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Biomedical subjects

Robert J Gropler

Publications and source records attributed to Robert J Gropler.

32 records · Page 2Linked to original sources
PubMed2003

Impact of aging on myocardial metabolic response to dobutamine.

In humans, under resting conditions there is an age-related decrease in myocardial fatty acid utilization (MFAU) and oxidation (MFAO) and a relative increase in myocardial glucose utilization (MGU). The impact of age on an individual's myocardial metabolic response to catecholamines is not well defined. Sixteen younger (mean age, 26 +/- 5 yr) and 14 older (mean age, 69 +/- 4 yr) volunteers underwent positron emission tomography to measure myocardial blood flow, myocardial oxygen consumption (M.VO2), MFAU, MFAO, and MGU both under resting conditions and during dobutamine infusion. In response to dobutamine administration, the rate-pressure product, myocardial blood flow, and M.VO2 measurements increased by similar amounts in both groups. No age-related differences were noted in the responses of plasma insulin, glucose, fatty acid, or lactate levels to dobutamine. With dobutamine infusion, MFAU and MFAO increased by a similar extent in both younger and older volunteers (age/dobutamine interactions, P = 0.62 and 0.75, respectively). In contrast, MGU increased with dobutamine administration in the younger (from 149 +/- 71 to 209 +/- 78 nmol.g(-1).min(-1); P = 0.04) but not in the older (from 235 +/- 147 to 176 +/- 84 nmol.g(-1).min(-1); P = 0.23; age/dobutamine interaction, P = 0.03) group. With dobutamine infusion, hearts in both younger and older volunteers responded by increasing their MFAU and MFAO values. Whereas younger hearts also responded with an increase in MGU, older hearts did not. Although the clinical significance of these findings awaits further study, these results may partially explain the impaired contractile reserve and the increased incidence of cardiovascular disease in older individuals.

Adrenergic beta-Agonists↗
PubMed2003

Impact of aging on substrate metabolism by the human heart.

BACKGROUND: Results of studies in experimental animals have shown that, with age, myocardial fatty acid metabolism decreases, and glucose metabolism increases. Whether similar changes occur in humans is unknown. METHODS: Seventeen healthy younger normal volunteers (six males, 26 +/- 5 years) and 19 healthy older volunteers (nine males, 67 +/- 5 years) underwent positron emission tomography (PET) under resting conditions in the fasted state. Myocardial blood flow (MBF), myocardial oxygen consumption (MVO(2)), myocardial fatty acid utilization (MFAU) and oxidation (MFAO), and myocardial glucose utilization (MGU) were quantified by PET with (15)O-water, (11)C-acetate, (11)C-palmitate, and(11)C-glucose, respectively. RESULTS: Although MBF was similar between the groups, MVO(2) was higher in the older subjects (5.6 +/- 1.6 micromol/g/min) compared with younger subjects (4.6 +/- 1.0 micromol/g/min, p < 0.04). Rates of MFAU and MFAO (corrected for MVO(2)) were significantly lower in older subjects than in younger subjects (MFAU/MVO(2): 35 +/- 10 vs. 51 +/- 20 nmol free fatty acids (FFA)/nmol O(2) x 10(-3), p < 0.005, and MFAO/MVO(2): 33 +/- 10 vs. 48 +/- 18 nmol FFA/nmol O(2) x 10(-3), p < 0.004). In contrast, the rates of MGU corrected for MVO(2) did not differ between the groups. CONCLUSIONS: With aging, humans exhibit a decline in MFAU and MFAO. Although absolute rates of MGU do not increase, by virtue of the decline in MFAU there is likely an increase in relative contribution of MGU to substrate metabolism. The clinical significance of this metabolic switch awaits further study.

Adult↗
PubMed2003

Myocardial fatty acid metabolism: independent predictor of left ventricular mass in hypertensive heart disease.

The expression of myocardial fatty acid beta-oxidation enzymes is downregulated at the gene transcriptional level in animal models of left ventricular hypertrophy and of heart failure. Humans with idiopathic dilated cardiomyopathy have decreased myocardial fatty acid oxidation. The extent to which molecular mechanisms, such as a reduction in myocardial fatty acid oxidation, regulate the cardiac hypertrophic response in humans in vivo is unknown. Positron emission tomography was used to measure myocardial blood flow, oxygen consumption, fatty acid utilization, and oxidation in two groups of patients: (1) hypertensive left ventricular hypertrophy (n=19; left ventricular mass, 211+/-39 g; left ventricular ejection fraction, 67+/-4%) and (2) left ventricular dysfunction (n=9; left ventricular mass, 210+/-36 g; left ventricular ejection fraction, 31+/-10%); these were compared with a normal control group (n=36; left ventricular mass, 139+/-25 g; left ventricular ejection fraction, 66+/-6%). Left ventricular mass showed significant correlation with gender, diastolic and systolic blood pressure, myocardial fatty acid uptake, utilization and oxidation, myocardial blood flow, body mass index, and left ventricular ejection fraction (all P<0.02). Independent predictors of increased left ventricular mass were male gender (r=0.38, P<0.001), myocardial fatty acid oxidation (r=-0.24, P<0.018), systolic blood pressure (r=0.41, P<0.001), and left ventricular ejection fraction (r=-0.29, P=0.005). Thus, myocardial fatty acid metabolism is an independent predictor of left ventricular mass in hypertension and in left ventricular dysfunction. The extent to which reduced myocardial fatty acid metabolism affects cardiovascular morbidity and mortality and whether pharmacologic modulation results in improved outcomes remains to be determined.

Adult↗
PubMed2002

Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy.

OBJECTIVES: The purpose of this study was to determine whether patients with idiopathic dilated cardiomyopathy (IDCM) exhibit alterations in myocardial fatty acid and glucose metabolism. BACKGROUND: Alterations in myocardial metabolism have been implicated in the pathogenesis of heart failure (HF); however, studies of myocardial metabolic function in human HF have yielded conflicting results. Animal models of HF have shown a downregulation of the expression of enzymes of fatty acid beta-oxidation that recapitulates the fetal energy metabolic program, in which fatty acid metabolism is decreased and glucose metabolism is increased. METHODS: Seven patients with IDCM (mean left ventricular ejection fraction 27 +/- 8%) and 12 normal controls underwent positron emission tomography for measurements of myocardial blood flow (MBF), myocardial oxygen consumption (MVO(2)), myocardial glucose utilization (MGU), myocardial fatty acid utilization (MFAU) and myocardial fatty acid oxidation (MFAO). RESULTS: The systolic and diastolic blood pressures, plasma substrates and insulin levels, MBF and MVO(2), were similar between groups. The rates of MFAU and MFAO were significantly lower in IDCM than in the normal control group (MFAU: 134 +/- 44 vs. 213 +/- 49 nmol/g/min, p = 0.003; and MFAO: 113 +/- 50 vs. 205 +/- 49 nmol/g/min, p = 0.001) and the rates of MGU were significantly higher in IDCM than the normal control group (MGU: 247 +/- 63 vs. 125 +/- 64 nmol/g/min, p < 0.001). CONCLUSIONS: Patients with IDCM exhibit alterations in myocardial metabolism characterized by decreased fatty acid metabolism and increased myocardial glucose metabolism, a pattern similar to that shown in animal models of HF. Whether alterations in myocardial metabolism constitute an adaptive response or mediate the development of HF remains to be determined.

Adult↗
PubMed2002

Dynamic coronary MR angiography and first-pass perfusion with intracoronary administration of contrast agent.

PURPOSE: To evaluate whether dynamic imaging of the coronary arteries can be performed with intracoronary infusion of low-dose gadolinium (Gd)-based contrast agent and assess the effect of long duration and multiple infusions on the image signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR). MATERIALS AND METHODS: Dynamic coronary magnetic resonance (MR) imaging (130 msec/image) and contrast agent first pass myocardial perfusion studies were performed with intracoronary infusions of low-dose Gd-based MR contrast agent on dogs (N = 4) using a fast multislice gradient recalled echo (GRE) sequence. RESULTS: Contrast-enhanced coronary arteries were clearly imaged during infusion periods as long as 2.3 minutes. The SNR and CNR of the contrast-enhanced coronary arteries remained essentially unchanged over multiple consecutive angiographic sessions. In addition, we demonstrated that first pass studies performed with intracoronary injection of MR contrast agent can be used as a means of assessing regional myocardial perfusion. CONCLUSION: These studies demonstrated that, using intracoronary infusion of Gd, coronary magnetic resonance angiography (MRA) can be performed with high temporal resolution, and multiple low-dose slow infusions of Gd-based MR contrast agent can be performed without compromise of the vessel SNR and CNR.

Animals↗
PubMed2002

Combined MR proton lung perfusion/angiography and helium ventilation: potential for detecting pulmonary emboli and ventilation defects.

Three-dimensional (3D) perfusion imaging allows the assessment of pulmonary blood flow in parenchyma and main pulmonary arteries simultaneously. MRI using laser-polarized (3)He gas clearly shows the ventilation distribution with high signal-to-noise ratio (SNR). In this report, the feasibility of combined lung MR angiography, perfusion, and ventilation imaging is demonstrated in a porcine model. Ultrafast gradient-echo sequences have been used for 3D perfusion and angiographic imaging, in conjunction with the use of contrast agent injections. 2D multiple-section (3)He imaging was performed subsequently by inhalation of 450 ml of hyperpolarized (3)He gas. The MR techniques were examined in a series of porcine models with externally delivered pulmonary emboli and/or airway occlusions. With emboli, perfusion deficits without ventilation defects were observed; airway occlusion resulted in matched deficits in perfusion and ventilation. High-resolution MR angiography can unambiguously reveal the location and size of the blood emboli. The combination of the three imaging methods may provide complementary information on abnormal lung anatomy and function.

Airway Obstruction↗
PubMed2002

Comparison of 1-(11)C-glucose and (18)F-FDG for quantifying myocardial glucose use with PET.

UNLABELLED: In this study, we compared the accuracy of the rate of myocardial glucose use (rMGU) measured using PET and 1-(11)C-glucose with the rate measured using PET and the more conventional tracer (18)F-FDG. METHODS: PET measurements of myocardial tracer uptake (K, in mL/g/min) and rMGU (in nmol/g/min) were obtained with 1-(11)C-glucose and (18)F-FDG in 21 dogs using kinetic modeling and the Patlak graphical method, respectively. Eighteen dogs were studied during hyperinsulinemic-euglycemic clamp performed either at rest or combined with phenylephrine, dobutamine, intralipid infusion, or intralipid infusion and dobutamine. Three dogs were studied during intralipid infusion alone under resting conditions. Arterial-coronary sinus sampling was performed to measure the K of both tracers (n = 14) and rMGU by the Fick method (n = 21). RESULTS: PET-derived values for K from either 1-(11)C-glucose or (18)F-FDG correlated closely with directly measured tracer K values (glucose: y = 0.98x + 0.01, r = 0.79, P < 0.001; (18)F-FDG: y = 0.74x + 0.03, r = 0.77, P < 0.001). In contrast, correlation with K values of unlabeled glucose measured directly was better for 1-(11)C-glucose (y = 0.92x + 0.02, r = 0.96, P < 0.0001) than for (18)F-FDG (y = 0.66x + 0.05, r = 0.72, P < 0.01) (P < 0.001 for comparison of correlation coefficients). As a consequence, PET-derived values for rMGU correlated more closely with Fick-derived measurements of unlabeled glucose using 1-(11)C-glucose (y = 0.82x + 168, r = 0.97, P < 0.0001) than with (18)F-FDG (y = 0.81x + 278, r = 0.79, P < 0.001) (P < 0.001 for comparison of correlation coefficients). CONCLUSION: Over a wide range of conditions, PET-derived measurements of rMGU are obtained more accurately with 1-(11)C-glucose than with (18)F-FDG.

Adrenergic Agonists↗
PubMed2002

Delineation of hypoxia in canine myocardium using PET and copper(II)-diacetyl-bis(N(4)-methylthiosemicarbazone).

UNLABELLED: Copper(II)-diacetyl-bis(N(4)-methylthiosemicarbazone) (copper-ATSM) is a hypoxia-avid tracer for the selective identification of hypoxic tissue. Using canine models of hypoxic myocardium, we report our findings on *Cu-ATSM PET (*Cu is defined as either (60)Cu, (61)Cu, or (64)Cu) for the delineation of ischemic and hypoxic myocardium. METHODS: In protocol I, myocardial hypoxia was induced by global hypoxia (n = 3). In protocol II, myocardial ischemia was generated by occlusion of the left anterior descending coronary artery (n = 9). In protocol III, coronary artery stenosis was induced by a stenosis in the left anterior descending coronary artery (n = 4). PET dynamic data were acquired immediately after tracer injection. Tracer retention kinetics were analyzed using either monoexponential analysis (1/k(mono)) or a simple 2-compartment model (1/k(4)). RESULTS: In protocol I, tracer retention in hypoxic myocardium was 2-fold greater than in normal myocardium, despite a 7-fold increase in blood flow (normal, 0.70 +/- 0.42 mL.min(-1).g(-1); hypoxic, 4.94 +/- 3.00 mL.min(-1).g(-1) [P < 0.005]). In protocol II, approximately 3 h after occlusion, retention of *Cu-ATSM within 20 min was greater in ischemic regions (myocardial blood flow, 0.28 +/- 0.26 mL.min(-1).g(-1)) than in normal tissue (myocardial blood flow, 0.52 +/- 0.19 mL.min(-1).g(-1)) (1/k(mono), 40.72 +/- 39.0 min vs. 26.69 +/- 22.29 min [P < 0.05]; 1/k(4), 6.85 +/- 4.90 min vs. 3.51 +/- 1.97 min [P < 0.05]). In selected dogs, tracer retention decreased at 24 h, suggesting the development of necrosis with no subsequent retention of *Cu-ATSM. In protocol III, dobutamine infusion after stenosis placement resulted in increased tracer retention consistent with hypoxia in the damaged regions. CONCLUSION: *Cu-ATSM PET has shown quantitative selective uptake in hypoxic myocardium within 20 min of tracer administration in 3 canine models of hypoxia.

Animals↗
PubMedDate not supplied

Imaging of myocardial metabolism.

There is compelling evidence that alterations in myocardial substrate use play a key role in a variety of normal and abnormal cardiac conditions such as aging, left ventricular hypertrophy, and diabetic heart disease. However, it is unclear whether the metabolic changes are adaptive or maladaptive. Development of transgenic models targeting key aspects of myocardial substrate use, such as uptake, oxidation, and storage, is accelerating our understanding of the metabolic perturbations of cardiac disease. However, whether the metabolic phenotype in these models is relevant to the human condition is frequently unknown. The importance of altered myocardial metabolism in the pathogenesis of cardiac disease is underscored by the current robust development of novel therapeutics that target myocardial substrate use. Currently, magnetic resonance spectroscopy, single photon emission computed tomography, and positron emission tomography are the 3 methods available to image myocardial substrate metabolism. In this review the role of metabolic imaging in the study of specific cardiac disease processes will be discussed. Both the current and future capabilities of metabolic imaging to furthering our understanding of cardiac disease are highlighted.

Cardiovascular Diseases↗
PubMedDate not supplied

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

BACKGROUND: 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. METHODS AND RESULTS: 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). CONCLUSIONS: 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.

Aged↗
PubMedDate not supplied

Hypertensive left ventricular hypertrophy is associated with abnormal myocardial fatty acid metabolism and myocardial efficiency.

BACKGROUND: Hypertension-induced left ventricular hypertrophy (LVH) is associated with an increased risk of cardiovascular morbidity and death by mechanisms not well characterized. METHODS AND RESULTS: Myocardial fatty acid (FA) metabolism and left ventricular (LV) mass were evaluated in 13 patients with hypertensive LVH with normal LV ejection fraction and 42 normal control subjects (primary cohort). Contractile performance was also evaluated in 5 hypertensive LVH patients and 5 matched normal control subjects (magnetic resonance [MR] substudy). Myocardial FA utilization (MFAU) and myocardial FA oxidation (MFAO) were assessed by positron emission tomography by use of 1-carbon-11 palmitate. Myocardial contractile function (strain and stress) was determined by cardiac MR imaging with tissue tagging and calibrated arterial pressure traces; myocardial external minute work and efficiency were derived. In the primary cohort decreased MFAO was predictive of increased LV mass (model r(2) = 0.61, P = .03). In the MR substudy decreased MFAO (corrected for myocardial oxygen consumption [MVO(2)]) in the hypertensive LVH group compared with the normal group (MFAU/MVO(2), 26 +/- 5 vs 37 +/- 8; MFAO/MVO(2), 24 +/- 6 vs 35 +/- 7; both P = .03) was paralleled by decreased myocardial external minute work (0.13 +/- 0.03 J x g(-1) x min(-1) vs 0.17 +/- 0.04 J x g(-1) x min(-1), P = .07) and decreased myocardial efficiency (5.2% +/- 1.4% vs 7.1% +/- 1.0%, P = .03). CONCLUSIONS: Abnormalities in myocardial FA metabolism are apparent in hypertensive LVH, and these abnormalities may be responsible, at least in part, for a reduction in myocardial efficiency.

Aged↗
PubMedDate not supplied

Quantification of myocardial glucose utilization by PET and 1-carbon-11-glucose.

BACKGROUND: Measurements of the rate of myocardial glucose utilization (rMGU) play a key role in the assessment of alterations in myocardial substrate metabolism in normal and abnormal cardiac states. In this study we determined whether rMGU could be quantified by positron emission tomography (PET) and 1-carbon-11-glucose. METHODS AND RESULTS: Twenty dogs were studied with a variety of interventions including fasting (n = 5), hyperinsulinemic-euglycemic clamp at rest (n = 6), clamp and phenylephrine (n = 5), and clamp and dobutamine (n = 4). Measurements of myocardial blood flow and rMGU were made by PET with oxygen-15-water and 1-C-11-glucose, respectively. Arterial-coronary sinus sampling was performed to measure rMGU by the Fick method. Values for rMGU ranged from 50 to 2436 nmol/g/min. Myocardial 1-C-11-glucose images of high quality were obtained. There was a close and direct correlation between values for rMGU measured by PET and those measured directly (y = 0.86 x + 112, r = 0.98, P <.0001). The coefficient of variation for the regional estimates of rMGU ranged from 11.3% +/- 7.4% during clamp at rest to 16.3% +/- 8.4% during clamp with phenylephrine. CONCLUSIONS: It now appears possible to quantify myocardial glucose utilization by PET with 1-C-11-glucose. This method should become a valuable tool in the assessment of alterations in myocardial glucose metabolism in both normal and abnormal myocardium.

Animals↗