Increased PDGFRB and NF-κB signaling caused by highly prevalent somatic mutations in intracranial aneurysms.

Intracranial aneurysms (IAs) are a high-risk factor for life-threatening subarachnoid hemorrhage. Their etiology, however, remains mostly unknown at present. We conducted screening for sporadic somatic mutations in 65 IA tissues (54 saccular and 11 fusiform aneurysms) and paired blood samples by whole-exome and targeted deep sequencing. We identified sporadic mutations in multiple signaling genes and examined their impact on downstream signaling pathways and gene expression in vitro and an arterial dilatation model in mice in vivo. We identified 16 genes that were mutated in at least one IA case and found that these mutations were highly prevalent (92%: 60 of 65 IAs) among all IA cases examined. In particular, mutations in six genes (PDGFRB, AHNAK, OBSCN, RBM10, CACNA1E, and OR5P3), many of which are linked to NF-κB signaling, were found in both fusiform and saccular IAs at a high prevalence (43% of all IA cases examined). We found that mutant PDGFRBs constitutively activated ERK and NF-κB signaling, enhanced cell motility, and induced inflammation-related gene expression in vitro. Spatial transcriptomics also detected similar changes in vessels from patients with IA. Furthermore, virus-mediated overexpression of a mutant PDGFRB induced a fusiform-like dilatation of the basilar artery in mice, which was blocked by systemic administration of the tyrosine kinase inhibitor sunitinib. Collectively, this study reveals a high prevalence of somatic mutations in NF-κB signaling pathway-related genes in both fusiform and saccular IAs and opens a new avenue of research for developing pharmacological interventions.

A preliminary biodistribution study of [99mTc]sodium pertechnetate prepared from an electron linear accelerator and activated carbon-based 99mTc generator.

INTRODUCTION: Production of 99Mo/99mTc using an electron linear accelerator (linac) and activated carbon (AC)-based 99mTc generator (linac-AC) is an alternative approach to the conventional fission production of 99Mo/99mTc. As a preliminary investigation of the clinical applicability of a linac-AC-derived 99mTc radiopharmaceutical, the biodistribution of linac-AC-derived [99mTc]sodium pertechnetate ([99mTc]NaTcO4) was measured and compared against fission-derived [99mTc]NaTcO4 at one time point. METHODS: 99Mo was produced by irradiating nonenriched MoO3 targets with bremsstrahlung photons generated from 55.5-MeV linac electron beams. 99mTc was then separated and purified from the 99Mo using an AC-based 99mTc generator. Subsequently, biodistribution of the linac-AC-derived [99mTc]NaTcO4 in healthy female Slc:ICR mice (n = 6) was measured by dissection and compared with that of fission-derived [99mTc]NaTcO4 (n = 4) at 30 min after injection. RESULTS: The two types of [99mTc]NaTcO4 exhibited similar biodistribution in all the organs and tissues examined: the uptakes of [99mTc]NaTcO4 prepared from the linac-AC method and those prepared from the fission method were 138.9 ± 69.9%ID/g and 160.6 ± 49.2%ID/g in the thyroids, respectively, 33.4 ± 5.5%ID/g and 29.4 ± 9.1%ID/g in the salivary glands, respectively, and less than 10%ID/g in blood and all the other organs. No adverse effects were observed in the mice administered with either [99mTc]NaTcO4. CONCLUSION: The clinical applicability of linac-AC-derived [99mTc]NaTcO4 was suggested by its similar biodistribution with fission-derived [99mTc]NaTcO4 at one time point. Further biodistribution studies at multiple time points are encouraged to demonstrate the bioequivalence between linac-AC- and fission-derived [99mTc]NaTcO4.

Radiolabeling of PSMA-617 with 89Zr: A novel use of DMSO to improve radiochemical yield and preliminary small-animal PET results.

INTRODUCTION: Novel diagnostic and therapeutic options are urgently needed for patients with metastatic castration-resistant prostate cancer (CRPC). PSMA-617 is one of the most promising ligands that bind to prostate specific membrane antigen (PSMA), the cell surface biomarker of CRPC. Of the radiolabeled PSMA ligands developed to date, [68Ga]Ga-PSMA-617 is most commonly used for PSMA positron emission tomography (PET) prior to radioligand therapy (RLT) with [177Lu]Lu-PSMA-617. However, the presence of 68Ga radioactivity (half-life 68 m) in urine at the early PET imaging time point complicates optimization of the therapeutic dose of PSMA-617 labeled with 177Lu (half-life 6.7 d). Thus, PET imaging with the long-lived positron emitter 89Zr (half-life 3.3 d) would be better suited in order to optimize the dose of [177Lu]Lu-PSMA-617 as 89Zr PET allows scans after excretion of the radioactive urine. Until now, PSMA-617 could not be radiolabeled with 89Zr with high radiochemical yield due to poor incorporation of 89Zr into 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). Here we report a novel method for radiolabeling PSMA-617 with 89Zr and the preliminary results of small-animal PET with [89Zr]Zr-PSMA-617. METHODS: We labeled PSMA-617 with 89Zr in a 1:1 mixture of DMSO and HEPES buffer at 90 °C for 30 min, followed by quality control analysis by HPLC. We then determined the dissociation constant (Kd) and logD values of [89Zr]Zr-PSMA-617. We obtained PET images of [89Zr]Zr-PSMA-617 at 24 h in mice bearing both LNCaP (PSMA-positive) and PC-3 (PSMA-negative) tumors (N = 5). The ex vivo [89Zr]Zr-PSMA-617 biodistribution was then examined separately using tissue samples of LNCaP-bearing mice at 2 h (N = 4) and 24 h (N = 4). RESULTS: [89Zr]Zr-PSMA-617 was prepared with a radiochemical yield of 70 ± 9%. The Kd value was 6.8 ± 3.5 nM. The logD value was -4.05 ± 0.20. PET images showed the highest uptake in LNCaP tumors (maximum standardized uptake value, SUVmax = 0.98 ± 0.32) and low uptake in kidneys (SUVmax = 0.18 ± 0.7) due to the absence of urine radioactivity. CONCLUSION: [89Zr]Zr-PSMA-617 was successfully prepared using DMSO and HEPES buffer. [89Zr]Zr-PSMA-617 visualized PSMA-positive LNCaP tumors in the absence of radioactive urine 24 h p.i. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: This method of radiolabeling PSMA-617 with 89Zr using DMSO would be suitable for future clinical trials. Prediction of radiation dose by using [89Zr]Zr-PSMA-617 leads to the safe and effective RLT with [177Lu]Lu-PSMA-617.

Activation of Sympathetic Signaling in Macrophages Blocks Systemic Inflammation and Protects against Renal Ischemia-Reperfusion Injury.

BACKGROUND: The sympathetic nervous system regulates immune cell dynamics. However, the detailed role of sympathetic signaling in inflammatory diseases is still unclear because it varies according to the disease situation and responsible cell types. This study focused on identifying the functions of sympathetic signaling in macrophages in LPS-induced sepsis and renal ischemia-reperfusion injury (IRI). METHODS: We performed RNA sequencing of mouse macrophage cell lines to identify the critical gene that mediates the anti-inflammatory effect of ß2-adrenergic receptor (Adrb2) signaling. We also examined the effects of salbutamol (a selective Adrb2 agonist) in LPS-induced systemic inflammation and renal IRI. Macrophage-specific Adrb2 conditional knockout (cKO) mice and the adoptive transfer of salbutamol-treated macrophages were used to assess the involvement of macrophage Adrb2 signaling. RESULTS: In vitro, activation of Adrb2 signaling in macrophages induced the expression of T cell Ig and mucin domain 3 (Tim3), which contributes to anti-inflammatory phenotypic alterations. In vivo, salbutamol administration blocked LPS-induced systemic inflammation and protected against renal IRI; this protection was mitigated in macrophage-specific Adrb2 cKO mice. The adoptive transfer of salbutamol-treated macrophages also protected against renal IRI. Single-cell RNA sequencing revealed that this protection was associated with the accumulation of Tim3-expressing macrophages in the renal tissue. CONCLUSIONS: The activation of Adrb2 signaling in macrophages induces anti-inflammatory phenotypic alterations partially via the induction of Tim3 expression, which blocks LPS-induced systemic inflammation and protects against renal IRI.

Vagus nerve stimulation even after injury ameliorates cisplatin-induced nephropathy via reducing macrophage infiltration.

The efficacy of prior activation of an anti-inflammatory pathway called the cholinergic anti-inflammatory pathway (CAP) through vagus nerve stimulation (VNS) has been reported in renal ischemia-reperfusion injury models. However, there have been no reports that have demonstrated the effectiveness of VNS after injury. We investigated the renoprotective effect of VNS in a cisplatin-induced nephropathy model. C57BL/6 mice were injected with cisplatin, and VNS was conducted 24 hours later. Kidney function, histology, and a kidney injury marker (Kim-1) were evaluated 72 hours after cisplatin administration. To further explore the role of the spleen and splenic macrophages, key players in the CAP, splenectomy, and adoptive transfer of macrophages treated with the selective α7 nicotinic acetylcholine receptor agonist GTS-21 were conducted. VNS treatment significantly suppressed cisplatin-induced kidney injury. This effect was abolished by splenectomy, while adoptive transfer of GTS-21-treated macrophages improved renal outcomes. VNS also reduced the expression of cytokines and chemokines, including CCL2, which is a potent chemokine attracting monocytes/macrophages, accompanied by a decline in the number of infiltrating macrophages. Taken together, stimulation of the CAP protected the kidney even after injury in a cisplatin-induced nephropathy model. Considering the feasibility and anti-inflammatory effects of VNS, the findings suggest that VNS may be a promising therapeutic tool for acute kidney injury.

Significant impact of left ventricular assist device models on the value of flow-mediated dilation: effects of LVAD on endothelial function.

The precise physiological changes associated with the use of left ventricular assist device (LVAD) are not well characterized. We examined the impact of changes in hemodynamic state using LVAD on endothelial function. We measured flow-mediated vasodilation (FMD) to evaluate endothelial vasodilator function of the brachial artery in 53 patients (dilated cardiomyopathy: 39, ischemic cardiomyopathy: 4, and others: 10) with an implanted LVAD (DuraHeart, EVAHEART, or HeartMate II). We found that FMD value in the HeartMateII LVAD group (9.3% ± 2.9%) was significantly higher than those in the other two groups (EVAHEART: 6.7% ± 2.8% and DuraHeart: 6.2% ± 4.0%). Other factors that affected the FMD value were age (r = - 0.31, p = 0.026), Brinkman index (r = - 0.30, p = 0.029); however, aortic opening, aortic regurgitation, and other hemodynamic parameters such as cardiac index or pulmonary capillary wedge pressure did not correlate with FMD. Multivariate analyses revealed that the difference among the LVAD models most significantly affected the FMD values after adjusting for age and smoking status (t = 2.6, p = 0.014). Event free survival rate of death and cerebral infarction was not significantly different according to the value of FMD. The difference among the LVAD groups most significantly affected the state of endothelial function and it had more impact than other clinical factors.

Association of subclinical carotid atherosclerosis with immediate memory and other cognitive functions.

AIM: To clarify whether carotid atherosclerosis and its risk factors are associated with cognitive decline. METHODS: We evaluated 206 individuals who visited our center for health screening. We carried out physical examinations, blood tests, intima-media thickness (IMT) measurement by carotid ultrasonography, brain magnetic resonance imaging scanning and cognitive function assessments. A total of 30 individuals, who had significant cerebrovascular lesions detected in magnetic resonance imaging scans, were excluded. To detect early cognitive decline, we defined "cognitive impairment (CI)" when a patient satisfied at least one of three criteria. These were Mini-Mental State Examination score <24, clock-drawing test score <4 coexisting with forgetfulness and Wechsler Memory Scale-revised delayed recall score below the normal range for the duration of education (>16 years of education: ≥9, 10-15 years: ≥5, 0-9 years: ≥3). RESULTS: Among 176 individuals, 27 were placed in the CI group. IMT was significantly higher in the CI group as compared with the non-CI group (mean ± SD: 2.0 ± 1.0 vs 1.7 ± 0.7, P = 0018 by Student's t-test). Other atherosclerotic risk factors, such as blood pressure, low-density lipoprotein cholesterol, and hemoglobin A1c, were not significantly different between the two groups. In multivariate analysis, maximum IMT was associated with impaired immediate recall score on Wechsler Memory Scale-revised, independent of the presence of deep white matter hyperintensities on the magnetic resonance imaging scan. CONCLUSIONS: Subclinical carotid atherosclerosis, defined as thickened IMT, could be a marker for early stages of CI, especially for immediate memory recall. The impairment is presumably caused by inducing cerebral microvascular dysfunction in the frontal lobe. Geriatr Gerontol Int 2018; 18: 65-71.

The association between orthostatic increase in pulse pressure and ischemic heart disease.

The clinical meaning of changes in PP with posture remains unclear. We performed treadmill exercise testing on 144 subjects to diagnose ischemic heart disease, and measured the PPs in the supine and standing positions. The differences in the two PPs ranged between -35 and 45 mmHg. Eleven subjects were diagnosed with significant coronary ischemia. The differences in the PPs were significantly increased, and PP in the standing position was significantly elevated in these subjects. A large difference in the PPs in the standing and supine positions was associated with significant coronary ischemia, independent of significant covariables.

The association between orthostatic increase in pulse pressure and ischemic heart disease.

The clinical meaning of changes in PP with posture remains unclear. We performed treadmill exercise testing on 144 subjects to diagnose ischemic heart disease, and measured the PPs in the supine and standing positions. The differences in the two PPs ranged between -35 and 45 mmHg. Eleven subjects were diagnosed with significant coronary ischemia. The differences in the PPs were significantly increased, and PP in the standing position was significantly elevated in these subjects. A large difference in the PPs in the standing and supine positions was associated with significant coronary ischemia, independent of significant covariables.

Brachial artery diameter has a predictive value in the improvement of flow-mediated dilation after aortic valve replacement for aortic stenosis.

Aortic stenosis (AS) is the most common valvular disease and aortic valve replacement (AVR) is one of its most effective interventions. AS affects not only the left ventricle, but also vascular function beyond the stenotic valve, which can lead to various types of vascular dysfunction. However, research evaluating the effect of AS on aortic vascular function is limited. In this study, we investigated clinical meaning to evaluate endothelial function in subjects with AS. From April 2011 to April 2012, 20 consecutive adult patients with degenerative AS (mean age, 74.7 ± 7.4 years; range 50-83 years) who underwent AVR at our institution were included in the study. We measured flow-mediated dilation (FMD) to evaluate the effect of AS on endothelial function. The difference between brachial artery diameter (BAD) before (4.0 ± 0.7 mm) and after AVR (3.9 ± 0.6 mm) was not significant (p = 0.043), but FMD significantly improved after AVR (from 3.1 ± 1.8 to 6.0 ± 2.7 %, p < 0.0001). We also analyzed FMD × BAD index, endogenous vasodilatory capability independent of BAD, resulting that it also significantly increased after AVR (12.3 ± 7.0-22.5 ± 9.3, p < 0.0001). We divided patients into two groups by pre- to post-AVR change in FMD (ΔFMD); large-ΔFMD group [ΔFMD >3.0 % (median value)] and small-ΔFMD group (ΔFMD <3.0 %). There were no significant changes in age, blood pressure, heart rate, B-type natriuretic peptide, or echocardiographic parameters in either group. In contrast, BAD was significantly larger in the small ΔFMD group (4.3 ± 0.7 mm) than in the large ΔFMD group (3.7 ± 0.7 mm) (p = 0.030). In addition, cardio-thoracic ratio was significantly greater in the small ΔFMD group (58.4 ± 7.1 %) than in the large ΔFMD group (53.7 ± 4.6 %) (p = 0.048). Receiver operating characteristic curve analysis of BAD to differentiate large and small ΔFMD demonstrated an area under the curve of 0.750 (p = 0.059) and that optimal cutoff for BAD was 4.28 mm (70 % sensitivity, 80 % specificity). AVR in subjects with AS is associated with a significant improvement in FMD in the brachial artery. Measurement of the BAD may be helpful in distinguishing whether the impairment of FMD in AS derives from a stenotic valve or vascular remodeling.

Elevated C-reactive protein levels and enhanced high frequency vasomotion in patients with ischemic heart disease during brachial flow-mediated dilation.

PURPOSE: The physiological role of vasomotion, rhythmic oscillations in vascular tone or diameter, and its underlying mechanisms are unknown. We investigated the characteristics of brachial artery vasomotion in patients with ischemic heart disease (IHD). METHODS: We performed a retrospective study of 37 patients with IHD. Endothelial function was assessed using flow-mediated dilation (FMD), and power spectral analysis of brachial artery diameter oscillations during FMD was performed. Frequency-domain components were calculated by integrating the power spectrums in three frequency bands (in ms2) using the MemCalc (GMS, Tokyo, Japan): very-low frequency (VLF), 0.003-0.04 Hz; low frequency (LF), 0.04-0.15 Hz; and high frequency (HF), 0.15-0.4 Hz. Total spectral power (TP) was calculated as the sum of all frequency bands, and each spectral component was normalized against TP. RESULTS: Data revealed that HF/TP closely correlated with FMD (r = -0.33, p = 0.04), whereas VLF/TP and LF/TP did not. We also explored the relationship between elevated C-reactive protein (CRP) levels and vasomotion. HF/TP was significantly increased in subjects with high CRP levels (CRP;>0.08 mg/dL) compared with subjects with low CRP levels (0.052±0.026 versus 0.035±0.022, p<0.05). The HF/TP value closely correlated with CRP (r = 0.24, p = 0.04), whereas the value of FMD did not (r = 0.023, p = 0.84). In addition, elevated CRP levels significantly increased the value of HF/TP after adjustment for FMD and blood pressure (ß = 0.33, p<0.05). CONCLUSION: The HF component of brachial artery diameter oscillation during FMD measurement correlated well with FMD and increased in the presence of elevated CRP levels in subjects with IHD.

Effect of add-on aliskiren to type 1 angiotensin receptor blocker therapy on endothelial function and autonomic nervous system in hypertensive patients with ischemic heart disease.

The aim of this study was to evaluate the add-on effect of aliskiren to valsartan on endothelial-dependent vasodilation in hypertensive patients with ischemic heart disease (IHD). After 4 weeks of treatment with 80 mg of valsartan, 28 patients were allocated to either continued treatment with valsartan or an add-on treatment with valsartan plus 150 mg of aliskiren. Aliskiren significantly decreased plasma renin activity, whereas endothelium-dependent vasodilation measured by flow-mediated dilation (FMD) did not change. In contrast, heart rate significantly decreased (73.1 ± 9.8 to 66.3 ± 7.0 beats per minute at baseline and 24 weeks, respectively [P = .009]) and the standard deviation of the R-R intervals (SDNN) significantly increased in the aliskiren group. The add-on aliskiren to valsartan therapy may not improve endothelial functions, although it significantly reduced resting heart rate via regulation of the autonomic nervous system in hypertensive patients with IHD.

Evaluation of preferable insertion routes for esophagogastroduodenoscopy using ultrathin endoscopes.

AIM: To evaluate the discomfort associated with esophagogastroduodenoscopy (EGD) using an ultrathin endoscope through different insertion routes. METHODS: This study (January 2012-March 2013) included 1971 consecutive patients [male/female (M/F), 1158/813, 57.5 ± 11.9 years] who visited a single institute for annual health checkups. Transnasal EGD was performed in 1394 patients and transoral EGD in 577. EGD-associated discomfort was assessed using a visual analog scale score (VAS score: 0-10). RESULTS: Multivariate analysis revealed gender (M vs F: 4.02 ± 2.15 vs 5.06 ± 2.43) as the only independent predictor of the VAS score in 180 patients who underwent EGD for the first time; whereas it revealed gender (M vs F 3.60 ± 2.20 vs 4.84 ± 2.37), operator, age group (A: < 39 years; B: 40-49 years; C: 50-59 years; D: 60-69 years; E: > 70 years; A/B/C/D/E: 4.99 ± 2.32/4.34 ± 2.49/4.19 ± 2.31/3.99 ± 2.27/3.63 ± 2.31), and type of insertion as independent predictors in the remaining patients. Subanalysis for gender, age group, and insertion route revealed that the VAS score decreased with age regardless of gender and insertion route, was high in female patients regardless of age and insertion route, and was low in males aged over 60 years who underwent transoral insertion. CONCLUSION: Although comprehensive analysis revealed that the insertion route may not be an independent predictor of the VAS score, transoral insertion may reduce EGD-associated discomfort in elderly patients.

Impairment of flow-mediated dilation correlates with aortic dilation in patients with Marfan syndrome.

Marfan syndrome is an inherited disorder characterized by genetic abnormality of microfibrillar connective tissue proteins. Endothelial dysfunction is thought to cause aortic dilation in subjects with a bicuspid aortic valve; however, the role of endothelial dysfunction and endothelial damaging factors has not been elucidated in Marfan syndrome. Flow-mediated dilation, a noninvasive measurement of endothelial function, was evaluated in 39 patients with Marfan syndrome. Aortic diameter was measured at the aortic annulus, aortic root at the sinus of Valsalva, sinotubular junction and ascending aorta by echocardiography, and adjusted for body surface area (BSA). The mean value of flow-mediated dilation was 6.5 ± 2.4 %. Flow-mediated dilation had a negative correlation with the diameter of the ascending thoracic aorta (AscAd)/BSA (R = -0.39, p = 0.020) and multivariate analysis revealed that flow-mediated dilation was an independent factor predicting AscAd/BSA, whereas other segments of the aorta had no association. Furthermore, Brinkman index had a somewhat greater influence on flow-mediated dilation (R = -0.42, p = 0.008). Although subjects who smoked tended to have a larger AscAd compared with non-smokers (AscA/BSA: 17.3 ± 1.8 versus 15.2 ± 3.0 mm/m(2), p = 0.013), there was no significant change in flow-mediated dilation, suggesting that smoking might affect aortic dilation via an independent pathway. Common atherogenic risks, such as impairment of flow-mediated dilation and smoking status, affected aortic dilation in subjects with Marfan syndrome.

Clinical correlation of brachial artery flow-mediated dilation in patients with systemic sclerosis.

OBJECTIVE: To investigate the clinical significance of flow-mediated dilation (FMD) in systemic sclerosis (SSc). METHODS: Thirty-three SSc patients and 12 healthy controls were studied. Ultrasound assessment of the brachial artery FMD was performed on all subjects. The results were expressed as the percentage of increase in brachial artery diameter following hyperemia. RESULTS: Limited cutaneous SSc (lcSSc) patients had significantly lower FMD values than healthy controls (5.3 ± 2.7 versus 7.7 ± 2.0 %, p < 0.05), while the values in diffuse cutaneous SSc (dcSSc) patients (6.7 ± 4.0 %) were comparable to those in lcSSc patients and healthy controls. Although FMD values did not correlate with any clinical features in dcSSc patients, there was an inverse correlation between FMD values and disease duration in lcSSc patients (r = -0.64, p < 0.05). Furthermore, lcSSc patients with decreased FMD values showed significantly higher prevalence of digital ulcers and elevated right ventricular systolic pressure than those with normal values (for each; 75 versus 10 %, p < 0.05). CONCLUSION: The FMD values represent the severity of vascular damages, which progress along with disease duration and lead to digital ulcers and pulmonary arterial hypertension, in lcSSc patients.

Clinical correlation of brachial artery flow-mediated dilation in patients with systemic sclerosis.

OBJECTIVE: To investigate the clinical significance of flow-mediated dilation (FMD) in systemic sclerosis (SSc). METHODS: Thirty-three SSc patients and 12 healthy controls were studied. Ultrasound assessment of the brachial artery FMD was performed on all subjects. The results were expressed as the percentage of increase in brachial artery diameter following hyperemia. RESULTS: Limited cutaneous SSc (lcSSc) patients had significantly lower FMD values than healthy controls (5.3 ± 2.7 versus 7.7 ± 2.0 %, p < 0.05), while the values in diffuse cutaneous SSc (dcSSc) patients (6.7 ± 4.0 %) were comparable to those in lcSSc patients and healthy controls. Although FMD values did not correlate with any clinical features in dcSSc patients, there was an inverse correlation between FMD values and disease duration in lcSSc patients (r = -0.64, p < 0.05). Furthermore, lcSSc patients with decreased FMD values showed significantly higher prevalence of digital ulcers and elevated right ventricular systolic pressure than those with normal values (for each; 75 versus 10 %, p < 0.05). CONCLUSION: The FMD values represent the severity of vascular damages, which progress along with disease duration and lead to digital ulcers and pulmonary arterial hypertension, in lcSSc patients.

Differences in body temperature variability between subjects with and without diabetes and predictive value for cardiovascular events.

BACKGROUND: Differences in regulating factors and the clinical implications of body temperature variability (BTV) between subjects with and without diabetes have not been clarified to date. METHODS AND RESULTS: In 66 subjects with ischemic heart disease (33 with diabetes and 33 without diabetes), BTV, the difference between the highest and lowest temperature measurements, and body temperature standard deviation (BT SD) were measured from axillary body temperature (ABT) records of 3 consecutive days and followed for 16.4±8.4 months. In subjects without diabetes BTV and BT SD were closely associated with endothelial function as evaluated on flow-mediated dilation (BTV, R=0.33, P=0.026; BT SD, R=0.41, P=0.029), whereas there was a poor association in subjects with diabetes. In the absence of an interrelationship between vascular function and thermoregulation, the contribution of inflammation to BTV was increased in subjects with diabetes (BTV, 0.59±0.21°C for C-reactive protein [CRP] <0.08 mg/dl vs. 0.79±0.28°C for CRP >0.08 mg/dl, P=0.014). Event-free survival analysis showed that in subjects with diabetes higher BT SD was associated with shorter event-free survival (log-rank P=0.012), but this relationship was not found in subjects without diabetes. CONCLUSIONS: In subjects with diabetes, the interrelationship between thermoregulation and vascular function was disrupted and the effect of inflammation on thermoregulation was enhanced, so that BTV had a sufficient predictive value for cardiovascular events in diabetic subjects.

Simultaneous heart rate variability monitoring enhances the predictive value of flow-mediated dilation in ischemic heart disease.

BACKGROUND: Endothelial dysfunction and autonomic nervous system imbalance are both risk markers of atherosclerotic vascular damage. The relationship between these 2 factors, however, has not been clarified concisely. METHODS AND RESULTS: Flow-mediated dilation (FMD) was measured in 47 patients with ischemic heart disease (IHD; mean age, 68.1±7.1 years) using an ultrasound semi-automatic measuring system (UNEXEF18G), and autonomic nervous system activity was evaluated by simultaneous measurements of heart rate variability. FMD was significantly correlated with standard deviation of normal-to-normal beats (r=0.33, P=0.022) and the power ratio of low-frequency power to high-frequency power (LF/HF; r=-0.38, P=0.0087). Furthermore, multiple regression analysis indicated that LF/HF was the most important predictor of the magnitude of FMD. This interaction was severely blunted by ß-blockers and the presence of diabetes. Moreover, standardized FMD according to autonomic nervous system activity was a better predictor of future cardiovascular events than FMD. Subjects with cardiovascular events had a significantly smaller corrected FMD (event (+), 3.62±0.41; event (-), 5.10±2.35; P=0.001), and the higher corrected FMD was associated with longer event-free survival. CONCLUSIONS: Autonomic nervous system activity is an important regulatory factor of FMD in subjects with IHD. Assessment of this interaction can help provide more accurate risk stratification of subjects with IHD.

Associations of variations in the MRF2/ARID5B gene with susceptibility to type 2 diabetes in the Japanese population.

Modulator recognition factor-2 (Mrf2/AT-rich interaction domain (Arid)5b) has been revealed to be involved in pathogenesis of atherosclerosis and adipogenesis. Single-nucleotide polymorphisms (SNPs) in the MRF2/ARID5B gene are associated with coronary artery disease (CAD) and has been proposed as a candidate gene for type 2 diabetes (T2D). The study was aimed to determine whether any of the four MRF2/ARID5B SNPs (rs2893880, rs10740055, rs7087507 and rs10761600) associated with susceptibility to CAD are also associated with T2D, and to determine whether SNP genotype influences the levels of adiponectin and other clinical factors. Association of MRF2/ARID5B SNPs was investigated in 500 diabetic patients from the Department of Metabolic Diseases at the University of Tokyo and 243 hospital-based nondiabetic individuals from the Institute for Adult Disease Asahi Life Foundation Hospital and 500 community-based nondiabetic individuals from the Hiroshima Atomic Bomb Casualty Council Health Management Center. Associations of haplotypes of these SNP with levels of adiponectin and other clinical factors were evaluated when the data was available. We found rs2893880C, rs10740055A, rs7087507A and rs10761600T were increasingly associated with T2D in terms of allele/genotype frequencies of each SNP and their haplotype combinations. Individuals with haplotype CAAT indicated an 1.86 times higher prevalence of diabetes compared with individuals with GCGA (OR 1.86 (95% confidence interval (CI) 1.43-2.41)). Furthermore, CAAT significantly associated with adiponectin levels and other clinical factors. In conclusion, polymorphisms on the MRF2/ARID5B gene were associated with susceptibility to T2D as well as adiponectin and other clinical factors, which was in a completely concordant way with their associations with CAD.