Peter Kies

Abnormal Myocardial Presynaptic Norepinephrine Recycling in Patients With Brugada Syndrome

Background—Life-threatening ventricular tachyarrhythmias can occur in young patients without structural heart disease (idiopathic forms). In many patients, these are typically triggered by an increased sympathetic tone, eg, by physical or mental stress. In contrast, in Brugada syndrome, ventricular tachyarrhythmias more often occur during rest or sleep when the vagal tone is predominant. Furthermore, adrenergic agonists can reduce the level of ST-segment elevation, whereas it is increased by parasympathetic agonists or adrenergic antagonists. The aim of this study was to investigate presynaptic and postsynaptic myocardial sympathetic function in patients with Brugada syndrome. Methods and Results—Nine patients with Brugada syndrome (6 male, 3 female; age, 41±13 years) were enrolled in this study. The cardiac autonomic nervous system was assessed noninvasively, quantifying myocardial presynaptic and postsynaptic sympathetic function by means of positron emission tomography with the norepinephrine analogue 11C-Hydroxyephedrine (11C-HED) and the nonselective &bgr;-blocker 11C-CGP 12177 (11C-CGP). Presynaptic sympathetic norepinephrine recycling, assessed by 11C-HED, was globally increased in patients with Brugada syndrome compared with a group of age-matched healthy control subjects (92.9±16.2 mL/g versus 69.1±14.2 mL/g; P<0.05), whereas postsynaptic &bgr;-adrenoceptor density, assessed by 11C-CGP, was similar in patients and control subjects (10.4±6.7 pmol/g versus 10.2±2.9 pmol/g; P=NS). Conclusions—The present study on autonomic innervation in Brugada syndrome describes an enhanced presynaptic norepinephrine recycling with preserved &bgr;-adrenoceptor density, further supporting the hypothesis of an autonomic dysfunction in Brugada syndrome. This is a further step toward the understanding of the pathophysiology of the disease with potential future impact on therapeutic strategies.

Impact of sympathetic innervation on recurrent life-threatening arrhythmias in the follow-up of patients with idiopathic ventricular fibrillation

PurposeIdiopathic ventricular fibrillation (IVF) is defined as VF in the absence of any identifiable structural or functional cardiac disease. The underlying pathophysiological mechanisms are unknown. This study was performed to investigate the potential impact of sympathetic dysfunction, assessed by 123I-meta-iodo-benzylguanidine scintigraphy (123I-MIBG SPECT), on the long-term prognosis of patients with IVF.Methods123I-MIBG SPECT was performed in 20 patients (mean age 37±13 years) with IVF. Mean follow-up of patients after study entry was 7.2±1.5 years (range 4.9–10.5 years). Ten patients (five men, five women; mean age 43±12 years; p=NS versus study group) with medullary carcinoma of the thyroid gland served as an age-matched control group.ResultsAbnormal 123I-MIBG uptake was observed in 13 patients (65%). During follow-up, 18 episodes of VF/fast polymorphic ventricular tachycardias occurred in four IVF patients with abnormal 123I-MIBG uptake whereas only two episodes of monomorphic ventricular tachycardia (and no VF) occurred in a single IVF patient with normal 123I-MIBG uptake.ConclusionImpairment of sympathetic innervation may indicate a higher risk of future recurrent episodes of life-threatening ventricular tachyarrhythmias in patients with IVF. Studies in larger cohorts are required to validate the significance of 123I-MIBG SPECT during the long-term follow-up of these patients.

Cardiac Sympathetic Dysfunction in Genotyped Patients with Arrhythmogenic Right Ventricular Cardiomyopathy and Risk of Recurrent Ventricular Tachyarrhythmias

Patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) typically present with ventricular tachyarrhythmias preferentially triggered by an elevated sympathetic tone. Previous studies demonstrated an impairment of the presynaptic catecholamine reuptake as assessed by 123I-labeled norepinephrine analog on metaiodobenzylguanidine (123I-MIBG) SPECT. Mutations in the gene encoding for plakophilin-2 (PKP-2) are the most common cause of autosomal dominant ARVC (ARVC-9). In this study, we investigated the potential role of adrenergic dysfunction on the arrhythmia profile in patients with ARVC and correlated these findings with the causative genotype. Methods: 123I-MIBG SPECT was performed for 42 patients with definite ARVC (10 women, 32 men; mean age ± SD, 43 ± 14 y). Images were acquired at 4 h after injection and analyzed for regional 123I-MIBG uptake in a standardized 33-segment polar map. Results were compared with those obtained from 10 control subjects (5 women, 5 men; mean age ± SD, 43 ± 12 y). Results: An abnormal tracer uptake was detected in 25 patients with ARVC (59%). The extents of right ventricular dilation and regional wall motion abnormalities as well as electrocardiographic markers of de- or repolarization were not significantly different between patients with normal and abnormal 123I-MIBG SPECT findings. However, during long-term follow-up of 11.9 ± 4.1 y, patients with abnormal 123I-MIBG SPECT findings experienced life-threatening ventricular tachyarrhythmias significantly more often (22/25 patients [88%]) and independent of the extent of right ventricular dysfunction than those with a normal sympathetic innervation (6/17 patients [35%]; P < 0.0005). Mutations in PKP-2 were identified in 17 patients (40%) but were not correlated with the degree of adrenergic dysfunction. Conclusion: In patients with ARVC, an impairment of adrenergic innervation independent of the underlying genotype is associated with a higher incidence for future recurrences of ventricular tachyarrhythmias. This finding may suggest a potential role of 123I-MIBG SPECT for individualized risk stratification in ARVC patients and asymptomatic PKP-2 mutation carriers alike.

Quantification of left ventricular volumes and ejection fraction from gated 99mTc-MIBI SPECT: validation of an elastic surface model approach in comparison to cardiac magnetic resonance imaging, 4D-MSPECT and QGS

PurposeThe segmentation algorithm ESM based on an elastic surface model was validated for the assessment of left ventricular volumes and ejection fraction from ECG-gated myocardial perfusion SPECT. Additionally, it was compared with the commercially available quantification packages 4D-MSPECT and QGS. Cardiac MRI was used as the reference method.MethodsSPECT and MRI were performed on 70 consecutive patients with suspected or proven coronary artery disease. End-diastolic (EDV) and end-systolic (ESV) volumes and left ventricular ejection fraction (LVEF) were derived from SPECT studies by using the segmentation algorithms ESM, 4D-MSPECT and QGS and from cardiac MRI.ResultsESM-derived values for EDV and ESV correlated well with those from cardiac MRI (correlation coeffients R = 0.90 and R = 0.95, respectively), as did the measurements for LVEF (R = 0.86). Both EDV and ESV were slightly overestimated for larger ventricles but not for smaller ventricles; LVEF was slightly overestimated irrespective of ventricle size. The above correlation coefficients are comparable to those for the 4D-MSPECT and QGS segmentation algorithms. However, results obtained with the three segmentation algorithms are not interchangeable.ConclusionThe ESM algorithm can be used to assess EDV, ESV and LVEF from gated perfusion SPECT images. Overall, the performance was similar to that of 4D-MSPECT and QGS when compared with cardiac MRI. Results obtained with the three tested segmentation methods are not interchangeable, so that the same algorithm should be used for follow-up studies and control subjects.

Clinical evaluation of no-carrier-added meta-[123I]iodobenzylguanidine for myocardial scintigraphy.

Abstract. In clinical and research studies, images obtained using carrier-added meta-[123I]iodobenzylguanidine (c.a. [123I]MIBG) have shown quite variable quality, with varying levels of uptake in lung, liver and mediastinum; this is a significant problem for quantification of the myocardial uptake by means of region ratios. First experimental and preliminary human data in respect of no-carrier-added (n.c.a.) [123I]MIBG are indicative of improved imaging quality. The aim of the present study was to evaluate the clinical value of myocardial scintigraphy with n.c.a. [123I]MIBG in patients with tachyarrhythmias. The study population comprised 24 patients with tachyarrhythmogenic diseases routinely studied by cardiac single-photon emission tomography (SPET) with [123I]MIBG. Twelve of the 24 patients were studied with c.a. [123I]MIBG (seven females and five males; mean age 42±13 years, range 20–60 years), whereas the other 12 were studied with n.c.a. [123I]MIBG (ten females, two males; mean age 41±11 years, range 18–60 years, P=NS). For quantification of the specific uptake in the different organs, count ratios were calculated on SPET images acquired 4 h p.i. Visual analysis of all [123I]MIBG scans showed improved image quality (improved contrast between heart and neighbouring organs) in n.c.a. studies as compared with c.a. studies. A significantly higher heart/left atrial blood ratio was found in the n.c.a. studies as compared with the c.a. studies (10.3±3.2 vs 5.3±1.3, P=0.0003); furthermore, significantly higher heart/lung and heart/liver ratios (2.5±0.6 vs 1.5±0.3, P=0.0002, and 0.8±0.2 vs 0.6±0.1, P=0.0006, respectively) were obtained in the c.a. studies, whereas lung/left atrial blood and liver/left atrial blood ratios showed no significant differences (4.2±1.3 vs 3.6±1.1, P=0.39, and 13.7±5.2 vs 9.6±2.2, P=0.21, respectively). In conclusion, the use of n.c.a. [123I]MIBG yields a significantly higher myocardial uptake associated with improvement in contrast between the heart and neighbouring organs and is therefore superior to the commercially available c.a. [123I]MIBG for use in clinical and research studies of the myocardial presynaptic sympathetic nervous system. Furthermore, our data indicate that for quantification the use of a left atrial blood reference region of interest, which is only available on SPET studies, is to be recommended.

Myocardial Perfusion in Nonischemic Dilated Cardiomyopathy With and Without Atrial Fibrillation

Recent studies have shown that idiopathic atrial fibrillation (AF) is associated with diminished myocardial perfusion and perfusion reserve, which are also impaired in various forms of cardiomyopathies. In many cases, AF develops during progression of dilated cardiomyopathy (DCM) and may aggravate heart failure. This study compared myocardial perfusion between patients with nonischemic DCM with and without AF. Methods: Twelve men (age ± SD, 55 ± 12 y) who had DCM and persistent AF were compared with a group of 18 men (mean age, 43 ± 15 y, P = not statistically significant) who had DCM and sinus rhythm and with 22 healthy controls (mean age, 47 ± 13 y, P = not statistically significant). Myocardial blood flow (MBF) was noninvasively quantified at rest and during adenosine infusion using PET and radioactive-labeled water (H215O PET). Results: Compared with controls, DCM patients without AF showed impaired hyperemic perfusion (2.52 ± 1.29 vs. 3.57 ± 0.88 mL/min/mL, P = 0.014) and perfusion reserve (2.10 ± 1.01 vs. 3.37 ± 0.97, P = 0.003). However, compared with DCM patients without AF, DCM patients with AF showed an additional impairment in resting perfusion (0.82 ± 0.31 mL/min/mL, P = 0.010) and hyperemic perfusion (1.32 ± 0.93 mL/min/mL, P = 0.022), and compared with controls, DCM patients with AF showed a further diminishment of perfusion reserve (1.68 ± 0.94 vs. 3.37 ± 0.97, P < 0.001) accompanied by the highest coronary vascular resistance of all groups. Conclusion: Compared with patients with sinus rhythm, patients with AF have significantly reduced myocardial perfusion reserve and increased coronary resistance in nonischemic DCM. Further studies on the underlying pathomechanisms are warranted.

Molecular cardiovascular imaging using scintigraphic methods

Molecular cardiovascular imaging plays an increasingly important role both in basic research and in clinical diagnosis. Scintigraphic methods have long been used to study pathophysiological changes on a cellular and molecular level, and they are likely to remain important molecular imaging modalities in the foreseeable future. This article provides an overview over current developments in cardiovascular molecular imaging using scintigraphic methods. The focus lies on imaging of cardiac innervation, plaque instability, hypoxia and angiogenesis, gene expression and stem and progenitor cell migration and proliferation.

Discrepancy between glucose metabolism and sympathetic nerve terminals in a patient with metastatic paraganglioma.

There are several radiotracers currently available for detecting tumors of the sympathetic nervous system. [I]-metaiodobenzylguanidine (MIBG) is commonly used with planar imaging and single photon emission computerised tomography (SPECT) and depicts presynaptic noradrenalin reuptake. Alternatively, the positron emitting radiopharmaceutical [C]-meta-hydroxyephedrine (mHED) may be used together with positron emission tomography (PET) to measure the same molecular process; the superior imaging characteristics may allow to detect tumours with a higher sensitivity compared to MIBG-SPECT [1]. We present a case of a 20-year-old male patient with an aggressive abdominal paraganglioma. Preoperative imaging was performed using MIBG-SPECT (a; anterior planar image) showing the large primary tumour. After resection of over 500 g of tumour tissue, further imaging was performed with mHEDPET/ CT. Images demonstrated residual tumour with prominent mHED uptake (b; top: coronal slice; bottom: transversal CTand fused PET/CT slice) and consecutive displacement of the superior vena cava and the abdominal aorta. In addition, CT demonstrated multiple pulmonal, hepatic and lymphogenic lesions without mHED or MIBG uptake (b). The possibility of poorly differentiated metastases was considered and, therefore, additional metabolic imaging using [F]-fluoro-deoxy-glucose (FDG) was performed. FDG-PET/CT revealed extended multifocal FDG uptake in liver, lung, bone, bone marrow and lymph nodes (c; top: maximum intensity projection; bottom: transversal CT and fused PET/CT slice). We conclude that FDG-PET/CT can be a valuable additional test for accurate detection and localisation of metastases for malignant tumours of the sympathetic nervous system, especially for aggressive tumours such as the aggressive paraganglioma shown in this case. A similar finding has been previously published for malignant phaeochromocytoma [2]. A precise staging of these heterogeneous tumours is essential for adequate treatment.

Sex differences in absolute myocardial perfusion. Non-invasive H215O-PET in young healthy adults.

AIM To investigate sex differences in myocardial perfusion especially in healthy individuals since former studies are rare and findings are controversial. Participants, methods: 26 subjects were enrolled: 16 healthy women (age: 34 ±7 years) were compared with 10 healthy men (age: 34 ± 3 years; p = ns). Myocardial blood flow (MBF) and coronary vascular resistance (CVR) were quantified at rest, during adenosine infusion and cold-pressor-testing, using positron emission tomography and radioactive-labelled water (H2(15)O-PET). RESULTS Women showed higher MBF than men at rest (1.10 ± 0.18 vs. 0.85 ± 0.20 ml/min/ml; p = 0.003) and cold-stress (1.39 ± 0.38 vs. 1.06 ± 0.28 ml/min/ml; p = 0.026). Corrected for rate-pressure-product, baseline findings maintained significance (1.41 ± 0.33 vs. 1.16 ± 0.19 ml/min/ml; p = 0.024). CVR was lower in women at baseline (81 ± 14 vs. 107 ± 22 mmHg*ml(-1)*min*ml; p = 0.006) and during cold-pressor-testing (71 ± 17 vs. 91 ± 20 mmHg*ml(-1)*min*ml; p = 0.013). Under adenosine neither maximal MBF (4.06 ± 1.0 vs. 3.91 ± 0.88 ml/min/ml; p = ns) nor coronary flow reserve (3.07 ± 1.12 vs. 3.44 ± 0.92; p = ns) nor CVR (24 ± 8 vs. 24 ± 6 mmHg*ml(-1)*min*ml; p = ns) showed sex-related differences. CONCLUSION Women show higher myocardial perfusion and lower coronary vascular resistance than men in physiologic states. Maximum perfusion and vasodilation under adenosine are not sex-specific.

Geschlechtsspezifische Unterschiede in der absoluten myokardialen Perfusion

AIM To investigate sex differences in myocardial perfusion especially in healthy individuals since former studies are rare and findings are controversial. Participants, methods: 26 subjects were enrolled: 16 healthy women (age: 34 ±7 years) were compared with 10 healthy men (age: 34 ± 3 years; p = ns). Myocardial blood flow (MBF) and coronary vascular resistance (CVR) were quantified at rest, during adenosine infusion and cold-pressor-testing, using positron emission tomography and radioactive-labelled water (H2(15)O-PET). RESULTS Women showed higher MBF than men at rest (1.10 ± 0.18 vs. 0.85 ± 0.20 ml/min/ml; p = 0.003) and cold-stress (1.39 ± 0.38 vs. 1.06 ± 0.28 ml/min/ml; p = 0.026). Corrected for rate-pressure-product, baseline findings maintained significance (1.41 ± 0.33 vs. 1.16 ± 0.19 ml/min/ml; p = 0.024). CVR was lower in women at baseline (81 ± 14 vs. 107 ± 22 mmHg*ml(-1)*min*ml; p = 0.006) and during cold-pressor-testing (71 ± 17 vs. 91 ± 20 mmHg*ml(-1)*min*ml; p = 0.013). Under adenosine neither maximal MBF (4.06 ± 1.0 vs. 3.91 ± 0.88 ml/min/ml; p = ns) nor coronary flow reserve (3.07 ± 1.12 vs. 3.44 ± 0.92; p = ns) nor CVR (24 ± 8 vs. 24 ± 6 mmHg*ml(-1)*min*ml; p = ns) showed sex-related differences. CONCLUSION Women show higher myocardial perfusion and lower coronary vascular resistance than men in physiologic states. Maximum perfusion and vasodilation under adenosine are not sex-specific.