Effect of Evolocumab on Vulnerable Coronary Plaques: A Serial Coronary Computed Tomography Angiography Study.

This study investigated the effects of evolocumab on vulnerable coronary plaques and factors associated with the change in stability and size of plaques in patients taking statins. Vulnerable coronary plaques were defined using coronary computed tomography (CT) angiography as having a density of <50 HU within the region of interest and a remodeling index ≥1.1. The changes in minimum CT density, remodeling index, and percent stenosis of vulnerable coronary plaques after six months of evolocumab administration were retrospectively analyzed in 136 vulnerable coronary plaques from 98 patients (68 men and 30 women; mean age: 72.9 ± 8.7 years) treated with a statin. The administration of evolocumab significantly increased the minimum CT density (39.1 ± 8.1 HU to 84.9 ± 31.4 HU, p < 0.001), reduced the remodeling index (1.29 ± 0.11 to 1.19 ± 0.10, p < 0.001), and decreased the percent stenosis (27.0 ± 10.4% to 21.2 ± 9.8%, p < 0.001). Multiple linear regression analysis revealed that baseline percent stenosis (standard coefficient (ß) = -0.391, p = 0.002) independently correlated with the change in minimum CT density, whereas the baseline remodeling index (ß = -0.368, p < 0.001) independently correlated with a change in the remodeling index. Evolocumab stabilized vulnerable coronary plaques and reduced their size. These results suggest that evolocumab protects against coronary artery disease progression in patients taking statins.

Effects of Evolocumab on Carotid Intima-Media Thickness and Clinical Parameters in Patients Taking a Statin.

We determined the effects of evolocumab, a fully human monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9, on carotid intima-media thickness (IMT) and the factors associated with the change in carotid IMT in patients taking a statin. The change in carotid mean and maximum IMT before and after the initiation of evolocumab treatment was retrospectively analyzed in 229 statin-treated patients. The changes in clinical parameters, including serum lipid concentrations, were also evaluated. Evolocumab significantly reduced the increase in carotid mean and maximum IMT (0.09 ± 0.13 mm/year to -0.04 ± 0.16 mm/year, p < 0.001 and 0.17 ± 0.38 mm/year to 0.08 ± 0.47 mm/year, p = 0.02). Evolocumab reduced serum total cholesterol, low-density lipoprotein-cholesterol, triglyceride, and lipoprotein (a) concentrations (each p < 0.001), and increased serum high-density lipoprotein (HDL)-cholesterol concentrations (p = 0.01). Multiple linear regression analysis revealed that the change in HDL-cholesterol (standard coefficient (ß) = -0.120, p = 0.04) and carotid mean IMT (ß = -0.467, p < 0.001) were independently correlated with the change in carotid mean IMT during the administration of evolocumab, whereas the change in HDL-cholesterol (ß = -0.208, p = 0.002) and log-triglyceride (ß = -0.167, p = 0.01) independently correlated with the change in carotid maximum IMT. Evolocumab reduced the increase in carotid IMT in patients taking a statin. These results suggest that evolocumab is protective against carotid atherosclerosis in patients undergoing statin therapy.

Risk factors and utility of maximum carotid intima-media thickness as a surrogate marker for coronary artery stenosis.

BACKGROUND: This study investigated the factors associated with coronary artery stenosis in outpatients. Furthermore, the usefulness of maximum carotid intima-media thickness (maximum-IMT) as a surrogate marker of coronary artery stenosis was evaluated. METHODS: We conducted a single-center retrospective study. A total of 601 outpatients (338 males; 263 females; mean age, 69.8±10.0 years) who underwent coronary computed tomography angiography between April 2006 and March 2012 were analyzed. The associations between coronary artery stenosis (≥75%) as determined by coronary computed tomography angiography and clinical and laboratory parameters were evaluated by multivariate logistic regression. Validation of maximum-IMT as measured by ultrasonography as a surrogate marker of coronary artery stenosis was analyzed by receiver operating characteristic (ROC) curve analysis. RESULTS: The estimated glomerular filtration rate (eGFR: mL/min/1.73 m2) (odds ratio [OR] 0.985, p<0.01), diabetes mellitus (OR 1.98, p<0.05), and maximum-IMT (mm) (OR 1.76, p<0.01) were significantly associated with coronary artery stenosis (≥75%). In analysis of each group categorized by identified factors, such as renal impairment (eGFR <60 mL/min/1.73 m2) and diabetes mellitus, the ROC curve of maximum-IMT was significant in the group of patients with diabetes mellitus without renal impairment (p<0.01) (cutoff value of maximum-IMT, 2.0 mm; sensitivity, 0.74; and specificity, 0.54) but not in other groups. CONCLUSION: Renal impairment, diabetes mellitus, and increased maximum-IMT may be significant risk factors of coronary artery stenosis. Maximum-IMT as measured by ultrasonography may be a useful surrogate marker for coronary artery stenosis in patients with diabetes mellitus without renal impairment but not in other patients.

The glucagon-like peptide-1 receptor agonist, liraglutide, attenuates the progression of overt diabetic nephropathy in type 2 diabetic patients.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Glucagon-like peptide-1 (GLP-1) is one of the incretins, gut hormones released from the intestine in response to food intake. GLP-1 receptor (GLP-1R) agonists have been used to treat type 2 diabetes. Here, we studied the effect of the administration of a GLP-1R agonist, liraglutide, on proteinuria and the progression of overt DN in type 2 diabetic patients. Twenty-three type 2 diabetic patients with overt DN, who had already been treated with blockade of renin-angiotensin system under dietary sodium restriction, were given liraglutide for a period of 12 months. Treatment with liraglutide caused a significant decrease in HbA1c from 7.4 ± 0.2% to 6.9 ± 0.3% (p = 0.04), and in body mass index (BMI) from 27.6 ± 0.9 kg/m² to 26.5 ± 0.8 kg/m² after 12 months (p < 0.001), while systolic blood pressure did not change. The progression of DN was determined as the rate of decline in estimated glomerular filtration rate (eGFR). The 12-month administration of liraglutide caused a significant decrease in proteinuria from 2.53 ± 0.48 g/g creatinine to 1.47 ± 0.28 g/g creatinine (p = 0.002). The administration of liraglutide also substantially diminished the rate of decline in eGFR from 6.6 ± 1.5 mL/min/1.73 m²/year to 0.3 ± 1.9 mL/min/1.73 m²/year (p = 0.003). Liraglutide can be used not only for reducing HbA1c and BMI, but also for attenuating the progression of nephropathy in type 2 diabetic patients.

C4B deficiency associated with membranoproliferative glomerulonephritis.

A 10-year-old girl was noted to have microscopic hematuria and proteinuria in 1986. As her urinary abnormalities were persistent, she underwent a renal biopsy on 4 occasions until 2003. Although the appearances of the renal biopsies were strongly suspicious of systemic lupus erythematosus, she never exhibited specific autoantibodies or distinctive symptoms. She received corticosteroid therapy and the urinary findings responded. The 4th component of complement remained low during the period of the observation. Both genotyping and allotyping analysis revealed complete C4B deficiency. Some case reports have mentioned renal disease associated with C4B deficiency and we consider the nephropathy in this case to be related to the C4B deficiency.

Stimulation of NHE3 in OKP cells by an autocrine mechanism.

BACKGROUND/AIMS: Chronic hypokalemia increases NHE3 activity in OKP cells. The aim of the present study was to determine whether an autocrine mechanism is involved in this activation. METHODS: After incubation of OKP cells in normal-K(+) and low-K(+) media for 24 h, the potassium concentration in the low-K(+) media was adjusted to a normal level. These conditioned media were then used as the normal-K(+) and low-K(+) supernatants. Other OKP cells were incubated in these normal-K(+) and low-K(+) supernatants and the mechanism of Na(+)/H(+) antiporter activation was examined. RESULTS: The EIPA-resistant Na(+)/H(+) antiporter activity of OKP cells increased after 4 h incubation in the low-K(+) supernatant, and the amount of NHE3 protein increased at 24 h. Since both BQ788 and saralasin blocked this antiporter activation, the supernatant concentration of endothelin I (ET-I) and angiotensin II (Ang-II) were measured. The ET-I concentration was reduced, but the Ang-II concentration remained unchanged. There was a significant association between a reduction in the ET-I concentration and an increase in Na(+)/H(+) antiporter activity, but only when Ang-II was present in the supernatant. CONCLUSION: An autocrine mechanism is involved in the activation of NHE3 in OKP cells. Both ET-I and Ang-II play a role in this activation.

Hyponatremia and/or hyperkalemia in patients treated with the standard dose of trimethoprim-sulfamethoxazole.

OBJECTIVE: High-dose trimethoprim-sulfamethoxazole (TMP-SMX) is known to cause hyperkalemia by blocking amiloride-sensitive sodium (Na) channels in distal nephrons. The purpose of this study was to establish whether the standard dose of TMP-SMX could cause electrolyte disorders. METHODS AND PATIENTS: Serum Na, potassium (K) and creatinine (Cr) levels were examined retrospectively in 53 of 77 patients prescribed TMP-SMX, before and after taking the antibiotic combination. RESULTS: Electrolyte disorders (Na < 135 mEq/l and/or K > 5.0 mEq/l) were found in 14 of the 53 patients (26.4%) during TMP-SMX treatment. The average dose was 145.7 +/- 24.9 mg/day. The dose of TMP was significantly larger in patients with electrolyte disorders (267.7 +/- 84.2 mg vs. 101.9 +/- 9.38 mg, p = 0.0024). Electrolyte disorders were also seen in 9.1% and 22.2% of patients given the low dose (TMP < 80 mg) or standard dose (TMP 80-120 mg) of TMP-SMX, respectively. Electrolyte disorders were seen in 85.7% of patients with renal dysfunction (Cr > 1.2 mg/dl), compared with 17.5% of patients with normal renal function (p = 0.0008). Logistic regression analysis showed that the dose of TMP and the presence of renal dysfunction increased the incidence of electrolyte disorders with an odds ratio of 2.35 and 80.29, respectively. CONCLUSION: Electrolyte disorders, particularly hyperkalemia and hyponatremia can be detected in patients given TMP-SMX. These disorders are more frequent in patients given high doses, but can also be detected after low-dose administration. Renal dysfunction accelerates the incidence of electrolyte disorders induced by TMP-SMX.

[A fatal case of shigellosis in an elderly patient].

A 71 year-old male, with no recent history of travelling abroad and a past history of lung cancer two years prior to presentation, which had been successfully treated, developed a sudden onset of watery diarrhea more than ten times a day on February 26, 2001, which gradually became bloody. The next day he visited the Department of Integrated Medicine of the Tokyo Metropolitan Komagome Hospital by ambulance because his consciousness was deteriorating and he was hospitalized. He was hypotensive on admission, and a dopamine preparation was used throughout. The peripheral WBC was 3,800/microliter and the lymphocyte count was 76/microliter which thus suggested the presence of cellular immune suppression. HIV was not tested. He died seven hours after admission. His stool culture yielded a growth of Shigella flexneri 2a, and a blood culture on admission was sterile. No verocyte toxin-producing Esherichia coli was not detected. The causes of death in cases with shigellosis have been reported in the literature to be an electrolyte imbalance, septicemia and disseminated intravasucular coagulation (DIC) in developed countries. Our present case was considered to be a debilitated patient complicated with hemolytic uremic syndrome due to an infection with Shigella bacteria which resulted in death despite performing intensive treatments.