Biomedical subjects

Stephan G Nekolla

Publications and source records attributed to Stephan G Nekolla.

29 records · Page 2Linked to original sources

PubMed2004

Sympathetic reinnervation, exercise performance and effects of beta-adrenergic blockade in cardiac transplant recipients.

AIMS: To evaluate effects of beta-adrenergic receptor blockade on allograft performance, and to correlate these effects with sympathetic reinnervation. METHODS AND RESULTS: Myocardial catecholamine storage capacity was determined in 12 non-rejecting transplant recipients using PET and C-11 adrenaline (epinephrine). Haemodynamics and left ventricular function were measured using radionuclide angiography at rest and during symptom-limited exercise before and after non-selective beta-blockade (propranolol iv). Exercise time and stress-induced increases of heart rate and LVEF before beta-blockade were significantly higher in reinnervated compared to denervated recipients. While resting LVEF remained unchanged, heart rate and blood pressure were generally reduced by beta-blockade, which was well tolerated by all patients. Exercise time and increases of heart rate and LVEF were more attenuated in reinnervated recipients. Differences of chronotropic and inotropic response to exercise between groups were no longer present following beta-blockade. Correlations between myocardial adrenaline retention, peak heart rate and increase of global, as well as regional ejection fraction during exercise were observed before, but not during beta-blockade. CONCLUSION: Acute, non-selective beta-blockade is well tolerated by transplant recipients, but significantly attenuates beneficial functional effects of sympathetic reinnervation on exercise performance. The data suggest that reappearance of sympathetic nerve terminals is associated with reestablishment of intact pre-/postsynaptic interaction.

Adrenergic beta-Antagonists↗

PubMed2004

Electromechanical properties of perfusion/metabolism mismatch: comparison of nonfluoroscopic electroanatomic mapping with 18F-FDG PET.

UNLABELLED: The aim of this study was to compare nonfluoroscopic electroanatomic mapping (NOGA), SPECT perfusion imaging, and PET metabolic imaging for assessment of myocardial viability. In particular, we sought to elucidate differences of electromechanical properties between the perfusion/metabolism mismatch as an indicator of a potentially reversible ischemic injury and the perfusion/metabolism match indicating irreversibly damaged myocardial tissue. METHODS: Twenty-one patients with coronary artery disease underwent NOGA mapping of endocardial unipolar voltage, cardiac 18F-FDG PET of glucose utilization, and resting 201Tl SPECT of myocardial perfusion. RESULTS: Electrical activity was 10.8 +/- 4.6 mV (mean +/- SD) in normal myocardium and was unchanged in hypoperfused segments with maintained glucose metabolism (perfusion/metabolism mismatch), 9.3 +/- 3.4 mV (P = not significant). In contrast, hypoperfused segments with a perfusion/metabolism match and nonviable segments showed significantly lower voltage (6.9 +/- 3.1 mV, P < 0.0001 and 4.1 +/- 1.1 mV, P < 0.0001 vs. normal). In hypoperfused segments, metabolic activity was more closely related to endocardial voltage than was myocardial perfusion (201Tl vs. voltage: r = 0.38, SEE = 3.2, P < 0.001; 18F-FDG PET vs. voltage: r = 0.6, SEE = 2.8, P < 0.0001). CONCLUSION: In hypoperfused myocardium, electrical activity by NOGA mapping is more closely related to PET metabolic activity than to SPECT myocardial perfusion. As NOGA mapping does not differentiate hypoperfused myocardium with enhanced glucose utilization from normal myocardium, results from NOGA mapping need to be correlated with results from perfusion imaging to identify hypoperfused, yet viable, myocardium and to stratify patients for revascularization procedures.

Coronary Artery Disease↗

PubMed2003

Noninvasive imaging of transgene expression by use of positron emission tomography in a pig model of myocardial gene transfer.

BACKGROUND: Radionuclide imaging of reporter gene expression may be useful for noninvasive monitoring of clinical cardiac gene therapy. Experience until now, however, has been limited to small animals. METHODS AND RESULTS: To evaluate feasibility in a clinically applicable setting, pigs were studied by conventional positron emission tomography (PET) 2 days after regional intramyocardial injection of control adenovirus or adenovirus carrying herpesviral thymidine kinase reporter gene (HSV1-tk). Myocardial blood flow was quantified by use of [13N]ammonia. Subsequently, kinetics of the reporter substrate [124I]-2'-fluoro-2'-deoxy-5-iodo-1-beta-d-arabino-furanosyluracil (FIAU) were assessed over a period of 2 hours. Areas infected with adenovirus expressing HSV1-tk showed significantly elevated FIAU retention during the first 30 minutes after injection. At later times, washout was observed, and retention was not different from that in areas infected with control virus or remote myocardium. Early in vivo FIAU uptake correlated with ex vivo images, autoradiography, and immunohistochemistry for reporter gene product after euthanasia. After intramyocardial injection of both adenoviruses, myocardial blood flow was mildly elevated compared with that in remote areas, consistent with histological signs of regional inflammation. CONCLUSIONS: In vivo quantification of regional myocardial transgene expression is feasible with clinical PET methodology, the radioiodinated reporter probe FIAU, and the HSV1-tk reporter gene. Radioactivity efflux after specific initial uptake was not observed previously in tumor studies, suggesting that tissue-specific differences in nucleoside metabolism influence reporter probe kinetics. By coregistering reporter gene expression with additional biological parameters such as myocardial blood flow, PET allows for noninvasive characterization of the success of cardiac gene transfer along with its functional correlates.

Animals↗

PubMed2003

Cardiac oxidative metabolism, function, and metabolic performance in mild hyperthyroidism: a noninvasive study using positron emission tomography and magnetic resonance imaging.

Using noninvasive imaging, we have previously demonstrated that myocardial efficiency is impaired in hypothyroidism and improves after establishing euthyroid conditions. Little is known about the effects of abnormally elevated thyroid hormone exposure on cardiac metabolic performance. We studied 10 patients without evidence of heart disease in mild hyperthyroidism, and after therapy under euthyroid conditions. Cardiac oxidative metabolism was quantified by positron emission tomography with [(11)C]acetate. Left ventricular geometry was determined by cine magnetic resonance imaging. Myocardial efficiency, defined by the relation between work and oxygen consumption, was estimated using the work metabolic index [WMI = stroke volume * systolic blood pressure * heart rate/(oxidative metabolism * ventricular mass)]. In hyperthyroidism, heart rate and cardiac output were expectedly higher. Peripheral vascular resistance was reduced. Differences of blood pressure, stroke volume, and ventricular mass were not observed. Oxidative metabolism was significantly higher, but WMI was not different from the euthyroid state. In summary, while improvement of efficiency through thyroid hormone substitution was observed previously in hypothyroidism, our data in mild hyperthyroidism suggest an increase of oxygen consumption, paralleled by an increase of work. Thus, moderately elevated thyroid hormone levels neither result in further increase nor in reduction of cardiac metabolic performance.

Acetates↗

PubMed2002

Dysregulation of coronary microvascular reactivity in asymptomatic patients with type 2 diabetes mellitus.

In diabetic patients, a number of studies have suggested an impairment of vascular reactivity in response to vasodilatory stimuli. The pattern of dysregulation at the coronary microcirculatory level, however, has not been clearly defined. Thus, it was the aim of this study to characterise coronary microvascular function non-invasively in a homogeneous group of asymptomatic type 2 diabetic patients. In 46 patients with type 2 diabetes, myocardial blood flow (MBF) was quantified at baseline, in response to cold pressor test (CPT) and during adenosine-mediated vasodilation using positron emission tomography and nitrogen-13 ammonia. None of the patients had been treated with insulin, and none had symptoms of cardiac disease. Decreased MBF during CPT, indicating microvascular dysregulation, was observed in 16 patients (CPT-), while 30 patients demonstrated increased MBF during CPT (CPT+). Response to CPT was mildly, but significantly correlated with response to adenosine ( r=0.44, P=0.0035). There was no difference in HbA1c, serum lipid levels or serum endothelial markers between the groups. Microvascular dysregulation in the CPT- group was associated with elevated baseline MBF ( P<0.0001), reduced baseline vascular resistance ( P=0.0026) and an abnormal increase in resistance during CPT ( P=0.0002). In conclusion, coronary microvascular dysregulation is present in approximately one-third of asymptomatic, non-insulin-treated type 2 diabetic patients. Elevated baseline blood flow and reduced microvascular resistance at rest are characteristics of this dysregulation. These data suggest a state of activation of endothelial-dependent vasodilation at baseline which appears to limit the flow response to stress conditions.

Adenosine↗

PubMed2002

Clinical determinants of ventricular sympathetic reinnervation after orthotopic heart transplantation.

BACKGROUND: It has been demonstrated that ventricular sympathetic reinnervation after cardiac transplantation improves exercise performance. The extent of reinnervation increases with time but is variable. Little is known about other influencing factors. METHODS AND RESULTS: Seventy-seven nonrejecting transplant recipients were cross-sectionally studied by PET with the catecholamine analogue C-11 hydroxyephedrine at 4.8+/-3.5 years after transplantation. Results were compared with history-derived parameters related to recipient's clinical course before, during, and after surgery; donor characteristics; and immunogenetics. Partial reinnervation was observed in 52 patients (extent, 21+/-16% of left ventricle). Complete denervation was found in 25 patients at various times after transplantation. Reinnervation extent correlated with time after surgery (r=0.387; P<0.001) but also inversely with donor age (r=-0.309, P=0.006) and recipient age (r=-0.243, P=0.032). Maximal hydroxyephedrine retention correlated inversely with frequency of rejection episodes (r=-0.267, P=0.019), was reduced when aortic complications occurred perioperatively (9 patients), and correlated inversely with aortic cross-clamp time (r=-0.331, P=0.006). Other parameters were not associated with reinnervation. Patients were surveyed for clinical complications over >12 months after PET (until 7.3+/-4.2 years after transplantation), but significant effects of reinnervation on outcome were not observed. CONCLUSIONS: The present data suggest that sympathetic reinnervation after cardiac transplantation is not simply a function of time. Reinnervation is more likely with young age, fast and uncomplicated surgery, and low rejection frequency. Despite few effects on prognosis in otherwise healthy recipients, improved understanding of clinical determinants may contribute to enhance allograft reinnervation and thereby augment exercise capacity in the future.

Adult↗

PubMed2002

Myocardial distribution of (18)F-FDG and (99m)Tc-sestamibi on dual-isotope simultaneous acquisition SPET compared with PET.

A dual-isotope simultaneous acquisition (DISA) single-photon emission tomography (SPET) protocol with fluorine-18 fluorodeoxyglucose ((18)F-FDG) and a technetium-99m labelled flow tracer is attractive because it permits assessment of both myocardial glucose utilisation and flow within a single study. Differences in physical and physiological characteristics between (18)F-FDG and the (99m)Tc-labelled flow tracer, however, may cause differences in myocardial activity distribution between the agents. The aim of this study was to investigate the relation between the myocardial distribution of (18)F-FDG and a (99m)Tc-labelled flow tracer on DISA SPET in comparison with nitrogen-13 ammonia/(18)F-FDG positron emission tomography (PET). Nine normal volunteers without cardiac disease and ten patients with known coronary artery disease (CAD) underwent (13)N-ammonia/(18)F-FDG PET and (99m)Tc-sestamibi/(18)F-FDG DISA SPET. Using a semiquantitative polar map approach, the left ventricular myocardium was divided into nine segments, and relative regional activity was calculated for each segment. A segment was considered to have concordant uptake between (18)F-FDG and flow tracer if the difference in measured regional activity between the tracers was < or =10% of peak activity, and the percentage of concordant segments was calculated for each subject. There was a good overall concordance of myocardial activity between the agents on DISA SPET (84.0%+/-14.8%) in normals, which was comparable to that seen on PET (86.4%+/-14.5%, NS vs DISA SPET). However, the myocardial activity distributions of (18)F-FDG and flow tracer were not identical in that reduced flow tracer activity was seen in the basal segments on DISA SPET in both normals and CAD patients. It is concluded that there is good overall concordance of activity between (18)F-FDG and flow tracer in normal myocardium on DISA SPET, which is comparable to that on PET, supporting the use of combined (99m)Tc-flow tracer/(18)F-FDG imaging for the detection of viable myocardium. However, there is a difference in the myocardial activity distribution between the agents in both normals and CAD patients, the difference being particularly evident in the basal segments. Therefore, careful image interpretation that takes into consideration the different normal activity distribution between the tracers and/or a tracer-specific normal database is necessary for comparison with patient studies.

Adult↗

PubMed2002

Deferoxamine improves coronary vascular responses to sympathetic stimulation in patients with type 1 diabetes mellitus.

Effects of oxygen-derived free radicals are suggested to be a potential pathogenic factor for endothelial dysfunction. In this study we sought to evaluate the effect of hydroxyl radicals on the human coronary vascular bed in type I diabetes mellitus using positron emission tomography (PET). Thirteen patients with type 1 diabetes underwent PET using nitrogen-13 ammonia at rest and during sympathetic stimulation with the cold pressor test (CPT). The rest-stress study protocol was repeated twice (on different days) using pre-stress infusion of either saline as placebo or deferoxamine, an iron chelator which inhibits generation of hydroxyl radicals. At rest, global MBF was higher in diabetics than in normal controls (78.1+/-17.5 vs 63.2+/-14.9 mg 100 g(-1) min(-1), P<0.05) and myocardial vascular resistance (MVR) showed a trend towards lower values (patients, 1.28+/-0.35; controls, 1.55+/-0.32, P=NS). CPT increased MBF in all controls while 7/13 diabetics responded normally. CPT decreased MVR in 10/13 controls but in only 4/13 diabetics. There was no significant difference in the duration of diabetes, HbA1c, daily insulin dose, body mass index, or lipid profiles between patients with and patients without abnormal MBF or MVR responses. Pre-stress infusion of deferoxamine normalized MBF response in all six patients, and MVR response in six of the nine patients. Another group consisting of seven patients underwent a rest-rest protocol after infusion of deferoxamine and saline to investigate the effect of deferoxamine on resting MBF. Deferoxamine did not change the resting MBF (deferoxamine, 81+/-17 ml 100 g(-1) min(-1); saline, 75+/-19 ml 100 g(-1) min(-1), P=NS) or MVR (deferoxamine, 1.0+/-0.5 mmHg ml(-1) 100 g(-1) min(-1); saline, 1.2+/-0.6 mmHg ml(-1) 100 g(-1) min(-1), P=NS). In conclusion, inhibition of hydroxyl radical formation using deferoxamine significantly improved the responses of coronary microvasculature to sympathetic stimulation. Hydroxyl radicals may play a role in the pathogenesis of flow abnormalities in type 1 diabetes.

Ammonia↗

PubMed2002

Assessment of coronary flow reserve: comparison between contrast-enhanced magnetic resonance imaging and positron emission tomography.

OBJECTIVES: The study compared flow reserve indices by magnetic resonance imaging (MRI) with quantitative measures of coronary angiography and positron emission tomography (PET). BACKGROUND: The noninvasive evaluation of myocardial flow by MRI has recently been introduced. However, a comparison to quantitative flow measurement as assessed by PET has not been reported in patients with coronary artery disease (CAD). METHODS: Two groups of healthy volunteers and 25 patients with angiographically documented CAD were examined by MRI and PET at rest and during adenosine stress. Dynamic MRI was performed using a multi-slice ultra-fast hybrid sequence and a rapid gadolinium-diethylenetriaminepenta-acetic acid bolus injection (0.05 mmol/l). Upslope and peak-intensity indices were regionally determined from first-pass signal intensity curves and compared to N-13 ammonia PET flow reserve measurements. RESULTS: In healthy volunteers, the upslope analysis showed a stress/rest index of 2.1 plus minus 0.6, which was higher than peak intensity (1.5 plus minus 0.3), but lower than flow reserve by PET (3.9 plus minus 1.1). Localization of coronary artery stenoses (> 75%, MRI < 1.2), based on the upslope index, yielded sensitivity, specificity and diagnostic accuracy of 69%, 89% and 79%, respectively. Upslope index correlated with PET flow reserve (r = 0.70). A reduced coronary flow reserve (PET < 2.0, MRI < 1.3) was detected by the upslope index with sensitivity, specificity and diagnostic accuracy of 86%, 84% and 85%, respectively. CONCLUSIONS: Magnetic resonance imaging first-pass perfusion measurements underestimate flow reserve values, but may represent a promising semi-quantitative technique for detection and severity assessment of regional CAD.

Adult↗

PubMed2002

Assessment of myocardial viability with contrast-enhanced magnetic resonance imaging: comparison with positron emission tomography.

BACKGROUND: Recent studies indicate that MRI, after administration of gadolinium-diethylenetriamine pentaacetic acid, can identify nonviable areas in dysfunctional myocardium. We compared MRI hyperenhancement with PET as a gold standard for detection and quantification of myocardial scar tissue. METHODS AND RESULTS: Thirty-one patients with ischemic heart failure (ejection fraction, 28+/-9%) were imaged with PET and MRI. Scar was defined as regionally increased MRI signal intensity 20 minutes after injection of 0.2 mmol/kg gadolinium-diethylenetriamine pentaacetic acid and as concordantly reduced perfusion and glucose metabolism as defined by PET. Sensitivity and specificity of MRI in identifying patients and segments (n=1023) with matched flow/metabolism defects was 0.96 of 1.0 and 0.86 of 0.94, respectively. Eleven percent of segments defined as viable by PET showed some degree of MRI hyperenhancement. Defect severity score based on visual analysis was 44.3+/-9.1 for PET and 47.6+/-11.1 for MRI (r=0.91, P<0.0001). Quantitatively assessed relative MRI infarct mass correlated well with PET infarct size (r=0.81, P<0.0001). Furthermore, MRI hyperenhancement was a better predictor of scar tissue than end-diastolic and end-systolic wall thickness or thickening. CONCLUSIONS: In severe ischemic heart failure, MRI hyperenhancement as a marker of myocardial scar closely agrees with PET data. Although hyperenhancement correlated with areas of decreased flow and metabolism, it seems to identify scar tissue more frequently than PET, reflecting the higher spatial resolution. Additional functional studies after revascularization are required to define the significance of small islands of scar detected by MRI.

Cell Survival↗

PubMed2002

Alterations of the sympathetic nervous system and metabolic performance of the cardiomyopathic heart.

Little is known about the effects of altered sympathetic innervation on the efficiency of the cardiomyopathic heart. Thus, it was the aim of this study to determine non-invasively the relationship between the metabolic cost of cardiac work and alterations of the sympathetic nervous system. In ten patients with chronic idiopathic dilated cardiomyopathy, left ventricular function and geometry were assessed by tomographic radionuclide angiography. Myocardial oxidative metabolism was quantified by the clearance constant k(mono) for carbon-11 acetate, determined by positron emission tomography (PET). Cardiac efficiency was then estimated by the work-metabolic index [WMI = stroke volume index x heart rate x systolic pressure/k(mono)]. Additionally, myocardial presynaptic sympathetic innervation was investigated in the same PET session using 11C-hydroxyephedrine, and plasma norepinephrine levels were determined by high-performance liquid chromatography. The WMI was 3.0+/-1.3 mmHg x ml x 10(6)/m2 and correlated significantly with left ventricular ejection fraction (19%+/-10%; r=0.66, P<0.04) and peripheral vascular resistance (3,638+/-1,085 dynes x s/cm5; r=-0.75, P<0.01). Cardiac hydroxyephedrine retention, reflecting integrity of presynaptic innervation, was abnormally low in 58%+/-38% of the left ventricle. Cardiac hydroxyephedrine retention (r=0.65, P<0.05) and plasma norepinephrine concentration (r=-0.80, P<0.01) both correlated significantly with the WMI. At multivariate stepwise linear regression, only plasma norepinephrine and peripheral vascular resistance were independent determinants of the WMI. In conclusion, metabolic performance of the cardiomyopathic heart decreases with increasing alterations of the sympathetic nervous system. Increasing afterload and effects of systemic sympathetic activation, however, seem to play a dominant role while direct alterations of cardiac presynaptic sympathetic innervation are not independently associated.

Acetic Acid↗