Kenjiro Kikuchi

Target Blood Pressure for Treatment of Isolated Systolic Hypertension in the Elderly: Valsartan in Elderly Isolated Systolic Hypertension Study

In this prospective, randomized, open-label, blinded end point study, we aimed to establish whether strict blood pressure control (<140 mm Hg) is superior to moderate blood pressure control (≥140 mm Hg to <150 mm Hg) in reducing cardiovascular mortality and morbidity in elderly patients with isolated systolic hypertension. We divided 3260 patients aged 70 to 84 years with isolated systolic hypertension (sitting blood pressure 160 to 199 mm Hg) into 2 groups, according to strict or moderate blood pressure treatment. A composite of cardiovascular events was evaluated for ≥2 years. The strict control (1545 patients) and moderate control (1534 patients) groups were well matched (mean age: 76.1 years; mean blood pressure: 169.5/81.5 mm Hg). Median follow-up was 3.07 years. At 3 years, blood pressure reached 136.6/74.8 mm Hg and 142.0/76.5 mm Hg, respectively. The blood pressure difference between the 2 groups was 5.4/1.7 mm Hg. The overall rate of the primary composite end point was 10.6 per 1000 patient-years in the strict control group and 12.0 per 1000 patient-years in the moderate control group (hazard ratio: 0.89; [95% CI: 0.60 to 1.34]; P=0.38). In summary, blood pressure targets of <140 mm Hg are safely achievable in relatively healthy patients ≥70 years of age with isolated systolic hypertension, although our trial was underpowered to definitively determine whether strict control was superior to less stringent blood pressure targets.

Lovastatin prevents angiotensin II-induced cardiac hypertrophy in cultured neonatal rat heart cells.

Angiotensin II activates p21ras, and mediates cardiac hypertrophic growth through the type 1 angiotensin II receptor in cardiac myocytes. An inhibitor of 3-hydroxy-3-methyglutaryl-coenzyme A (HMG-CoA) reductase has been shown to block the post-translational farnesylation of p21ras and inhibit protein synthesis in several cell types. Primary cultures of neonatal cardiac myocytes were used to determine whether HMG-CoA reductase inhibitors, lovastatin, simvastatin and pravastatin inhibit the angiotensin II-induced hypertrophic growth. Angiotensin II (10(-6) M) significantly increased protein-DNA ratio, RNA-DNA ratio, ratios of protein synthesis and mitogen-activated protein (MAP) kinase activity. Lipid-soluble HMG-CoA reductase inhibitors, lovastatin (10(-6) M) and simvastatin (10(-6) M) partially and significantly inhibited the angiotensin II-induced increases in these parameters, but a water-soluble HMG-CoA reductase inhibitor, pravastatin (10(-6) M) did not. Mevalonate (10(-4) M) overcame the inhibitory effects of lovastatin and simvastatin on angiotensin II-induced increases in these parameters. A selective protein kinase C inhibitor, calphostin C (10(-6) M) partially and significantly prevented angiotensin II-induced increases in these parameters, and treatment with both lovastatin and calphostin C inhibited completely. Angiotensin II increased p21ras activity and membrane association, and lovastatin inhibited them. These studies demonstrate that a lipid-soluble HMG-CoA reductase inhibitor, lovastatin, may prevent angiotensin II-induced cardiac hypertrophy, at least in part, through p21ras/MAP kinase pathway, which is linked to mevalonate metabolism.

Genomic organization and mutational analysis of KVLQT1, a gene responsible for familial long QT syndrome.

Abstract To elucidate the role of the KVLQT1 gene in the pathogenesis of long QT syndrome (LQTS), we have established a screening system for detecting KVLQT1 mutations by the polymerase chain reaction-single strand conformation polymorphism technique (PCR-SSCP). We first determined exon/intron boundaries and flanking intronic sequences, and found that the KVLQT1 gene consists of 17 coding exons. Subsequently, we synthesized oligonucleotide primers to cover the coding region and the flanking intronic sequences, and searched for mutations in 31 Japanese LQTS families. When genomic DNA from each proband was examined by PCR-SSCP followed by direct DNA sequencing, mutations were detected in five families; two independent families carried the same mutation and three of the four were novel. Each mutation was present in affected relatives of the respective proband. This work will enable us to search more thoroughly for LQTS mutations associated with KVLQT1, and eventually will help us in finding genotype/phenotype relationships.

Hypertrophic growth of cultured neonatal rat heart cells mediated by vasopressin V1A receptor

Primary cultures of neonatal cardiac myocytes were used to determine both the identity of second messengers that are involved in vasopressin receptor-mediated effects on cardiac hypertrophy and the type of vasopressin receptor that is involved in vasopressin-induced cell growth. Neonatal rat myocytes were plated at a density of 1x10(6) cells per 60 mm dish and were incubated with serum-free medium for 7 days. Treatment of myocytes with vasopressin significantly increased the RNA-to-DNA ratio, by 18-25%, at culture days 4-6 and the protein-to-DNA ratio by 18-20% at culture days 5-7. Rates of protein synthesis were determined to assess their contribution to protein contents during myocyte growth. Vasopressin significantly accelerated rates of protein synthesis by 25% at culture day 6. Intracellular free Ca(2+) ([Ca(2+)](i)) was transiently increased after vasopressin exposure. After the peak increase in [Ca(2+)](i) at less than 30 s, there was a sustained increase for at least 5 min. The specific activity of protein kinase C in the particulate fraction was increased rapidly after exposure to vasopressin, and its activity remained higher for 30 min, returning to its control level within 60 min. The activity of protein kinase C in the cytosol was significantly decreased at all times after exposure to vasopressin. After vasopressin treatment, the content of c-fos mRNA was increased. The stimulatory effects of vasopressin on these parameters were significantly inhibited by vasopressin V(1A) receptor antagonist, OPC-21268, but not by vasopressin V(2) receptor antagonist, OPC-31260. These results suggest that vasopressin directly induces myocyte hypertrophic growth via the V(1A) receptor in neonatal rat heart cells.

Arginine vasopressin increases the rate of protein synthesis in isolated perfused adult rat heart via the V1 receptor.

Arginine vasopressin (AVP) is known to contribute significantly to the pathogenesis of congestive heart failure and hypertension. However, little is known about its effect on the myocardium. The present study was conducted to determine whether AVP directly increases the rate of protein synthesis in isolated, perfused rat heart, and, if so, the mechanism involved. Elevation of the aortic pressure from 60 to 120 mmHg in perfused rat heart accelerated the rate of protein synthesis which was associated with increases in cAMP levels and Ca2+ uptake. AVP (100 μM) increased Ca2+ uptake and accelerated the rate of protein synthesis without a change in cAMP concentration. The latter events were inhibited by OPC-21268 (100 μM), a selective V1 receptor antagonist, or amiloride (100 μM), an inhibitor of the Na+/H+ exchange system. However, increases in cAMP concentrations, Ca2+ uptake, and rates of protein synthesis associated with the elevated aortic pressure were not inhibited by amiloride. Thus, AVP directly increased the rate of protein synthesis via the V1 receptor that is sensitive to amiloride, a mechanism that differs from the cAMP-dependent mechanism that is responsible for the cardiac hypertrophy induced by pressure overload.

A cardiac sodium channel mutation identified in Brugada syndrome associated with atrial standstill

Abstract.  Takehara N, Makita N, Kawabe J, Sato N, Kawamura Y, Kitabatake A, Kikuchi K (Asahikawa Medical College, Asahikawa; Hokkaido University Graduate School of Medicine, Sapporo, Japan; and Cardiovascular Research Institute, Newark, NY, USA). A cardiac sodium channel mutation identified in Brugada syndrome associated with atrial standstill (Case Report). J Intern Med 2004; 255: 137–142.

Collapsin response mediator protein-2 accelerates axon regeneration of nerve-injured motor neurons of rat.

The rat collapsin response mediator protein‐2 (CRMP‐2) is a member of CRMP family (CRMP‐1–5). The functional consequence of CRMP‐2 during embryonic development, particularly in neurite elongation, is relatively understood; however, the role in nerve regeneration is unclear. Here we examined the role of CRMP‐2 during nerve regeneration using rat hypoglossal nerve injury model. Among the members, CRMP‐1, CRMP‐2, CRMP‐5 mRNA expressions increased after nerve injury, whereas CRMP‐3 and CRMP‐4 mRNA did not show any significant change. In the N1E‐115 cells, CRMP‐2 has the most potent neurite elongation activity among the CRMP family members. In dorsal root ganglion (DRG) organ culture, CRMP‐2 overexpression by adenoviral vector demonstrated substantial neurite elongation. On the other hand, CRMP‐2 (ΔC381), which acts as a dominant negative form of CRMP‐2, inhibited neurite formation. Collectively, it would be plausible that CRMP‐2 has potent nerve regeneration activity after nerve injury. We therefore examined whether CRMP‐2 overexpression in the injured hypoglossal motor neurons accelerates nerve regeneration. A retrograde‐tracer, Fluoro‐Gold (FG), was used to evaluate the number of reprojecting motor neurons after nerve injury. CRMP‐2‐overexpressing motor neurons demonstrated the accelerated reprojection. The present study suggests that CRMP‐2 has potent neurite elongation activity in nerve regeneration in vivo.

Controlled-release nifedipine and candesartan low-dose combination therapy in patients with essential hypertension : the NICE Combi (Nifedipine and Candesartan Combination) Study

Objective To compare the clinical efficacy of low-dose controlled-release (CR) nifedipine (20 mg/day) plus candesartan (8 mg/day) combination therapy with that of up-titrated candesartan (12 mg/day) monotherapy. Design Randomized, double-blind study. Setting Outpatient study. Patients and participants Patients with essential hypertension, who did not achieve their target blood pressure with baseline treatment of candesartan 8 mg/day for 8 weeks. Main outcome measures Blood pressure, pulse pressure, urinary microalbumin excretion. Results Blood pressure was significantly reduced in both groups (P < 0.05), but the reduction was significantly greater in the combination therapy group (12.1 ± 1.4/8.7 ± 0.9 mmHg) than in the up-titrated monotherapy group (4.1 ± 1.4/4.6 ± 0.9 mmHg) (P < 0.0001). The reduction in pulse pressure was significantly greater in the combination therapy group (3.3 ± 1.2 mmHg) than in the up-titrated monotherapy group (0.7 ± 1.2 mmHg) (P = 0.0031). Urinary microalbumin excretion decreased significantly in the combination therapy group (from 61.9 to 40.5 mg/g creatinine; P < 0.05), but not in the up-titrated monotherapy group. Conclusions These findings suggest that the low-dose combination therapy of nifedipine CR and candesartan is superior to the up-titrated monotherapy of candesartan in terms of blood pressure control and renal protection in patients with essential hypertension.

Prediction of Cardiac Death in Hemodialysis Patients by Myocardial Fatty Acid Imaging

OBJECTIVES The aim was to evaluate the potential of single-photon emission computed tomography (SPECT) to predict cardiac death in chronic hemodialysis patients using the iodinated fatty acid analogue iodine-123 123I-beta-methyl iodophenyl-pentadecanoic acid (BMIPP). BACKGROUND We previously reported that BMIPP SPECT could detect asymptomatic coronary artery disease with high sensitivity in hemodialysis patients. METHODS We prospectively enrolled 375 asymptomatic hemodialysis patients who had undergone dual SPECT using 123I-BMIPP and 201thallium (Tl) chloride. Patients who had a clinical history of myocardial infarction and/or coronary revascularization were excluded from the study. Uptake on SPECT images was graded in 17 segments on a 5-point scale (0 normal, 4 absent) and assessed as summed BMIPP or Tl scores. RESULTS During a 3.6 +/- 1.0-year follow-up, 57 patients who had undergone coronary revascularization within 60 days of SPECT were excluded from the analysis. Among the remaining 318 patients (male/female: 170/148; 64 +/- 12 years of age), 50 died of cardiac events (acute myocardial infarction 22, congestive heart failure 17, cardiac sudden death 11). Stepwise Cox hazard analysis associated cardiac death with age (> or =70 years) and with severely abnormal BMIPP SPECT images (BMIPP summed scores > or =12: hazard ratio 21.894; p < 0.0001). Kaplan-Meier analysis showed that the cardiac death-free survival rates at 3 years were 61% and 98% in patients with BMIPP summed scores of > or =12 and <12, respectively. CONCLUSIONS Severely impaired myocardial fatty acid metabolism, which might mainly reflect repetitive myocardial ischemia, can identify a high-risk group of cardiac death among hemodialysis patients.

An Overview of Regular Dialysis Treatment in Japan (as of 31 December 2004)

Abstract:  A statistical survey of 3932 nationwide hemodialysis (hereafter, dialysis) facilities was carried out at the end of 2004, and 3882 facilities (98.73%) responded. The population undergoing dialysis at the end of 2004 was 248 166, an increase of 10 456 patients (4.4%) from that at the end of 2003. The number of dialysis patients per million people was 1943.5. The crude death rate of dialysis patients from the end of 2003 to the end of 2004 was 9.4%. The mean age of patients who underwent dialysis in 2004 was 65.8 years, and that of the total dialysis population was 63.3 years. The percentage distribution of patients who underwent dialysis according to a newly underlying disease showed that 41.3% of patients had diabetic nephropathy and 28.1% had chronic glomerulonephritis. The frequency of calcium carbonate use for dialysis patients was 75.1% and that of sevelamer hydrochloride use was 26.2%. The frequency of sevelamer hydrochloride use does not necessarily have a strong correlation with the dose of calcium carbonate. Patients who received high doses of sevelamer hydrochloride tended to have a low concentration of arterial blood HCO3–. Approximately 15% of dialysis patients used an intravenous vitamin D preparation, generally maxacalcitol. The longer the patients had been on dialysis, the higher the frequency of use of an intravenous vitamin D preparation. When the concentration of serum intact parathyroid hormone (PTH) was more than 200 pg/mL, the frequency of use of an orally administered vitamin D preparation decreased; but that of intravenous vitamin D preparation increased. The percentage of dialysis patients who received percutaneous ethanol injection therapy (PEIT) was 1.4%. The percentage was more than 50% in the patients who had been on dialysis for more than 10 years. The percentage of patients who received PEIT again was 35.0%. The percentage of patients who had been on hemodialysis for more than 10 years and received PEIT again was more than 50%.