The Clinical Usefulness of Cardiac Sympathetic Nerve Imaging using 123 Iodine-Meta-iodobenzylguanidine Scintigraphy to Evaluate the Effectiveness of Pharmacological Treatments in Patients with Heart Failure

Abstract The autonomic nervous system plays an important role in the human heart. Activation of the cardiac sympathetic nerve system is a cardinal pathophysiological abnormality associated with the failing human heart. Myocardial imaging using 123 I-metaiodobenzylguanidine（MIBG） , an analogue of norepinephrine, has been applied to investigate the activity of the predominant neurotransmitter of the sympathetic nervous system. 123 I-MIBG uptake in the myocardium is known to be reduced after the onset of heart failure, and improves when heart failure is controlled; therefore, treatments for heart failure may be assessed based on improvements in 123 I-MIBG scintigraphic parameters. In this review, we summarized studies that have focused on the use of cardiac sympathetic nerve imaging using 123 I-MIBG scintigraphy to evaluate the effectiveness of pharmacological treatments in heart failure patients. Keywords: Sympathetic nerve system， 123 I-MIBG scintigraphy，Heart failure Ann Nucl Cardiol 2015；1（1） ：117-126 H eart failure has a ＞20% mortality rate in the first year after its diagnosis and a 5-year mortality rate of approximately 50%（1） . The cardiac sympathetic nervous system and renin-angiotensin-aldosterone-system（RAAS）are crucial compensatory mechanisms during heart failure（2） . Activation of the sympathetic nervous system has been identified as one of the cardinal pathophysiological abnormalities associated with human heart failure（3） . An enhanced sympathetic response is initially favorable because it compensates for decreased cardiac output. However, as heart failure progresses, this response leads to deleterious neurohormonal and myocardial structural changes that worsen the condition and increase the likelihood of arrhythmias and cardiac death（4） . The pharmacological treatment of heart failure involves neurohormonal antagonism, adrenergic blockade, and vasodilators. β-adrenergic blocking agents, such as bisoprolol, metoprolol, and carvedilol, have been shown to improve left ventricular（LV）function and increase the transplant-free survival rate in heart failure patients（5-7） . Angiotensin-converting enzyme（ACE）inhibitors decrease afterload and increase cardiac output, which improves the survival of heart failure patients（8,9） . However, ACE inhibitors do not fully suppress the production of angiotensin II（10） . Therefore, non-ACEmediated enzymatic pathways are important in the conversion of angiotensin I to angiotensin II（11） . Angiotensin II receptor blockers（ARBs）may exert Annals of Nuclear Cardiology Vol. The cellular mechanism of MIBG uptake and storage in pre-synaptic vesicles is identical to that of NE. MIBG and NE share two uptake systems: specific（type-1 or uptake-1）and non-specific（type-2） , using passive diffusion（24） . Type-1 uptake is an active process catalyzed by a temperature-and Na-dependent membrane carrier protein with high affinity and low capacity, which is oxygen-dependent and desipramine-and cocaine-sensitive（25） . Type-2 uptake is temperature-dependent, but Na-and oxygen-independent. In addition, it is nonsaturable up to 5 mM MIBG（24） . At low concentrations, MIBG is primarily taken up via the type-1 mechanism. However, the type-2 mechanism is predominant at high concentrations, for example with 131 I-MIBG. After diffusing through the cell membrane, the tracer is taken up by neurosecretory vesicles via an active transport mechanism（26） . In the scintigraphic method of cardiac sympathetic A and B based on those who did and did not reach a daily dose of ＞20 mg metoprolol by 3 months. The baseline WR in group A was lower than that in group B. After 1 month, the delayed H/M ratio increased in group A, but not in group B. Moreover, de Milliano et al.（30） examined 58 patients with heart failure who were randomized to a maximal tolerable dose of metoprolol or placebo, and found a 21.9% increase in 123 I-MIBG uptake after 6 months, whereas the placebo group showed a 7.8% decrease. The third-generation β-blocker, carvedilol, has been shown to reduce morbidity and mortality in heart failure patients（7） the RAAS in the failing heart than enalapril（50） ; therefore, it may induce a greater improvement in CSNA. Kasama et al.（51）randomly assigned 40 patients with heart failure（LVEF ＜45%）to a perindopril（n＝20）or enalapril（n＝20）group. Six months after the treatment with perindopril, the delayed H/M ratio increased（1.62±0.27 to 1.76±0.29, p＜0.01） and WR decreased（50%±14% to 42%±14%, p＜0.05） . In contrast, no significant differences were observed in patients receiving enalapril. A similar comparative study was conducted by Tsutamoto et al.（52） . Fortyfive heart failure patients undergoing conventional treatments, including enalapril, were randomized into 2 groups; enalapril switched to perindopril group（n＝21） and a continuous enalapril treatment group（n＝24） . In the perindopril group, the delayed H/M ratio significantly increased（2.00±0.07 to 2.15±0.07, p＝0.013）and WR decreased（33.0%±1.4% to 30.5%±1.2%, p＝0.03） after 6 months. Conversely, no significant changes were noted in the enalapril group. These findings（51,52） suggested that perindopril was superior to enalapril and exerted more favorable effects on CSNA, in addition to improved cardiovascular outcomes. 3）Angiotensin II receptor blockers（ARBs） Shinohara et al.（53）published the first study investigating the effects of ARBs on CSNA in heart failure patients. They examined 34 patients with a fractional shortening of the LV diameter ≤25% or LVEF ≤45%, treated with losartan or candesartan. Although no significant difference was observed in the delayed H/M ratio, the WR significantly decreased（32.6%± 7.6% to 28.2%±7.5%; p＜0.001）after 6 months. Thereafter, ARBs were clearly shown to improve CSNA in patients with heart failure when these drugs were administered with ACE inhibitors. Kasama et al. p＜0.001）and WR decreased（47%±9% to 39%±10%; p＜0.01）after 6 months in group A. In contrast, no significant changes were noted in group B. Furthermore, ARBs were suggested to improve the condition of patients with heart failure and preserve LVEF. Kasama et al.（55）selected 50 patients with non-ischemic heart failure and preserved LVEF（＞40%）who were treated with standard treatments. Patients were randomly selected to receive candesartan（n＝25）or placebo（n＝25） . 123 I-MIBG scintigraphic parameters in the candesartan group significantly improved after 6 months, whereas no significant changes were observed in the placebo group. These findings suggested that the addition of candesartan to an ACE inhibitor resulted in the stronger inhibition of RAAS and an increase in the myocardial uptake of NE in heart failure patients with preserved LVEF. The same investigators showed that ARB induced a greater improvement in CSNA than an ACE inhibitor （56） . They examined 50 patients with heart failure （LVEF ＜40%） who were randomly assigned to receive valsartan（n＝25）or enalapril（n＝25） . The delayed H/M ratio increased（1.70±0.17 to 1.78±0.22; p＜ 0.05）and WR decreased（46%±11% to 41%±10%; p＜ 0.05）after a 6-month treatment with valsartan. In contrast, no significant differences were noted after the enalapril treatment. ）Aldosterone blockers（ mineralocorticoid receptor antagonists） Aldosterone has been shown to prevent the uptake of NE in the myocardium（46） ; therefore, several trials were designed to assess improvements in CSNA in patients with heart failure who were being chronically treated with aldosterone receptor blockers. Barr et al. These parameters did not significantly change in group B. These findings were confirmed in a subsequent study by the same investigators（59） . They assessed 30 patients with DCM who were randomly assigned to a spironolactone or conventional treatment, and found that the delayed H/M ratio increased（1.64±0.20 to 1.86±0.27; p＜0.0001）and WR decreased（55%±12% to 41%±15%; p＜0.0005）in the spironolactone only group. Therefore, they concluded that the addition of spironolactone to standard therapy may be more effective for non-ischemic cardiomyopathy than for ischemic cardiomyopathy. were randomly assigned to a candesartan plus spironolactone（group A; n＝25）or to candesartan alone （group B; n＝25）group. After 6 months, all MIBG scintigraphic parameters had improved in both groups. However, the degree of changes in these parameters was significantly better in group A than in group B. 5）Diuretics Loop diuretic treatments activate the RAAS and CSNA and may lead to poor prognoses in heart failure （62） . However, the long-acting loop diuretic, azosemide, has been shown to have a milder effect on the RAAS and CSNA than the short-acting loop diuretic, furosemide （62） . A comparative study of azosemide and furosemide was undertaken by Hisatake et al.（63）and performed using a crossover design: two groups of 11 patients with heart failure were randomized to either azosemide or furosemide. The treatments were administered for 6 months and patients were then transferred over to the second treatment. The delayed H/M ratio（p＝0.011） was significantly higher, while the WR was significantly lower（p＜0.0001）after the final administration in the azosemide group than in the furosemide group. Moreover, torasemide, another loop diuretic, was previously reported to inhibit the RAAS and exhibited anti-aldosteronergic properties in pharmacological stu

Endotracheal tube, by the venturi effect, reduces the efficacy of increasing inlet pressure in improving pendelluft.

In mechanically ventilated severe acute respiratory distress syndrome patients, spontaneous inspiratory effort generates more negative pressure in the dorsal lung than in the ventral lung. The airflow caused by this pressure difference is called pendelluft, which is a possible mechanisms of patient self-inflicted lung injury. This study aimed to use computer simulation to understand how the endotracheal tube and insufficient ventilatory support contribute to pendelluft. We established two models. In the invasive model, an endotracheal tube was connected to the tracheobronchial tree with 34 outlets grouped into six locations: the right and left upper, lower, and middle lobes. In the non-invasive model, the upper airway, including the glottis, was connected to the tracheobronchial tree. To recreate the inspiratory effort of acute respiratory distress syndrome patients, the lower lobe pressure was set at -13 cmH2O, while the upper and middle lobe pressure was set at -6.4 cmH2O. The inlet pressure was set from 10 to 30 cmH2O to recreate ventilatory support. Using the finite volume method, the total flow rates through each model and toward each lobe were calculated. The invasive model had half the total flow rate of the non-invasive model (1.92 L/s versus 3.73 L/s under 10 cmH2O, respectively). More pendelluft (gas flow into the model from the outlets) was observed in the invasive model than in the non-invasive model. The inlet pressure increase from 10 to 30 cmH2O decreased pendelluft by 11% and 29% in the invasive and non-invasive models, respectively. In the invasive model, a faster jet flowed from the tip of the endotracheal tube toward the lower lobes, consequently entraining gas from the upper and middle lobes. Increasing ventilatory support intensifies the jet from the endotracheal tube, causing a venturi effect at the bifurcation in the tracheobronchial tree. Clinically acceptable ventilatory support cannot completely prevent pendelluft