Validation of an axially distributed model for quantification of myocardial blood flow using ¹³N-ammonia PET.

BACKGROUND: Estimation of myocardial blood flow (MBF) with cardiac PET is often performed with conventional compartmental models. In this study, we developed and evaluated a physiologically and anatomically realistic axially distributed model. Unlike compartmental models, this axially distributed approach models both the temporal and the spatial gradients in uptake and retention along the capillary. METHODS: We validated PET-derived flow estimates with microsphere studies in 19 (9 rest, 10 stress) studies in five dogs. The radiotracer, (13)N-ammonia, was injected intravenously while microspheres were administered into the left atrium. A regional reduction in hyperemic flow was forced by an external occluder in five of the stress studies. The flow estimates from the axially distributed model were compared with estimates from conventional compartmental models. RESULTS: The mean difference between microspheres and the axially distributed blood flow estimates in each of the 17 segments was 0.03 mL/g/minute (95% CI [-0.05, 0.11]). The blood flow estimates were highly correlated with each regional microsphere value for the axially distributed model (y = 0.98x + 0.06 mL/g/minute; r = 0.74; P < .001), for the two-compartment (y = 0.64x + 0.34; r = 0.74; P < .001), and for three-compartment model (y = 0.69x + 0.54; r = 0.74; P < .001). The variance of the error of the estimates is higher with the axially distributed model than the compartmental models (1.7 [1.3, 2.1] times higher). CONCLUSION: The proposed axially distributed model provided accurate regional estimates of MBF. The axially distributed model estimated blood flow with more accuracy, but less precision, than the evaluated compartmental models.

Diagnostic performance of resting CT myocardial perfusion in patients with possible acute coronary syndrome.

OBJECTIVE: Coronary CT angiography has high sensitivity, but modest specificity, to detect acute coronary syndrome. We studied whether adding resting CT myocardial perfusion imaging improved the detection of acute coronary syndrome. SUBJECTS AND METHODS: Patients with low-to-intermediate cardiac risk presenting with possible acute coronary syndrome received both the standard of care evaluation and a research thoracic 64-MDCT examination. Patients with an obstructive (> 50%) stenosis or a nonevaluable coronary segment on CT were diagnosed with possible acute coronary syndrome. CT perfusion was determined by applying gray and color Hounsfield unit maps to resting CT angiography images. Adjudicated patient diagnoses were based on the standard of care and 3-month follow-up. Patient-level diagnostic performance for acute coronary syndrome was calculated for coronary CT, CT perfusion, and combined techniques. RESULTS: A total of 105 patients were enrolled. Of the nine (9%) patients with acute coronary syndrome, all had obstructive CT stenoses but only three had abnormal CT perfusion. CT perfusion was normal in all other patients. To detect acute coronary syndrome, CT angiography had 100% sensitivity, 89% specificity, and a positive predictive value of 45%. For CT perfusion, specificity and positive predictive value were each 100%, and sensitivity was 33%. Combined cardiac CT and CT perfusion had similar specificity but a higher positive predictive value (100%) than did CT angiography. CONCLUSION: Resting CT perfusion using CT angiographic images may have high specificity and may improve CT positive predictive value for acute coronary syndrome without added radiation and contrast. However, normal resting CT perfusion cannot exclude acute coronary syndrome.

Selective improvement in Seattle Heart Failure Model risk stratification using iodine-123 meta-iodobenzylguanidine imaging.

BACKGROUND: The Seattle Heart Failure Model (SHFM) is a multivariable model that uses demographic and clinical markers to predict survival in patients with heart failure. Inappropriate activation of the sympathetic nervous system, which contributes to the progression of heart failure and increased mortality, can be assessed using iodine-123 meta-iodobenzylguanidine (MIBG) cardiac imaging. This study investigated the incremental value of MIBG cardiac imaging when added to the SHFM for prediction of all-cause mortality. METHODS: Survival data from 961 NYHA II-III subjects in the ADMIRE-HFX trial were included in this analysis. The predictive value of the SHFM alone and in combination with MIBG heart-to-mediastinum ratio (H/M) was compared for all-cause mortality (101 deaths during a median follow-up of 2 years). RESULTS: The addition of H/M to the SHFM in a Cox model significantly improved risk prediction (P < .0001), with a greater utility in higher risk SHFM patients. The observed 2-year mortality in the highest-risk SHFM subjects (rounded SHFM score of 1) was 24%, but varied from 46% with H/M <1.2 to 0% with H/M >1.8. Net reclassification improvement was 22.7% (P < .001), with 14.9% of subjects who died reclassified into a higher risk category than suggested by SHFM score alone (P = .01) and 7.9% of subjects who survived reclassified into a lower risk category (P < .0001). The 2-year integrated discrimination improvement (+4.14%, P < .0001) and the 1-year area under the receiver-operator characteristic curve (+0.04, P = .026) both showed significant improvement for the combined model with H/M compared to the SHFM alone. CONCLUSION: The addition of MIBG imaging to the SHFM improves risk stratification, especially in higher risk patients. MIBG may have clinical utility in higher risk patients who are being considered for devices such as ICD, CRT-D, LVAD, and cardiac transplantation.

Psychosocial modulators of angina response to myocardial ischemia.

BACKGROUND: Although angina is often caused by atherosclerotic obstruction of the coronary arteries, patients with similar amounts of myocardial ischemia may vary widely in their symptoms. We sought to compare clinical and psychosocial characteristics associated with more frequent angina after adjusting for the amount of inducible ischemia. METHODS AND RESULTS: From 2004 to 2006, 788 consecutive patients undergoing single-photon emission computed tomography stress perfusion imaging at 2 Seattle hospitals were assessed for their frequency of angina over the previous 4 weeks with the Seattle Angina Questionnaire and for a broad range of psychosocial characteristics. Among patients with demonstrable ischemia on single-photon emission computed tomography (summed difference score >or=2; n=191), angina frequency was categorized as none (Seattle Angina Questionnaire score=100; n=68), monthly (score=61 to 99; n=66), and weekly or daily (score=0 to 60; n=57). Using multivariable ordinal logistic regression, increasing angina was significantly associated with a history of coronary revascularization (odds ratio 2.24, 95% confidence interval 1.19 to 4.19), anxiety (odds ratio 4.72, 95% confidence interval 1.91 to 11.66), and depression (odds ratio 3.12, 95% confidence interval 1.45 to 6.69) after adjustment for the amount of inducible ischemia. CONCLUSIONS: Among patients with a similar burden of inducible ischemia, a history of coronary revascularization and current anxiety and depressive symptoms were associated with more frequent angina. These results support the study of angina treatment strategies that aim to reduce psychosocial distress in conjunction with efforts to lessen myocardial ischemia.

Attenuation-emission alignment in cardiac PET/CT based on consistency conditions.

PURPOSE: In cardiac PET and PET/CT imaging, misaligned transmission and emission images are a common problem due to respiratory and cardiac motion. This misalignment leads to erroneous attenuation correction and can cause errors in perfusion mapping and quantification. This study develops and tests a method for automated alignment of attenuation and emission data. METHODS: The CT-based attenuation map is iteratively transformed until the attenuation corrected emission data minimize an objective function based on the Radon consistency conditions. The alignment process is derived from previous work by Welch et al. ["Attenuation correction in PET using consistency information," IEEE Trans. Nucl. Sci. 45, 3134-3141 (1998)] for stand-alone PET imaging. The process was evaluated with the simulated data and measured patient data from multiple cardiac ammonia PET/CT exams. The alignment procedure was applied to simulations of five different noise levels with three different initial attenuation maps. For the measured patient data, the alignment procedure was applied to eight attenuation-emission combinations with initially acceptable alignment and eight combinations with unacceptable alignment. The initially acceptable alignment studies were forced out of alignment a known amount and quantitatively evaluated for alignment and perfusion accuracy. The initially unacceptable studies were compared to the proposed aligned images in a blinded side-by-side review. RESULTS: The proposed automatic alignment procedure reduced errors in the simulated data and iteratively approaches global minimum solutions with the patient data. In simulations, the alignment procedure reduced the root mean square error to less than 5 mm and reduces the axial translation error to less than 1 mm. In patient studies, the procedure reduced the translation error by > 50% and resolved perfusion artifacts after a known misalignment for the eight initially acceptable patient combinations. The side-by-side review of the proposed aligned attenuation-emission maps and initially misaligned attenuation-emission maps revealed that reviewers preferred the proposed aligned maps in all cases, except one inconclusive case. CONCLUSIONS: The proposed alignment procedure offers an automatic method to reduce attenuation correction artifacts in cardiac PET/CT and provides a viable supplement to subjective manual realignment tools.

Negative ECG-gated cardiac CT in patients with low-to-moderate risk chest pain in the emergency department: 1-year follow-up.

OBJECTIVE: The purpose of this article is to determine the frequency of adverse cardiac events during the year following a negative cardiac CT angiogram in a population of patients presenting to the emergency department with low-to-moderate risk chest pain. SUBJECTS AND METHODS: Eighty-one consecutive patients who had standard of care evaluation for low-to-moderate risk chest pain in the emergency department were enrolled and consented to have a cardiac CT angiogram added to their workup and to have follow-up for 1 year. Eleven patients were excluded, six because their cardiac CT examinations were unsuccessful, four because of a positive cardiac CT angiogram result, and one was lost to follow-up. Seventy patients with negative cardiac CT angiographic results (< 50% stenosis) were included and were interviewed in detail at 3, 6, and 12 months about intervening cardiac events, diagnostic testing, and therapy. Electronic medical records were also reviewed at each time point. RESULTS: None of the 70 patients reported an adverse cardiac event over the 12-month follow-up period. At 1 year, the cause of chest pain was unknown in 49 patients, gastrointestinal in nine patients, anxiety in seven patients, musculoskeletal in three patients, and other in two patients. Three of four patients with 50% or greater stenosis on their cardiac CT had subsequent cardiac catheterization and stent placement. CONCLUSION: In patients with low-to-moderate risk chest pain evaluated in the emergency department, adverse cardiac events may be rare during the 12 months following a negative cardiac CT angiogram.

Whole-chest 64-MDCT of emergency department patients with nonspecific chest pain: Radiation dose and coronary artery image quality with prospective ECG triggering versus retrospective ECG gating.

OBJECTIVE: The purpose of this study was to compare the patient radiation dose and coronary artery image quality of long-z-axis whole-chest 64-MDCT performed with retrospective ECG gating with those of CT performed with prospective ECG triggering in the evaluation of emergency department patients with nonspecific chest pain. SUBJECTS AND METHODS: Consecutively registered emergency department patients with nonspecific low-to-moderate-risk chest pain underwent whole-chest CT with retrospective gating (n = 41) or prospective triggering (n = 31). Effective patient radiation doses were estimated and compared by use of unpaired Student's t tests. Two reviewers independently scored the quality of images of the coronary arteries, and the scores were compared by use of ordinal logistic regression. RESULTS: Age, heart rate, body mass index, and z-axis coverage were not statistically different between the two groups. For retrospective gating, the mean effective radiation dose was 31.8 +/- 5.1 mSv; for prospective triggering, the mean effective radiation dose was 9.2 +/- 2.2 mSv (prospective triggering 71% lower, p < 0.001). Two of 512 segments imaged with retrospective gating were nonevaluable (0.4%), and two of 394 segments imaged with prospective triggering were nonevaluable (0.5%). Prospectively triggered images were 2.2 (95% CI, 1.1-4.5) times as likely as retrospectively gated images to receive a high image quality score for each segment after adjustment for segment differences (p < 0.05). CONCLUSION: For long-z-axis whole-chest 64-MDCT of emergency department patients with nonspecific chest pain, use of prospective ECG triggering may result in substantially lower patient radiation doses and better coronary artery image quality than is achieved with retrospective ECG gating.

Low-risk patients with chest pain in the emergency department: negative 64-MDCT coronary angiography may reduce length of stay and hospital charges.

OBJECTIVE: The current standard-of-care workup of low-risk patients with chest pain in an emergency department takes 12-36 hours and is expensive. We hypothesized that negative 64-MDCT coronary angiography early in the workup of such patients may enable a shorter length of stay and reduce charges. MATERIALS AND METHODS: The standard-of-care evaluation consisted of serial cardiac enzyme tests, ECGs, and stress testing. After informed consent, we added cardiac CT early in the standard-of-care workup of 53 consecutive patients. Fifty patients had negative CT findings and were included in this series. The length of stay and charges were analyzed using actual patient data for all patients in the standard-of-care workup and for two earlier discharge scenarios based on negative cardiac CT results: First, CT plus serial enzyme tests and ECGs during an observation period followed by discharge if all were negative; and second, CT plus one set of enzyme tests and one ECG followed by discharge if all were negative. Comparisons were made using paired Student's t tests. RESULTS: For standard of care and the two CT-based earlier discharge analyses, the mean lengths of stay were 25.4, 14.3, and 5.0 hours; mean charges were $7,597, $6,153, and $4,251. Length of stay and charges were both significantly less (p < 0.001) for the two CT-based analyses. CONCLUSION: In low-risk patients with chest pain, discharge from the emergency department based on negative cardiac CT, enzyme tests, and ECG may significantly decrease both length of stay and hospital charges compared with the standard of care.

Evaluating presynaptic and postsynaptic innervation in heart failure.

Congestive heart failure increasingly contributes to the overall morbidity and mortality associated with cardiovascular disease. Although significant advances in therapies allow patients to feel better and have improved functional status and survival, not all patients respond equally to these therapies. Moreover, for any given level of left ventricular systolic dysfunction, it is difficult to predict who will have progressive heart failure leading to death or transplantation or who will die suddenly. It has long been recognized that the sympathetic nervous system plays a major role in the morbidity and mortality associated with congestive heart failure from systolic left ventricular dysfunction. Although some of the sympathetic effect occurs at the systemic level, malfunction at the ventricular myocyte-sympathetic nerve terminal interface is likely a major contributor to sudden death and progressive heart failure. Imaging the cardiac sympathetic nervous system can be used to evaluate this myoneural interface and to predict outcome.

Accuracy of Myocardial Blood Flow Estimation From Dynamic Contrast-Enhanced Cardiac CT Compared With PET.

Background The accuracy of absolute myocardial blood flow (MBF) from dynamic contrast-enhanced cardiac computed tomography acquisitions has not been fully characterized. We evaluate computed tomography (CT) compared with rubidium-82 positron emission tomography (PET) MBF estimates in a high-risk population. Methods In a prospective trial, patients receiving clinically indicated rubidium-82 PET exams were recruited to receive a dynamic contrast-enhanced cardiac computed tomography exam. The CT protocol included a rest and stress dynamic portion each acquiring 12 to 18 cardiac-gated frames. The global MBF was estimated from the PET and CT exam. Results Thirty-four patients referred for cardiac rest-stress PET were recruited. Of the 68 dynamic contrast-enhanced cardiac computed tomography scans, 5 were excluded because of injection errors or mismatched hemodynamics. The CT-derived global MBF was highly correlated with the PET MBF (r=0.92; P<0.001) with a mean difference of 0.7±26.4%. The CT MBF estimates were within 20% of PET estimates ( P<0.02) with a mean of (1) MBF for resting flow of PET versus CT of 0.9±0.3 versus 1.0±0.2 mL/min per gram and (2) MBF for stress flow of 2.1±0.7 versus 2.0±0.8 mL/min per gram. Myocardial flow reserve was -14±28% underestimated with CT (PET versus CT myocardial flow reserve, 2.5±0.6 versus 2.2±0.6). The proposed rest+stress+computed tomography angiography protocol had a dose length product of 598±76 mGy×cm resulting in an approximate effective dose of 8.4±1.1 mSv. Conclusions In a high-risk clinical population, a clinically practical dynamic contrast-enhanced cardiac computed tomography provided unbiased MBF estimates within 20% of rubidium-82 PET. Although unbiased, the CT estimates contain substantial variance with an standard error of the estimate of 0.44 mL/min per gram. Myocardial flow reserve estimation was not as accurate as individual MBF estimates.

Prospective versus retrospective ECG gating for 64-detector CT of the coronary arteries: comparison of image quality and patient radiation dose.

PURPOSE: To compare image quality and patient radiation dose in a group of patients who underwent 64-detector computed tomography (CT) coronary angiography performed with prospective electrocardiographic (ECG) gating with image quality and radiation dose in a group of patients matched for clinical features who underwent 64-detector CT coronary angiography performed with retrospective ECG gating. MATERIALS AND METHODS: Institutional review board approval was obtained for this HIPAA-compliant study, and the informed consent requirement was waived due to the retrospective study design. Two independent reviewers separately scored coronary artery segment image quality and overall image quality for 100 cardiac CT studies (50 in each group). Interobserver variability was calculated. Patient radiation dose for the actual examination z-axis length was recorded, and a normalized dose was calculated for a 12-cm z-axis length of a typical heart. RESULTS: The two groups matched well for clinical characteristics and CT parameters. There was good agreement for coronary artery segment image quality scores between the independent reviewers (kappa = 0.72). Of the 1253 coronary artery segments scored, the number of coronary artery segments that could not be evaluated in each group was similar (1.1% [seven of 614] in the prospective group vs 1.5% [10 of 647] in the retrospective group, P = .53). Image quality scores were not significantly different when matched for chest cross-sectional area (P > .05). Mean patient radiation dose was 77% lower for prospective gating (4.2 mSv) than for retrospective gating (18.1 mSv) (P < .01). CONCLUSION: Use of 64-detector CT coronary angiography performed with prospective ECG gating has similar subjective image quality scores but 77% lower patient radiation dose when compared with use of retrospective ECG gating.

Evidence for pre- to postsynaptic mismatch of the cardiac sympathetic nervous system in ischemic congestive heart failure.

UNLABELLED: Pre- and postsynaptic cardiac sympathetic function is altered in ischemic congestive heart failure (CHF). Whether there is a presynaptic-to-postsynaptic mismatch or whether mismatch is related to adverse cardiac events is unknown. METHODS: In 13 patients with ischemic CHF and 25 aged-matched healthy volunteers, presynaptic function was measured by PET of (11)C-meta-hydroxyephedrine ((11)C-mHED), a norepinephrine (NE) analog. Postsynaptic function, beta-adrenergic receptor (BAR) density (B'(max)), was measured by imaging (11)C-CGP12177. Myocardial blood flow (MBF) was measured by imaging (15)O-water. Each heart was analyzed both globally and regionally, excluding infarcted regions, and a mismatch score, defined as the ratio of B'(max) to NE uptake (PS(nt))(,) was used to indicate mismatch of post- and presynaptic function. RESULTS: Global and regional MBF was not different between CHF and healthy subjects. The global measure of PS(nt) was lower in CHF (0.32 +/- 0.34) than that in healthy subjects (0.81 +/- 0.33, P < 0.0001) and in all 12 regions. Global B'(max) tended to be lower in CHF than that in healthy subjects (10.0 +/- 6.4 pmol/mL vs. 13.4 +/- 4.2, P = 0.056) and in all 12 regions. The global mismatch score (B'(max):PS(nt)) in CHF patients was significantly greater than that in healthy subjects (50.3 +/- 50.7 vs. 19.3 +/- 9.7, P = 0.005) and also greater in 11 of 12 regions. After 1.5 y of follow-up, 4 individuals had an adverse outcome (CHF death, new or recurrent sudden death, or progressive CHF leading to transplantation). Three of the 4 had mismatch scores > 3 times that of the healthy subjects or the CHF patients without an adverse outcome. CONCLUSION: Mismatch between pre- and postsynaptic left ventricular sympathetic function is present in patients with severe CHF and may be more marked in those with adverse outcomes.

Effect of reconstruction algorithms on myocardial blood flow measurement with 13N-ammonia PET.

UNLABELLED: Filtered backprojection (FBP) is the traditional method for 13N-NH3 PET studies. Ordered-subsets expectation maximization (OSEM) is popular for PET studies because of better noise properties. Scant data exist on the effect of reconstruction algorithms on quantitative myocardial blood flow (MBF) estimation. METHODS: Twenty patients underwent dynamic acquisition rest/stress 13N-NH3 studies. In Part 1, 19 rest/stress image pairs were reconstructed by FBP (10-mm Hanning filter) and by OSEM with 28 subsets and 2 (OSEM2), 6 (OSEM6), or 8 iterations (OSEM8), and a 10-mm postreconstruction smoothing gaussian filter. In Part 2, 9 image pairs were reconstructed by FBP (10-mm Hanning filter) and by OSEM with 28 subsets, 8 iterations, and a gaussian 5-, 10-, or 15-mm postreconstruction smoothing filter. Average MBF (mL/min/mL of myocardium) was calculated using a 3-compartment model. RESULTS: Part 1: For rest MBF, the correlations between FBP and each of the OSEM algorithms were r2 = 0.71, 0.73, and 0.77, respectively. MBF by OSEM6 (0.98 +/- 0.48 [mean +/- SD]) and OSEM8 (0.96 +/- 0.46) was not significantly different from FBP (1.02 +/- 0.39), but OSEM2 (0.80 +/- 0.37) was significantly lower (P < 0.0003). With stress, the correlations were high between FBP and OSEM6 and OSEM8 (r2 = 0.85 and 0.90), and MBF by OSEM6 and OSEM8 was not significantly different from FBP. Part 2: Resting MBF correlated well between FBP and all OSEM smoothing filters (r2 = 0.82, 0.85, and 0.88). Rest MBF using postsmoothing 5- or 10-mm filters was not different from FBP but was significantly lower with the 15-mm filter (P < 0.05). With stress, the correlations were good between FBP and OSEM regardless of smoothing (r2 = 0.76, 0.77, and 0.79). However, MBF with postsmoothing 10- and 15-mm filters was significantly lower than by FBP (P < 0.05). CONCLUSION: Reconstruction algorithms significantly affect the estimation of quantitative blood flow data and should not be assumed to be interchangeable. Although aggressive smoothing may produce visually appealing images with reduced noise levels, it may cause an underestimation of absolute quantitative MBF. In selecting a reconstruction algorithm, an optimal balance between noise properties and diagnostic accuracy must be emphasized.

Risk assessment of patients with clinical manifestations of cardiac sarcoidosis with positron emission tomography and magnetic resonance imaging.

BACKGROUND: Prior studies have shown that late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) and fluorodeoxyglucose (FDG) positron emission tomography (PET) confer incremental risk assessment in patients with cardiac sarcoidosis (CS). However, the incremental prognostic value of the combined use of LGE and FDG compared to either test alone has not been investigated, and this is the aim of the present study. METHODS: Retrospective observational study of 56 symptomatic patients with high clinical suspicion for CS who underwent LGE-CMR and FDG-PET and were followed for the occurrence of death and/or malignant ventricular arrhythmias (VA). RESULTS: The combination of PET and CMR yielded the following groups: 1) LGE-negative/normal-PET (n=20), 2) LGE-positive/abnormal-FDG (n=20), and 3) LGE-positive/normal FDG (n=16). After a median follow-up of 2.6years (IQR 1.2-4.1), 16 patients had events (7 deaths, 10 VA). All, but 1, events occurred in patients with LGE. LGE-positive/abnormal-FDG (7 events, HR 10.1 [95% CI 1.2-84]; P=0.03) and LGE-positive/normal-FDG (8 events, HR 13.3 [1.7-107]; P=0.015) patients had comparable risk of events compared to the reference LGE-negative/normal-PET group. In adjusted Cox-regression analysis, presence of LGE (HR 18.1 [1.8-178]; P=0.013) was the only independent predictor of events. CONCLUSION: CS patients with LGE alone or in association with FDG were at similar risk of future events, which suggests that outcomes may be driven by the presence of LGE (myocardial fibrosis) and not FDG (inflammation).

Exercise training bradycardia is largely explained by reduced intrinsic heart rate.

INTRODUCTION: Resting heart rate (RHR) declines with exercise training. Possible mechanisms include: 1) increased parasympathetic tone, 2) decreased responsiveness to beta-adrenergic stimulation, 3) decreased intrinsic heart rate or 4) combination of these factors. OBJECTIVE: To determine whether an increase in resting parasympathetic tone or decrease in response to beta-adrenergic stimulation contributes to the decrease in RHR with training. METHODS: 51 screened healthy subjects aged 18-32 (n=20, mean age 26, 11 female) or 65-80 (n=31, mean age 69, 16 female) were tested before and after 6months of supervised exercise training. Heart rate response to parasympathetic withdrawal was assessed using atropine and beta-adrenergic responsiveness during parasympathetic withdrawal using isoproterenol. RESULTS: Training increased VO2 max by 17% (28.7±7.7 to 33.6±9.20ml/kg/min, P<0.001). RHR decreased from 62.8±6.6 to 57.6±7.2 beats per minute (P<0.0001). The increase in heart rate in response to parasympathetic withdrawal was unchanged after training (+37.3±12.8 pre vs. +36.4±12.2 beats per min post, P=0.41). There was no change in the heart rate response to isoproterenol after parasympathetic blockade with training (+31.9±10.9 pre vs. +31.0±12.0 post beats per min, P=0.56). The findings were similar in all four subgroups. CONCLUSIONS: We did not find evidence that an increase in parasympathetic tone or a decrease in responsiveness to beta-adrenergic activity accounts for the reduction in resting heart rate with exercise training. We suggest that a decline in heart rate with training is most likely due to decrease in the intrinsic heart rate.

Assessment of the Effects of Age, Gender, and Exercise Training on the Cardiac Sympathetic Nervous System Using Positron Emission Tomography Imaging.

BACKGROUND: Using positron emission tomography (PET) imaging, we sought to determine whether normal age or exercise training cause changes in the cardiac sympathetic nervous system function in male or female healthy volunteers. METHODS: Healthy sedentary participants underwent PET studies before and after 6 months of supervised exercise training. Presynaptic uptake by the norepinephrine transporter-1 function was measured using PET imaging of [(11)C]-meta-hydroxyephedrine, a norepinephrine analog, and expressed as a permeability-surface area product (PSnt in mL/min/mL). Postsynaptic function was measured as ß-adrenergic receptor density (ß'max in pmol/mL tissue) by imaging the ß-receptor antagonist [(11)C]-CGP12177. Myocardial blood flow (MBF in mL/min/mL tissue) was measured by imaging [(15)O]-water. RESULTS: At baseline, there was no age difference in ß'max or MBF but PSnt declined with age (1.12±0.11 young vs 0.87±0.06 old, p = .036). Before training, women had significantly greater MBF (0.87±0.03 vs 0.69±0.03, p < .0001) and PSnt (1.14±0.08 vs 0.75±0.07, p < .001) than men. Training increased VO2 max by 13% (p < .0001), but there were no training effects on ß'max, PSnt, or MBF. Greater MBF in females and a trend to increased PSnt post-training persisted. CONCLUSION: With age, presynaptic uptake as measured by PSnt declines, but there were no differences in ß'max. Endurance training significantly increased VO2 max but did not cause any changes in the measures of cardiac sympathetic nervous system function. These findings suggest that significant changes do not occur or that current PET imaging methods may be inadequate to measure small serial differences in a highly reproducible manner.

High resolution FDG-microPET of carotid atherosclerosis: plaque components underlying enhanced FDG uptake.

This study sought to discover which atherosclerotic plaque components co-localize with enhanced [(18)F]-fluorodeoxyglucose (FDG) uptake in carotid positron emission tomography (PET) images. Although in vivo PET currently lacks the resolution, high-resolution ex vivo FDG-microPET with histology validation of excised carotid plaque might accomplish this goal. Thirteen patients were injected with FDG before carotid endarterectomy. After excision, the plaque specimens were scanned by microPET and magnetic resonance imaging, and then serially sectioned for histological analysis. Two analyses were performed using generalized linear mixed models: (1) a PET-driven analysis which sampled high and low FDG uptake areas from PET images to identify their components in matched histology specimens; and (2) a histology-driven analysis where specific plaque components were selected and matched to corresponding PET images. In the PET-driven analysis, regions of high FDG uptake were more likely to contain inflammatory cells (p < 0.001) and neovasculature (p = 0.008) than regions of low FDG uptake. In the histology-driven analysis, regions with inflammatory cells (p = 0.001) and regions with loose extracellular matrix (p = 0.001) were associated with enhanced FDG uptake. Furthermore, areas of complex inflammatory cell infiltrate (co-localized macrophages, lymphocytes and foam cells) had the highest FDG uptake among inflammatory subgroups (p < 0.001). In conclusion, in carotid plaque, regions of inflammatory cell infiltrate, particularly complex one, co-localized with enhanced FDG uptake in high-resolution FDG-microPET images. Loose extracellular matrix and areas containing neovasculature also produced FDG signal. This study points to the potential ability of FDG-PET to detect the cellular components of the vulnerable plaque.

Effects of aging on cardiovascular responses to parasympathetic withdrawal.

OBJECTIVES: The study was done to determine whether the effects of parasympathetic withdrawal on heart rate, blood pressure (BP), and systolic and diastolic function are altered with normal aging. BACKGROUND: Cardiac responses to beta-adrenergic sympathetic stimulation decline with aging as does the heart rate response to parasympathetic withdrawal, but the extent to which other responses to parasympathetic withdrawal decrease is less clear. METHODS: Heart rate, BP, systolic function, and diastolic filling responses to parasympathetic withdrawal induced by atropine (0.02 mg/kg) were compared in 50 healthy subjects, 28 older (ages 65 to 80 years, mean 70 years; 18 females all on estrogen) and 22 young (age 18 to 32 years, mean 26 years; 12 females) subjects, using radionuclide angiography. RESULTS: Parasympathetic withdrawal in the older group caused less of an increase in heart rate (+33 vs. +48 beats/min), cardiac index (+0.6 vs. +1.5 l/m(2)), systolic blood pressure (-1 vs. +7 mm Hg), and early diastolic filling rate (+1.7 vs. +2.4 end-diastolic volumes/s) (all p < or = 0.01). At similar declines in the diastolic filling period, end-diastolic volume index (EDVI) fell substantially more in the older group (-11.6 vs. -2.4 ml/m(2), p < 0.001). The only gender difference was in diastolic filling rate, which was similar in the young males and females, but significantly less in older males than in older females. CONCLUSIONS: The responses to parasympathetic withdrawal as well as sympathetic stimulation decline with aging, and both contribute to the reduced cardiovascular responses to stress with advancing age.

Effect of chronic total coronary occlusion on treatment strategy.

In a registry analysis of 8,004 consecutive patients presenting for diagnostic catheterization at a single institution from 1990 to 2000, chronic total occlusion (CTO) was found in 52% of patients with significant (> or = 70% diameter stenosis) coronary artery disease. Peripheral vascular disease was the strongest clinical predictor of the presence of a CTO. In a multivariate analysis, CTO was the strongest predictor against the selection of percutaneous coronary intervention (PCI) as a treatment strategy, indicating that efforts to improve the success rate of PCI in CTO may have a significant impact on management of coronary disease.

PET measures of pre- and post-synaptic cardiac beta adrenergic function.

Positron Emission Tomography was used to measure global and regional cardiac beta-adrenergic function in 19 normal subjects and 9 congestive heart failure patients. [(11)C]-meta-hydroxyephedrine was used to image norepinephrine transporter function as an indicator of pre-synaptic function and [(11)C]-CGP12177 was used to measure cell surface beta-receptor density as an indicator of post-synaptic function. Pre-synaptic, but not post-synaptic, function was significantly different between normals and CHF patients. Pre-synaptic function was well matched to post-synaptic function in the normal hearts but significantly different and poorly matched in the CHF patients studied. This imaging technique can help us understand regional sympathetic function in cardiac disease.