodophenyl 9-methylpentadecanoic acid (9MPA) and expression of fatty acid utilization enzymes in volume-overloaded hearts.

The peroxisome proliferator-activated receptor (PPAR) alpha is a member of the nuclear receptor superfamily and regulates gene expression of fatty acid utilization enzymes. In cardiac hypertrophy and heart failure by pressure-overload, myocardial energy utilization reverts to the fetal pattern, and metabolic substrate switches from fatty acid to glucose. However, myocardial metabolism in volume-overloaded hearts has not been rigorously studied. The aim of the present study was to examine fatty acid metabolism and protein expressions of PPARalpha and fatty acid oxidation enzymes in volume-overloaded rabbit hearts. Volume-overload was induced by carotid-jugular shunt formation. Sham-operated rabbits were used as control. Chronic volume-overload increased left ventricular weight and ventricular cavity size, and relative wall thickness was decreased, indicating eccentric cardiac hypertrophy. (125)I-iodophenyl 9-methylpentadecanoic acid (9MPA) was intravenously administered, and animals were sacrificed at 5 min after injection. The 9MPA was rapidly metabolized to iodophenyl-3-methylnonanoic acid (3MNA) by beta-oxidation. Lipid extraction from the myocardium was performed by the Folch method, and radioactivity distribution of metabolites was assayed by thin-layer chromatography. The protein was extracted from the left ventricular myocardium, and levels of PPARalpha and fatty acid oxidation enzymes were examined by Western blotting. Myocardial distribution of 9MPA tended to be more heterogeneous in shunt than in sham rabbits (P = 0.06). In volume-overloaded hearts by shunt, the conversion from 9MPA to 3MNA by beta-oxidation was faster than the sham-control hearts (P < 0.05). However, protein levels of PPARalpha and fatty acid utilization enzymes were unchanged in shunt rabbits compared with sham rabbits. These data suggest that myocardial fatty acid metabolism is enhanced in eccentric cardiac hypertrophy by volume-overload without changes in protein expressions of PPARalpha and fatty acid utilization enzymes. Our data may provide a novel insight into the subcellular mechanisms for the pathological process of cardiac remodelling in response to mechanical stimuli.

A Tc-99m-labeled long chain fatty acid derivative for myocardial imaging.

C-11- and I-123-labeled long chain fatty acid derivatives have been reported as useful radiopharmaceuticals for the estimation of myocardial fatty acid metabolism. We have reported that Tc-99m-labeled N-[[[(2-mercaptoethyl)amino]carbonyl]methyl]-N-(2-mercaptoethyl)-6-aminohexanoic acid ([(99m)Tc]MAMA-HA), a medium chain fatty acid derivative, is metabolized by beta-oxidation in the liver and that the MAMA ligand is useful for attaching to the omega-position of fatty acid derivatives as a chelating group for Tc-99m. On the basis of these findings, we focused on developing a Tc-99m-labeled long chain fatty acid derivative that reflected fatty acid metabolism in the myocardium. In this study, we synthesized a dodecanoic acid derivative, MAMA-DA, and a hexadecanoic acid derivative, MAMA-HDA, and performed radiolabeling and biodistribution studies. [(99m)Tc]MAMA-DA and [(99m)Tc]MAMA-HDA were prepared using a ligand-exchange reaction. Biodistribution studies were carried out in normal mice and rats. Then, a high initial uptake of Tc-99m was observed, followed by a rapid clearance from the heart. The maximum heart/blood ratio was 3.6 at 2 min postinjection of [(99m)Tc]MAMA-HDA. These kinetics were similar to those with postinjection of p-[(125)I]iodophenylpentadecanoic acid. Metabolite analysis showed [(99m)Tc]MAMA-HDA was metabolized by beta-oxidation in the body. In conclusion, [(99m)Tc]MAMA-HDA is a promising compound as a long chain fatty acid analogue for estimating beta-oxidation of fatty acid in the heart.

Cardiac Wall Motion Abnormalities Observed in a Patient With Transient Hyperthyroidism

A 74-year-old woman, with a history of hypertension and hyperlipidemia, was admitted to our hospital. She was found to have a sinus tachycardia with ST-segment elevations in leads II, III, (a)V(F), and V(3) through V(6) in electrocardiography, hypokinesis of the left ventricular apex by echocardiography, and normal findings on coronary angiography. Blood analysis revealed an increase in the creatine kinase MB fraction, a significant positive detection in troponin T, and transient elevations in the concentrations of free triiodothyronine, free thyroxine, thyroid globulin antibody, and thyroid peroxidase antibody. Defects in myocardial perfusion and fatty acid metabolism in the apical area were also demonstrated by myocardial scintigraphy. These data suggest that tako-tsubo syndrome or myocardial infarction may be induced in patients with mild and transient hyperthyroidism.