Glucagon-like Peptide-1 analogues and delipidation of coronary atheroma in statin-treated type 2 diabetic patients with coronary artery disease: The prespecified sub-analysis of the OPTIMAL randomized clinical trial.

Background and aims: Randomized clinical trials have demonstrated the ability of glucagon-like peptide-1 analogues (GLP-1RAs) to reduce atherosclerotic cardiovascular disease events in patients with type 2 diabetes (T2D). How GLP-1RAs modulate diabetic atherosclerosis remains to be determined yet. Methods: The OPTIMAL study was a prospective randomized controlled study to compare the efficacy of 48-week continuous glucose monitoring- and HbA1c-guided glycemic control on near infrared spectroscopty (NIRS)/intravascular ultrasound (IVUS)-derived plaque measures in 94 statin-treated patients with T2D (jRCT1052180152, UMIN000036721). Of these, 78 patients with evaluable serial NIRS/IVUS images were analyzed to compare plaque measures between those treated with (n = 16) and without GLP-1RAs (n = 72). Results: All patients received a statin, and on-treatment LDL-C levels were similar between the groups (66.9 ± 11.6 vs. 68.1 ± 23.2 mg/dL, p = 0.84). Patients receiving GLP-1RAs demonstrated a greater reduction of HbA1c [-1.0 (-1.4 to -0.5) vs. -0.4 (-0.6 to -0.2)%, p = 0.02] and were less likely to demonstrate a glucose level >180 mg/dL [-7.5 (-14.9 to -0.1) vs. 1.1 (-2.0 - 4.2)%, p = 0.04], accompanied by a significant decrease in remnant cholesterol levels [-3.8 (-6.3 to -1.3) vs. -0.1 (-0.8 - 1.1)mg/dL, p = 0.008]. On NIRS/IVUS imaging analysis, the change in percent atheroma volume did not differ between the groups (-0.9 ± 0.25 vs. -0.2 ± 0.2%, p = 0.23). However, GLP-1RA treated patients demonstrated a greater frequency of maxLCBI4mm regression (85.6 ± 0.1 vs. 42.0 ± 0.6%, p = 0.01). Multivariate analysis demonstrated that the GLP-1RA use was independently associated with maxLCBI4mm regression (odds ratio = 4.41, 95%CI = 1.19-16.30, p = 0.02). Conclusions: In statin-treated patients with T2D and CAD, GLP-1RAs produced favourable changes in lipidic plaque materials, consistent with its stabilization.

Effect of Luseogliflozin on Myocardial Flow Reserve in Patients with Type 2 Diabetes Mellitus (LUCENT-J Study).

INTRODUCTION: In patients with type 2 diabetes (T2D), treatment with sodium-glucose cotransporter-2 (SGLT2) inhibitors has been shown to reduce hospital admission rates for heart failure (HF). However, the multiple mechanisms hypothesized and investigated to explain the cardioprotection of SGLT2 inhibitors are not fully understood. OBJECTIVES: The effect of luseogliflozin on myocardial flow reserve (MFR) in patients with T2D (LUCENT-J) study aims to examine the effects of SGLT2 inhibitors on myocardial perfusion. METHODS: The LUCENT-J study is a prospective, single-center, randomized, two-arm, parallel-group, open-label (i.e., the radiology readers are blinded), active-controlled study. A cohort of 40 patients with T2D with no or stable (with no history of myocardial infarction and with or without previous percutaneous coronary intervention) coronary artery disease will be included. Patients will be randomized in a 1:1 ratio to luseogliflozin or control and treated for 24 weeks. The primary outcome is the change in MFR, as measured by 13N-ammonia positron emission tomography/computed tomography, from baseline to 24 weeks after treatment initiation. PLANNED OUTCOMES: The LUCENT-J study will elucidate the mechanisms of cardioprotection by SGLT2 inhibitors in patients with T2D. TRIAL REGISTRATION: Japan Registry of Clinical Trials (JRCTs051220016).

The effect of continuous glucose monitoring-guided glycemic control on progression of coronary atherosclerosis in type 2 diabetic patients with coronary artery disease: The OPTIMAL randomized clinical trial.

BACKGROUND: Continuous glucose monitoring (CGM) improves glycemic fluctuation and reduces hypoglycemic risk. Whether CGM-guided glycemic control favorably modulates coronary atherosclerosis in patients with type 2 diabetes (T2DM) remains unknown. METHODS: The OPTIMAL trial was a prospective, randomized, single-center trial in which 94 T2DM patients with CAD were randomized to CGM- or HbA1c-guided glycemic control for 48 weeks (jRCT1052180152). The primary endpoint was the nominal change in total atheroma volume (TAV) measured by serial IVUS. The secondary efficacy measure was the nominal change in maxLCBI4mm on near-infrared spectroscopy imaging. RESULTS: Among the 94 randomized patients, 82 had evaluable images at 48 weeks. Compared to HbA1c-guided glycemic control, CGM-guided control achieved a greater reduction in %coefficient of variation [-0.1 % (-1.8 to 1.6) vs. -3.3 % (-5.1 to -1.5), p = 0.01] and a greater increase in the duration with glucose between 70 and 180 mg/dL [-1.5 % (-6.0 to 2.9) vs. 6.7 % (1.9 to 11.5), p = 0.02]. TAV increased by 0.11 ± 1.9 mm3 in the HbA1c-guided group and decreased by -3.29 ± 2.00 mm3 in the CGM-guided group [difference = -3.4 mm3 (95%CI: -8.9 to 2.0 mm3), p = 0.22]. MaxLCBI4mm, increased by 90.1 ± 25.6 in the HbA1c-guided group and by 50.6 ± 25.6 in the CGM-guided group (difference = -45.6 (95%CI: -118.1 to 26.7) p = 0.21]. A post-hoc exploratory analysis showed a greater regression of maxLCBI4mm in the CGM-guided group [difference = 20.4 % (95%CI:1.3 to 39.5 %), p = 0.03]. CONCLUSIONS: CGM-guided control for 48 weeks did not slow disease progression in T2DM patients with CAD. A greater regression of lipidic plaque under CGM-guided glycemic control in the post-hoc analysis requires further investigation.

Diabetic microvascular complications predicts non-heart failure with reduced ejection fraction in type 2 diabetes.

AIMS: The relationship between diabetic microvascular complications and the incidence of two types of heart failure-heart failure with reduced ejection fraction (HFrEF) (left ventricular ejection fraction [LVEF] < 40%) and non-HFrEF (LVEF ≥ 40%)-in patients without prior heart failure has not been clarified. We herein examined the association between diabetic microvascular complications and HFrEF or non-HFrEF in patients with type 2 diabetes mellitus (T2DM) without prior heart failure. METHODS AND RESULTS: In this retrospective cohort study, we assessed the relationship between the presence of diabetic microvascular complications or severity of diabetic retinopathy (no apparent, non-proliferative and proliferative retinopathy) and nephropathy (normoalbuminuria, microalbuminuria, and macroalbuminuria) at baseline, with the primary outcome of first heart failure hospitalization classified as HFrEF or non-HFrEF in patients with type 2 diabetes mellitus without prior heart failure. Among 568 patients (69.2% males, mean age 66.2 ± 9.6 years), 70 experienced heart failure hospitalization (HFrEF: 24 and non-HFrEF: 46). Non-HFrEF hospitalization but not HFrEF hospitalization was significantly associated with the presence of diabetic microvascular complications. The incidence of non-HFrEF hospitalization was significantly higher in the proliferative retinopathy group than that in the no apparent retinopathy group (adjusted hazard ratio [HR] 2.96, 95% confidence interval [CI]: 1.09-6.83, P = 0.035) and in those with macroalbuminuria than in those with normoalbuminuria (adjusted HR 4.23, 95% CI: 2.24-7.85, P < 0.001) even after adjustment for age and sex. When non-HFrEF was classified into heart failure with mildly reduced ejection fraction (HFmrEF) (40% ≤ LVEF < 50%) and heart failure with preserved ejection fraction (HFpEF) (50% ≤ LVEF), HFmrEF and HFpEF hospitalizations were also found to be associated with the progression of retinopathy and nephropathy. CONCLUSIONS: In patients with T2DM without prior heart failure, non-HFrEF hospitalization was more closely associated with the progression of diabetic microangiopathy than HFrEF. The development of non-HFrEF may be mediated through a mechanism similar to that of microvascular complications in these patients.

First Case Report of Arrhythmogenic Right Ventricular Cardiomyopathy Showing Refractory Ventricular Tachycardia Induced by Thyroid Storm due to Graves' Disease.

A 48-year-old man who was diagnosed with arrhythmogenic right ventricular cardiomyopathy (ARVC) due to a plakophilin 2 gene mutation developed acute both-sided heart failure with rapid atrial fibrillation and was hospitalized. After admission, sustained ventricular tachycardia, which was refractory to antiarrhythmic agents, occurred repeatedly, and required electrical cardioversion. He was diagnosed with thyroid storm due to Graves' disease, and treatment for hyperthyroidism was initiated. After the treatment, lethal arrhythmia did not reoccur, and biventricular heart failure ameliorated. To our best knowledge, this is the first report in English of a patient with ARVC showing refractory arrhythmia induced by thyroid storm due to Graves' disease.

A Prospective Longitudinal Study on the Relationship Between Glucose Fluctuation and Cognitive Function in Type 2 Diabetes: PROPOSAL Study Protocol.

INTRODUCTION: Although the risk of dementia among patients with type 2 diabetes mellitus (T2DM) is double that of those without T2DM, the mechanism remains to be elucidated and the glycemic goal to prevent progression of cognitive impairment is unclear. Results from cross-sectional studies suggest that glucose fluctuations are associated with impairment of cognitive function among T2DM patients. Therefore, the aim of the longitudinal study described here is to evaluate the relationships between glucose fluctuation indexes assessed by continuous glucose monitoring (CGM) and cognitive function among elderly patients with T2DM. METHODS: This will be a prospective, single-center, 2-year longitudinal study in which a total of 100 elderly patients with T2DM showing mild cognitive impairment (MCI) will be enrolled. Glucose fluctuations, assessed using the FreeStyle Libre Pro continuous glucose monitoring system (Abbott Laboratories), and results of cognitive tests, namely the Montreal Cognitive Assessment (MoCA) and Alzheimer's Disease Assessment Scale (ADAS), will be evaluated at baseline, 1-year visit and 2-year visit. The primary endpoint is the relationships between indexes of glucose fluctuation and change in MoCA and ADAS scores. Secondary endpoints are the relationships between the indexes of glucose fluctuation or cognitive scores and the following: indexes representing intracranial lesions obtained by magnetic resonance imaging and angiography of the head; Geriatric Depression Scale score; Apathy Scale score; carotid intima-media thickness assessed by echography; inflammatory markers; fasting glucose; glycated hemoglobin; blood pressure; and the development of cardiovascular and renal events. PLANNED OUTCOMES: The current study is scheduled for completion in June 2022. The results could lead to the elucidation of novel glycemic goals to prevent the progression of cognitive impairment and/or of relationships between glucose fluctuations and cognitive function among T2DM patients. The findings of the study will be reported in publications and conference presentations. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trial Registry (UMIN000038546).

Effect of tofogliflozin on cardiac and vascular endothelial function in patients with type 2 diabetes and heart diseases: A pilot study.

Recent studies have shown that sodium-glucose cotransporter 2 inhibitors decrease the risk of heart failure in patients with type 2 diabetes. However, the precise mechanisms of action of these drugs are not well understood. In the present study, we evaluated the effect of treatment with tofogliflozin for 6 months on cardiac and vascular endothelial function in 26 patients with type 2 diabetes and heart diseases. Tofogliflozin treatment significantly decreased left ventricular end-diastolic dimensions and significantly increased flow-mediated vasodilation. Although E/e' did not significantly change after treatment, the decrease observed in the E/e' ratio was significantly correlated with the increase in acetoacetic acid and 3-hydroxybutyrate levels. These results suggest that sodium-glucose cotransporter 2 inhibitor might improve left ventricular dilatation and vascular endothelial function in patients with type 2 diabetes. Furthermore, it is suggested that the elevation of ketone bodies induced by sodium-glucose cotransporter 2 inhibitors might contribute to a protective effect in left ventricular diastolic dysfunction.

The efficacy of glycemic control with continuous glucose monitoring on atheroma progression: rationale and design of the Observation of Coronary Atheroma Progression under Continuous Glucose Monitoring Guidance in Patients with Type 2 Diabetes Mellitus (OPTIMAL).

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) are high-risk subjects who more frequently have micro- and macrovascular diseases including coronary artery disease (CAD). Since impaired glycemic homeostasis directly influences the formation and propagation of atherosclerotic plaques, optimal management of glycemic status is required for the prevention of diabetic atherosclerosis. Continuous glucose monitoring (CGM) provides not only average glucose level but also the degree of glucose fluctuation and hypoglycemia. Given the association of glycemic variability with diabetic macrovascular diseases, CGM-based glycemic management could favorably modulate glycemic fluctuation, thereby potentially modifying atheroma burden in T2DM subjects. To test this hypothesis, the Observation of Coronary Atheroma Progression under Continuous Glucose Monitoring Guidance in Patients with Type 2 Diabetes Mellitus (OPTIMAL) study has been designed (Japan Registry of Clinical Trials: jRCT1052180152, University Hospital Medical Information Network Clinical Trial Registry UMIN000036721). METHODS: The OPTIMAL is a single-center, randomized trial to evaluate the efficacy of CGM-based glycemic control on atheroma progression in T2DM patients with CAD by using serial intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS) imaging. A total of 90 eligible subjects will be randomized 1:1 into two groups to receive either CGM-based glycemic control or HbA1c-baded glycemic management. Coronary angiography and NIRS/IVUS imaging is repeated at the end of the assigned treatment period. RESULTS: The primary endpoint is the normalized absolute change in total atheroma volume (TAV) from baseline to 12 months. The secondary endpoints include (I) the absolute change in percent atheroma volume, (II) the percent change in lipid core burden index, (III) the change in coefficient variance measured by CGM, (IV) the change in atherogenic markers (high-density lipoprotein functionality, proprotein convertase subxilisin/kexin type 9 and fatty-acid binding proteins), and (V) the frequency of hypoglycemia. Safety will also be evaluated. CONCLUSIONS: The collaboration of CGM use with serial NIRS/IVUS imaging will enable to compare atheroma progression rate under CGM-based glycemic management and HbA1c-based approach.

Efficacy of visceral fat estimation by dual bioelectrical impedance analysis in detecting cardiovascular risk factors in patients with type 2 diabetes.

BACKGROUND: Visceral fat area (VFA) is a good surrogate marker of obesity-related disorders, such as hypertension, dyslipidemia and glucose intolerance. Although estimating the VFA by X-ray computed tomography (CT) is the primary index for visceral obesity, it is expensive and requires invasive radiation exposure. Dual bioelectrical impedance analysis (BIA) is a simple and reliable method to estimate VFA; however, the clinical usefulness of dual BIA remains unclear in patients with type 2 diabetes (T2D). METHODS: We estimated the VFAs by dual BIA and CT in 98 patients with T2D and assessed anthropometric parameters, blood test results, and the presence of comorbid hypertension and dyslipidemia. We compared the correlation between the VFAs examined by dual BIA and CT. Furthermore, we performed the receiver operating characteristic (ROC) analyses for the VFAs to detect the presence of comorbid hypertension and/or dyslipidemia with T2D, which are major comorbidities of visceral obesity, and estimated the area under the curve (AUC). RESULTS: The measurement error between the VFAs by dual BIA and CT was significantly higher among patients with brain natriuretic peptide (BNP) ≥ 100 pg/mL than those with BNP < 100 pg/mL (39.2% ± 31.1% vs. 24.1% ± 18.6%, P < 0.05). After excluding patients with BNP ≥ 100 pg/mL, the VFA by dual BIA significantly correlated with the VFA by CT (r = 0.917; P < 0.0001). The AUC in the ROC analysis for the VFA by dual BIA to detect the presence of comorbid hypertension and/or dyslipidemia with T2D was almost equivalent to that for the VFA by CT. CONCLUSIONS: In patients with T2D without elevated BNP > 100 pg/mL as indicator for fluid accumulation interfering with BIA, estimation of the VFA by dual BIA significantly correlated with that by CT and also detected comorbid hypertension and/or dyslipidemia with T2D equivalent to those detected by CT. Hence, dual BIA could be an alternative to CT as a standard method for estimating the VFA in patients with diabetes.

Familial Hypercholesterolemia and Lipoprotein Apheresis.

Lipoprotein apheresis has been developed as the treatment for refractory familial hypercholesterolemia (FH) to remove low-density lipoprotein (LDL), which is the main pathogenic factor. Currently, three procedures are available in Japan, including the plasma exchange, double-membrane filtration, and selective LDL adsorption. Selective LDL adsorption, which was developed in Japan, has been one of the most common treatment methods in the world. Lipoprotein apheresis enabled the prevention of atherosclerosis progression even in homozygous FH (HoFH) patients. However, in our observational study, HoFH patients who started lipoprotein apheresis in adulthood had a poorer prognosis than those who started in childhood. Therefore, HoFH patients need to start lipoprotein apheresis as early as possible. Although the indication for lipoprotein apheresis in heterozygous FH (HeFH) patients has been decreasing with the advent of strong statins, our observational study showed that HeFH patients who discontinued lipoprotein apheresis had a poorer prognosis than patients who continued apheresis therapy. These results suggest that it is beneficial for very-high-risk HeFH patients to be treated by lipoprotein apheresis even if their LDL cholesterol is controlled well by lipid-lowering agents. Since launching a new class of lipid-lowering agents, proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody and microsome triglyceride transfer protein inhibitors, the indication for lipoprotein apheresis in FH has been changing. However, despite the development of these drugs, lipoprotein apheresis is still an option with a high therapeutic effect for FH patients with severe atherosclerotic cardiovascular disease.

Effect of linagliptin on oxidative stress markers in patients with type 2 diabetes: a pilot study.

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors are commonly used for the treatment of type 2 diabetes and have been previously shown to prevent diabetic renal injury via various mechanisms, including the attenuation of oxidative stress. Therefore, we hypothesized that linagliptin, a DPP-4 inhibitor, attenuates oxidized stress and diabetic renal injury. METHODS: In total, 30 patients with type 2 diabetes who were undergoing treatment with linagliptin (5 mg) during the 3-month study period were enrolled. Oxidative stress markers [serum malondialdehyde-modified LDL (MDA-LDL) and urinary 8-hydroxydeoxyguanosine (8-OHdG)], an inflammatory marker (high-sensitive CRP), urinary albumin excretion, estimated GFR, and a urinary tubulointerstitial injury marker [urinary liver-type fatty acid-binding protein (L-FABP)] were evaluated at baseline and after 3 months of treatment. RESULTS: Following linagliptin treatment, serum MDA-LDL, serum HbA1c, and urinary L-FABP levels significantly decreased, while urinary 8-OHdG tended to decrease. In contrast, 1,5-AG levels increased, and high-sensitive CRP and urinary albumin excretion remained unchanged. CONCLUSION: In this study, we demonstrated that linagliptin partially attenuated oxidative stress. We also demonstrated that linagliptin treatment reduced urinary L-FABP excretion, suggesting that renal tubule-interstitial injury may be attenuated by linagliptin (UMIN 000015308).

LDL apheresis in Japan.

LDL apheresis has been developed as the treatment for refractory familial hypercholesterolemia (FH). Currently, plasma exchange, double membrane filtration, and selective LDL adsorption are available in Japan, and selective LDL adsorption is most common method. LDL apheresis can prevent atherosclerosis progression even in homozygous (HoFH). However, in our observational study, HoFH who started LDL apheresis from adulthood had poor prognosis compared with patients who started from childhood. Therefore, as far as possible, HoFH patients need to start LDL apheresis from childhood. Although indication of LDL apheresis in heterozygous FH (HeFH) has been decreasing with the advent of strong statin, our observational study showed that HeFH patients who were discontinued LDL apheresis therapy had poor prognosis compared with patients who were continued apheresis therapy. These results suggest that high risk HeFH need to be treated by LDL apheresis even if their LDLC is controlled by lipid-lowering agents. However, by launching new class of lipid lowering agents, that is, PCSK-9 antibody and MTP inhibitor, indication of LDL-apheresis in FH may be changed near the future. LDL-apheresis can provide symptom relief of peripheral artery disease (PAD). Therefore, PAD patients who have insufficient effect by other therapeutic approach including revascularization are also treated by LDL apheresis. Thus, LDL apheresis is still one of good therapeutic options for severe atherosclerotic diseases in Japan.

Proprotein convertase subtilisin/kexin 9 V4I variant with LDLR mutations modifies the phenotype of familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is caused by mutations in the genes encoding low-density lipoprotein receptor (LDLR), apolipoprotein B, or proprotein convertase subtilisin/kexin 9 (PCSK9). However, FH shows variability of the clinical phenotype modified by other genetic variants or environmental factors. OBJECTIVE: Our objective was to determine the distribution of PCSK9 variants in Japanese FH heterozygotes and to clarify whether those variants and the combination of those variants and LDLR mutations modify the clinical phenotypes. METHODS: A direct sequence analysis was performed for all 18 exons of LDLR gene and 12 exons of PCSK9 gene in 269 clinically diagnosed FH heterozygotes. The serum lipid levels of the carriers of each variant were compared to those of noncarriers. We also assessed Achilles tendon xanthoma and the prevalence of coronary artery disease (CAD) in the patients aged ≥30 years. RESULTS: Eleven PCSK9 variants were detected. There were 4 frequent PCSK9 variants: L21_22insL, A53 V, V4I, and E32 K. The PCSK9 L21_22insL and A53 V were in linkage disequilibrium with each other. There were no significant differences in serum lipids levels and the prevalence of CAD at the age of ≥ 30 years between PCSK9 V4I, L21_22insL/A53 V, or E32 K variant carriers and noncarriers without LDLR mutations. In the patients carrying LDLR mutations and aged ≥ 30 years, the additional PCSK9 V4I variant was linked to a significantly increased prevalence of CAD in accord with the elevation of the LDL-cholesterol level. CONCLUSIONS: The addition of the PCSK9 V4I was suggested to modify the phenotype of patients carrying LDLR mutations by affecting their LDLR metabolism.

Intensity of statin therapy and new hospitalizations for heart failure in patients with type 2 diabetes.

OBJECTIVE: To examine a relationship between statin intensity and heart failure (HF) incidence in diabetes. RESEARCH DESIGN AND METHODS: We performed a retrospective cohort study of patients with type 2 diabetes (n=600; age, 66.3 years; men, 68%). Patients were categorized into three groups by baseline statin treatments-moderate-intensity, low-intensity, or no statin-and the independent association between the statin category and HF hospitalization during follow-up was examined. RESULTS: Over the course of the median 6-year follow-up, 17.7% of the patients were hospitalized for HF. Cox regression analysis revealed a significant association between the baseline statin category and HF incidence (p=0.002), independently of age, sex, hypertension, B-type natriuretic peptide, glycated hemoglobin, estimated glomerular filtration rate, and low-density lipoprotein (LDL) cholesterol levels. The moderate-intensity statin group had a significantly lower risk for HF than the low-intensity statin group with an adjusted HR of 0.31 (95% CI 0.13 to 0.65, p=0.0014). Interestingly, among patients with prevalent coronary artery diseases (CAD) and with baseline LDL controlled to less than 100 mg/dL, the frequency of HF was still significantly lower in the moderate-intensity group than in the low-intensity group or the no statin group. The effect of baseline statin category on HF was independent of incident CAD events during follow-up. CONCLUSIONS: In type 2 diabetes, moderate-intensity statins, in comparison to low-intensity or no statin, were associated with lower HF incidence independently of LDL levels or of CAD events.

Removal of plasma mature and furin-cleaved proprotein convertase subtilisin/kexin 9 by low-density lipoprotein-apheresis in familial hypercholesterolemia: development and application of a new assay for PCSK9.

CONTEXT: Proprotein convertase subtilisin/kexin 9 (PCSK9) is known to be a good target to decrease LDL cholesterol (LDL-C) and two forms of PCSK9, mature and furin-cleaved PCSK9, circulate in blood. However, it has not been clarified whether and how the levels of each PCSK9 are affected by LDL-apheresis (LDL-A) treatment, a standard therapy in patients with severe forms of familial hypercholesterolemia (FH). OBJECTIVE: Our objective was to investigate the differences in LDL-A-induced reduction of mature and furin-cleaved PCSK9 between homozygous and heterozygous FH, and between dextran sulfate (DS) cellulose adsorption and double membrane (DM) columns and to clarify the mechanism of their removal. DESIGN: A sandwich ELISA to measure two forms of PCSK9s using monoclonal antibodies was developed. Using the ELISA, PCSK9 levels were quantified before and after LDL-A with DS columns in 7 homozygous and 11 heterozygous FH patients. A crossover study between the two column types was performed. The profiles of PCSK9s were analyzed after fractionation by gel filtration chromatography. Immunoprecipitation of apolipoprotein B (apoB) in FH plasma was performed. RESULTS: Both mature and furin-cleaved PCSK9s were significantly decreased by 55-56% in FH homozygotes after a single LDL-A treatment with DS columns, and by 46-48% or 48-56% in FH heterozygotes after treatment with DS or DM columns. The reduction ratios of LDL-C were strongly correlated with that of PCSK9 in both FH homozygotes and heterozygotes. In addition, more than 80% of plasma PCSK9s were in the apoB-deficient fraction and a significant portion of mature PCSK9 was bound to apoB, as shown by immunoprecipitation. CONCLUSIONS: Both mature and furin-cleaved PCSK9s were removed by LDL-A in homozygous and heterozygous FH either by binding to apoB or by other mechanisms. The ELISA method to measure both forms of plasma PCSK9 would be useful for investigating physiological or pathological roles of PCSK9.

A family of RTHß with p.R316C mutation presenting occasional syndrome of inappropriate secretion of TSH.

The syndrome of inappropriate secretion of thyrotropin (SITSH) is a hallmark of resistance to thyroid hormone (RTH) due to mutations in the ß isoform of the thyroid hormone receptor (TRß). Here, we report on a family of RTH due to a TRß mutation (RTHß) and presenting occasional SITSH. The proband was a 16 year-old girl with a goiter, detected at a school physical examination. She was initially diagnosed as having euthyroid Hashimoto thyroiditis because her thyroid function was normal with a positive anti-thyroglobulin antibody. Follow-up examinations resulted in mild SITSH on some occasions and euthyroid on the other occasions. A magnetic resonance imaging (MRI) revealed a normal pituitary gland. Because her mother also had mild SITSH, genetic analysis was performed and revealed a heterozygous point mutation in TRß (p.R316C). Previously, the p.R316C had only been found in severe RTH cases with homozygous mutations or with an ectopic thyroid. Her mother with a heterozygous mutation showed variable RTH phenotype on T3 suppression testing. In conclusion, the prevalence of RTHß might be underestimated and occasional SITSH could also suggest RTHß. TRß gene mutation is not always correlated with the RTH phenotype.

Hemoglobin A1c predicts heart failure hospitalization independent of baseline cardiac function or B-type natriuretic peptide level.

AIMS: Diabetes is a major risk factor for heart failure (HF). We examined whether baseline HbA1c level predicts HF incidence independent of other HF risk factors, including baseline cardiac structural and functional abnormalities. METHODS: In patients with type 2 diabetes, multivariable Cox regression models were constructed to examine the independent association between baseline HbA1c and future HF hospitalization. RESULTS: In 608 subjects (mean age, 66.5 years; men, 68%; mean HbA1c, 9.1% (76 mmol/mol)), 92 were hospitalized for HF during a median follow-up of 6 years. For a 1% (11 mmol/mol) increase in baseline HbA1c, the hazard ratio for HF was 1.23 (95% confidence interval, 1.1-1.7, p<0.001) with adjustment for age, sex, body mass index, blood pressure and plasma B-type natriuretic peptide (BNP) level. The effect of HbA1c on HF was independent of baseline left ventricular (LV) ejection fraction, the ratio of peak early to late diastolic filling velocity, and prevalent/incident coronary heart disease (CHD), and was more evident in patients with enlarged LV, decreased systolic function, prevalent CHD, or prevalent HF. CONCLUSION: In patients with type 2 diabetes, HbA1c significantly predicts future HF hospitalization independent of baseline BNP level or echocardiographic parameters.

Serum levels of IgG and IgG4 in Hashimoto thyroiditis.

Although IgG4-related disease is characterized by extensive infiltration of IgG4-positive plasma cells and lymphocytes of various organs, the details of this systemic disease are still unclear. We screened serum total IgG levels in the patients with Hashimoto thyroiditis (HT) to illustrate the prevalence of IgG4-related thyroiditis in HT. Twenty-four of 94 patients with HT (25.5%) had elevated serum IgG levels and their serum IgG4 was measured. Five of the 24 cases had more than 135 mg/dL of IgG4, which is the serum criterion of IgG4-related disease. One was a female patient who was initially treated as Graves' disease and rapidly developed a firm goiter and hypothyroidism. The biopsy of her thyroid gland revealed that follicular cells were atrophic with squamous metaplasia, replaced with fibrosis, which was compatible with the fibrous variant of HT. Immunohistochemical examination revealed diffuse infiltration of IgG4-positive plasma cells, and the serum IgG4 level was 179 mg/dL. The levels of IgG and IgG4 were positively correlated with the titers of anti-thyroglobulin antibody or anti-thyroid peroxidase antibody. In conclusion, at least a small portion of patients with HT with high titers of anti-thyroid antibodies may overlap the IgG4-related thyroiditis.

Pituitary ischemic apoplexy in a young woman using oral contraceptives: a case report.

Estrogen is suggested to be one of the plausible risk factors for pituitary hemorrhagic apoplexy through pituitary hyperemia. We experienced a 33-year-old woman with pituitary ischemic apoplexy of a nonfunctional macroadenoma under oral contraceptive use. Our case indicates that hypercoagulable state, but not hyperemia, associated with estrogen may promote pituitary ischemic apoplexy.

Novel tandem germline RET proto-oncogene mutations in a patient with multiple endocrine neoplasia type 2B: report of a case and a literature review of tandem RET mutations with in silico analysis.

BACKGROUND: Multiple endocrine neoplasia type 2B (MEN2B) is the rarest and most aggressive form of MEN2. MEN2B cases usually carry either an M918T or A883T mutation of the RET, but to date, there are 3 atypical MEN2B caused by tandem mutations. METHODS AND RESULTS: A 32-year-old woman with no family history of medullary thyroid carcinoma (MTC) presented with a neck tumor and multiple mucosal nodules. She was diagnosed with MEN2B. Genetic analyses of RET revealed that she had 2 mutations, Q781R and V804M. Subclone and genetic analyses revealed that Q781R was on the paternal allele and V804M was a de novo. In silico analysis of the tandem mutations showed a high prediction score. CONCLUSIONS: We describe a novel combination of tandem RET mutations (Q781R/V804M) in a MEN2B-like patient. In silico analysis showed a high prediction score, which was compatible with the clinical phenotype in the present case.