A Pooled Analysis of Multicenter Cohort Studies of 123I-mIBG Imaging of Sympathetic Innervation for Assessment of Long-Term Prognosis in Heart Failure

ObjectivesThe study objectives were to create a cardiac metaiodobenzylguanidine (mIBG) database using multiple prospective cohort studies and to determine the quantitative iodine-123–labeled mIBG indices for identifying patients with chronic heart failure (HF) at greatest and lowest risk of lethal events.BackgroundAlthough the prognostic value of cardiac mIBG imaging in patients with HF has been shown, clinical use of this procedure has been limited. It is required to define universally accepted quantitative thresholds for high and low risk that could be used as an aid to therapeutic decision-making using a large cohort database.MethodsSix prospective HF cohort studies were updated, and the individual datasets were combined for the present patient-level analysis. The database consisted of 1,322 patients with HF followed up for a mean interval of 78 months. Heart-to-mediastinum ratio (HMR) and washout rate of cardiac mIBG activity were the primary cardiac innervation markers. The primary outcome analyzed was all-cause death.ResultsLethal events were observed in 326 patients, and the population mortality rate was 5.6%, 11.3%, and 19.7% at 1, 2, and 5 years, respectively. Multivariate Cox proportional hazard model analysis for all-cause mortality identified age (p < 0.0001), New York Heart Association (NYHA) functional class (p < 0.0001), late HMR of cardiac mIBG activity (p < 0.0001), and left ventricular ejection fraction (LVEF) (p = 0.0029) as significant independent predictors. Analysis of the 512-patient subpopulation with B-type natriuretic peptide (BNP) results showed BNP (p < 0.0001), greater NYHA functional class (p = 0.0002), and late HMR (p = 0.0011) as significant predictors, but LVEF was not. The receiver-operating characteristic–determined threshold of HMR (1.68) identified patients at significantly increased risk in any LVEF category. Survival rates decreased progressively with decreasing HMR, with 5-year all-cause mortality rates >7% annually for HMR <1.25, and <2% annually for HMR ≥1.95. Addition of HMR to clinical information resulted in a significant net reclassification improvement of 0.175 (p < 0.0001).ConclusionsPooled analyses of independent cohort studies confirmed the long-term prognostic value of cardiac mIBG uptake in patients with HF independently of other markers, such as NYHA functional class, BNP, and LVEF, and demonstrated that categoric assessments could be used to define meaningful thresholds for lethal event risk

Prevention of hypoglycemia by intermittent-scanning continuous glucose monitoring device combined with structured education in patients with type 1 diabetes mellitus : A randomized, crossover trial

Aims: We conducted a randomized, crossover trial to compare intermittent-scanning continuous glucose monitoring (isCGM) device with structured education (Intervention) to self-monitoring of blood glucose (SMBG) (Control) in the reduction of time below range. Methods: This crossover trial involved 104 adults with type 1 diabetes mellitus (T1DM) using multiple daily injections. Participants were randomly allocated to either sequence Intervention/Control or sequence Control/Intervention. During the Intervention period which lasted 84 days, participants used the first-generation FreeStyle Libre (Abbott Diabetes Care, Alameda, CA, USA) and received structured education on how to prevent hypoglycemia based on the trend arrow and by frequent sensor scanning (≥10 times a day). Confirmatory SMBG was conducted before dosing insulin. The Control period lasted 84 days. The primary endpoint was the decrease in the time below range (TBR; <70 mg/dL). Results: The time below range was significantly reduced in the Intervention arm compared to the Control arm (2.42 ± 1.68 h/day [10.1 %±7.0 %] vs 3.10 ± 2.28 h/day [12.9 %±9.5 %], P = 0.012). The ratio of high-risk participants with low blood glucose index >5 was significantly reduced (8.6 % vs 23.7 %, P < 0.001). Conclusions: The use of isCGM combined with structured education significantly reduced the time below range in patients with T1DM

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

A prediction model for 5-year cardiac mortality in patients with chronic heart failure using 123I-metaiodobenzylguanidine imaging

Purpose Prediction of mortality risk is important in the management of chronic heart failure (CHF). The aim of this study was to create a prediction model for 5-year cardiac death including assessment of cardiac sympathetic innervation using data from a multicenter cohort study in Japan. Methods The original pooled database consisted of cohort studies from six sites in Japan. A total of 933 CHF patients who underwent 123I-metaiodobenzylguanidine (MIBG) imaging and whose 5-year outcomes were known were selected from this database. The late MIBG heart-to-mediastinum ratio (HMR) was used for quantification of cardiac uptake. Cox proportional hazard and logistic regression analyses were used to select appropriate variables for predicting 5-year cardiac mortality. The formula for predicting 5-year mortality was created using a logistic regression model. Results During the 5-year follow-up, 205 patients (22 %) died of a cardiac event including heart failure death, sudden cardiac death and fatal acute myocardial infarction (64 %, 30 % and 6 %, respectively). Multivariate logistic analysis selected four parameters, including New York Heart Association (NYHA) functional class, age, gender and left ventricular ejection fraction, without HMR (model 1) and five parameters with the addition of HMR (model 2). The net reclassification improvement analysis for all subjects was 13.8 % (p < 0.0001) by including HMR and its inclusion was most effective in the downward reclassification of low-risk patients. Nomograms for predicting 5-year cardiac mortality were created from the five-parameter regression model. Conclusion Cardiac MIBG imaging had a significant additive value for predicting cardiac mortality. The prediction formula and nomograms can be used for risk stratifying in patients with CHF. © 2014 The Author(s).Article in pressThis article has Supplemental materrial and methods

The Relationship between Tumor Development and Sarcoidosis in Aspects of Carcinogenesis before and after the Onset of Sarcoidosis

Background and Objectives: It is still unclear whether sarcoidosis is likely to be associated with tumors. In addition, the use of an immune checkpoint inhibitor has been reported to initiate the onset of sarcoidosis. We retrospectively analyzed tumor development before and after the diagnosis of sarcoidosis and examined the impact of having a history of tumors on the activity or the severity of sarcoidosis. Materials and Methods: We recruited 312 consecutive cases of sarcoidosis and analyzed the tumor development before and after the onset of sarcoidosis. Results: Among them, 25 cases were diagnosed with malignant tumor after diagnosis of sarcoidosis. In the analysis of the tumor-development group after diagnosis of sarcoidosis, both serum angiotensin I-converting enzyme and mediastinal lymph node size were significantly reduced at the time of malignant tumor diagnosis compared to at the onset of sarcoidosis, indicating that the decreasing activity of sarcoidosis may be partly associated with tumor development. Furthermore, we examined 34 cases having tumor history before the onset of sarcoidosis and analyzed the effect of tumor history on the severity of sarcoidosis. Cases with a malignant tumor in the past were older and had less complicated organs of sarcoidosis than cases without malignant tumors in the past. Oral corticosteroid therapy was administrated more frequently in cases without malignant tumors in the past, indicating that the history of a malignant tumor may influence the severity of sarcoidosis. Conclusion: These results indicate that tumor development may be partly associated with the activity or severity of sarcoidosis