Two Cases of Acquired High-Density Lipoprotein Deficiency with Immunoglobulin G4-Related Lecithin-Cholesterol Acyltransferase Autoantibody.

Lecithin-cholesterol acyltransferase (LCAT) plays a significant role in the progression from premature to mature high-density lipoprotein (HDL) in circulation. Consequently, primary or secondary LCAT deletion or reduction naturally results in low serum HDL cholesterol levels. Recently, rare cases of acquired HDL deficiency with LCAT autoantibodies have been reported, mainly from Japan, where LCAT autoantibodies of immunoglobulin G (IgG) caused the HDL deficiency. Here to our knowledge, we report for the first time two cases of acquired HDL deficiency caused by IgG4 linked LCAT autoantibodies with or without a high serum IgG4 level. Furthermore, these cases can extend to a new concept of "IgG4 autoimmune disease" from the viewpoint of verifying the serum autoantibody and/or renal histopathology.

Depressor effect of the young leaves of Polygonum hydropiper Linn. in high-salt induced hypertensive mice.

A novel chymase inhibitor has been reported to have depressor effect in salt-induced hypertension. Therefore, we examined the hypothesis that chymase inhibitory dried young leaves of Polygonum hydropiper (PPH) or young leaves extract of Polygonum hydropiper (PHE) could reduce salt-induced hypertension. In this study, 8-wk old wild-type mice were allocated into three experiments and experiment I included groups, I- normal water drinking, II- high salt (2% NaCl) water (HSW) drinking, and III- HSW plus PPH (500 mg kg-1, orally) for 12-wk. Blood pressure (BP) and heart rate (HR) were measured at baseline and weekly up to wk-12. In experiment II, mice were given HSW for 12-wk followed by 8-wk treatment with PPH plus HSW (62.5, 125, 250 and 500 mg kg-1 for groups I, II, III and IV, respectively). BP and HR were measured at baseline and monthly until wk-12, following weekly for 8-wk. Experiment III comprised of four groups of mice for 12-wk HSW and 8-wk treatment with PHE plus HSW (2.5, 5, 10 and 20 mg kg-1 for groups I-IV, respectively). BP and HR were measured at baseline and monthly up to wk-12, following weekly for 8-wk. Significant reduction in BP and HR were observed in mice treated with PPH (500 mg kg-1) compared to HSW control. PPH reduced BP and HR dose dependently in hypertensive mice and the higher dose showed maximum reduction. PHE at its maximum dose (20 mg kg-1) significantly suppressed BP and HR. Over all, we found that the young leaves of Polygonum hydropiper suppressed salt-induced hypertension.

Rivaroxaban, a factor Xa inhibitor, induces the secondary prevention of cardiovascular events after myocardial ischemia reperfusion injury in mice.

OBJECTIVES: Rivaroxaban has been shown to reduce overall death from cardiovascular causes in patients with recent acute coronary syndrome. Therefore, we evaluated the secondary prevention of cardiovascular events after myocardial ischemia reperfusion injury and its mechanisms in mice. METHODS: After myocardial reperfusion injury, C57BL/6J mice were randomized to receive either no treatment or treatment for 14days with low and high doses of rivaroxaban. After 7days, mice were administered tissue factor as a secondary event. RESULTS: Based on a Kaplan-Meier curve analysis, the high-dose rivaroxaban group showed a significantly higher % survival than the no-treatment group from day 7 (after the administration of tissue factor) to day 14 (at the end of the experimental period). Left ventricular (LV) ejection fraction in both the low- and high-dose rivaroxaban groups improved compared to that in the no-treatment group. Moreover, mRNA levels of interleukin-6 and collagens 1α2 and 3α1 in the LV in the high-dose group were significantly suppressed compared to those in the no-treatment group. CONCLUSIONS: Rivaroxaban improved the survival rate, probably by improving cardiac function through the reduction of inflammatory and fibrotic factors in the LV. This effect may be due to the pleiotropic effects of rivaroxaban beyond its main effect as an anti-coagulant.

Efficacy and safety of combination therapy of high-dose losartan and hydrochlorothiazide in patients with hypertension.

OBJECTIVE: We analyzed the efficacy and safety of combination therapy of high-dose losartan (100 mg/day) and hydrochlorothiazide (HCTZ, 12.5 mg/day) compared with those of the combination of high-dose telmisartan (80 mg/day) and HCTZ (12.5 mg/day). METHODS: Forty hypertensive patients who received a combination of high-dose telmisartan and HCTZ were enrolled. We applied a changeover strategy with switching from a combination of high-dose telmisartan and HCTZ to high-dose losartan and HCTZ. We divided the patients into two groups; those who achieved the target blood pressure (controlled group) and those who did not reach the target blood pressure (uncontrolled group) before the changeover and performed further analysis. RESULTS: The uncontrolled group showed a significant decrease in systolic blood pressure (SBP) (143±12 mmHg to 126±11 mmHg at three months). In addition, serum uric acid significantly decreased in all subjects, and in each of the controlled and uncontrolled groups. There were no significant changes in other biochemical parameters, such as potassium and hemoglobin A1c, at three months after the changeover in all subjects. CONCLUSION: Combination therapy with high-dose losartan and HCTZ was superior to the combination of telmisartan and HCTZ with respect to significant decreases in systolic blood pressure and serum uric acid in hypertensive patients.

Efficacy and safety of a single-pill fixed-dose combination of high-dose telmisartan/hydrochlorothiazide in patients with uncontrolled hypertension.

OBJECTIVE: Many patients still have high blood pressure (BP) after treatment with high-dose angiotensin II type 1 receptor blockers (ARBs) or Preminent® (medium-dose of losartan (50 mg/day)/hydrochlorothiazide (HCTZ) (12.5 mg/day)). Therefore, we analyzed whether Micombi®BP (high-dose telmisartan (80 mg/day)/HCTZ (12.5 mg/day)) could provide better results with regard to efficacy and safety for patients with uncontrolled hypertension. METHODS: In total, 44 hypertensive patients (22 males, age 71±14 years) who showed uncontrolled BP despite the use of high-dose ARBs or Preminent® were enrolled in this study. We used a changeover design in which the patients were switched from high-dose ARBs or Preminent® to Micombi®BP. We analyzed BP, heart rate (HR), and biochemical parameters before and after treatment for 3 months. RESULTS: Systolic BP and diastolic BP significantly decreased (125±15/69±11 mmHg) and 85% of the patients achieved their target BP at 3 months after changeover. Patients who switched from ARBs and those who switched from Preminent® showed similar BP-lowering effects. In addition, the reductions in BP after 3 months in patients with or without chronic kidney disease and in those with or without metabolic syndrome (MetS) were also similar. There were no significant changes in HR during the study period. Although blood levels of potassium, hemoglobin A1c and uric acid (UA) significantly increased after 3 months for all of the patients, none of the patients showed serious adverse effects. CONCLUSION: High-dose telmisartan/HCTZ therapy was associated with a significant reduction in BP and helped patients achieve their target BP.

The central helices of ApoA-I can promote ATP-binding cassette transporter A1 (ABCA1)-mediated lipid efflux. Amino acid residues 220-231 of the wild-type ApoA-I are required for lipid efflux in vitro and high density lipoprotein formation in vivo.

We have mapped the domains of lipid-free apoA-I that promote cAMP-dependent and cAMP-independent cholesterol and phospholipid efflux. The cAMP-dependent lipid efflux in J774 mouse macrophages was decreased by approximately 80-92% by apoA-I[delta(185-243)], only by 15% by apoA-I[delta(1-41)] or apoA-I[delta(1-59)], and was restored to 75-80% of the wild-type apoA-I control value by double deletion mutants apoA-I[delta(1-41)delta(185-243)] and apoA-I[delta(1-59)delta(185-243)]. Similar results were obtained in HEK293 cells transfected with an ATP-binding cassette transporter A1 (ABCA1) expression plasmid. The double deletion mutant of apoA-I had reduced thermal and chemical stability compared with wild-type apoA-I. Sequential carboxyl-terminal deletions showed that cAMP-dependent cholesterol efflux was diminished in all the mutants tested, except the apoA-I[delta(232-243)] which had normal cholesterol efflux. In cAMP-untreated or in mock-transfected cells, cholesterol efflux was not affected by the amino-terminal deletions, but decreased by 30-40% and 50-65% by the carboxyl-terminal and double deletions, respectively. After adenovirus-mediated gene transfer in apoA-I-deficient mice, wild-type apoA-I and apoA-I[delta(1-41)] formed spherical high density lipoprotein (HDL) particles, whereas apoA-I[delta(1-41)delta(185-243)] formed discoidal HDL. The findings suggest that although the central helices of apoA-I alone can promote ABCA1-mediated lipid efflux, residues 220-231 are necessary to allow functional interactions between the full-length apoA-I and ABCA1 that are required for lipid efflux and HDL biogenesis.