Masayoshi Yoshii

Diagnostic value of carotid intima-media thickness and plaque score for predicting target organ damage in patients with essential hypertension

Carotid intima–media thickness (IMT) assessed by ultrasonography is regarded as an early predictor of general arteriosclerosis in patients with essential hypertension. However, the methods of measuring IMT have not been globally standardized, and it remains unclear whether conventional measurement of IMT represents the prevalence of hypertensive target organ damage. In this study, we verified the association between several commonly used carotid ultrasonographical parameters and the severity of hypertensive target organ damage (retinal arteriosclerosis, microalbuminuria, left ventricular hypertrophy (LVH)). Carotid ultrasonography, echocardiography, urinalysis, and funduscopy were performed in 184 patients (64 ± 12 years, 96 males and 88 females) with various stages of essential hypertension. Carotid arteriosclerosis was assessed using four methodologically different methods: conventional-IMT, maximum-IMT (Max-IMT), Mean-IMT, and Plaque Score (the sum of all plaque thicknesses). Age and all carotid ultrasonographical parameters were significantly associated with albuminuria, retinal arteriosclerosis, and left ventricular mass index. High-sensitivity CRP was significantly correlated with retinopathy and LVH. Carotid parameters in patients with histories of cardiovascular events were significantly greater in those without events. Among all carotid parameters, Max-IMT showed the highest correlation coefficient of the severity of target organ damage, and showed significant association with CRP. Stepwise regression analysis revealed that Max-IMT was the independent factor for predicting target organ damage. Max-IMT is suggested to be the most reliable and simplest parameter for predicting hypertensive target organ damage including microangiopathy in patients with essential hypertension.

Association of single nucleotide polymorphisms in endothelin family genes with the progression of atherosclerosis in patients with essential hypertension

Endothelin-1 (ET-1) is a potent vasoconstrictive peptide and its activity is mediated by the receptors ET type A (EDNRA) and ET type B (EDNRB). Although ET-1 is thought to play an important role in the development of atherosclerosis, it remains unclear whether polymorphisms of ET-1 family genes, including the ET-1 gene (EDN1), EDNRA, EDNRB and the genes for endothelin converting enzymes 1 and 2 (ECE1 and ECE2), are associated with the progression of atherosclerosis. We investigated the relationship between 11 single nucleotide polymorphisms (SNPs) of ET-1 family genes (including three in EDN1, one in EDNRA, two in EDNRB, four in ECE1 and one in ECE2) and atherosclerotic changes assessed using pulse wave velocity (PWV) and carotid ultrasonography in 630 patients with essential hypertension (EHT). In male subjects, we found significant differences in brachial-ankle PWV (baPWV) in additive and recessive models in EDNRB-rs5351 after Bonferroni correction. Also in male subjects, there were significant differences in mean intima-media thickness (IMT) in additive and recessive models in EDNRA-rs5333 after Bonferroni correction. We found no significant correlation between any SNPs in the ET family genes and baPWV, IMT and Plaque score (PS) in female subjects. Furthermore, after multiple logistic regression analysis, only EDNRB-rs5351 indicated as an independent risk of atherosclerosis in male hypertensive subjects. Of the endothelin-related genes, EDNRB-rs5351 was the most susceptible SNP associated with atherosclerosis in male hypertensives, and the genetic background may be involved in the progression of atherosclerosis in EHT patients.

Associations of Hypertension and Its Complications with Variations in the Xanthine Dehydrogenase Gene

Hyperuricemia and oxidative stress participate in the pathophysiology of hypertension and its complications. Xanthine dehydrogenase (XDH) produces urate and, in its oxidase isoform, reactive oxygen species. Here we have studied whether or not the genetic variations in XDH could be implicated in hypertension and its complications. By sequencing the promoter region and all exons of XDH in 48 subjects, we identified three missense mutations (G172R, A932T, N1109T) in a heterozygous state in addition to 34 variations, including 15 common single nucleotide polymorphisms (SNPs). The three missense mutations and eight common SNPs (11488C>G, 37387A>G, 44408A>G, 46774G>A, 47686C>T, 49245A>T, 66292C>G, and 69901A>C) were genotyped in 953 hypertensive Japanese subjects and in 1,818 subjects from a general Japanese population. Four hypertensive patients with rare missense mutations (G172R or N1109T) in homozygous form had severe hypertension. Multivariate logistic regression analysis showed a significant association of three SNPs with hypertension in men: 47686C>T (exon 22, odds ratio [OR]: 1.52, p=0.047) and 69901A>C (intron 31, OR: 3.14, p=0.039) in the recessive model, and 67873A>C (N1109T) (exon 31, OR: 1.84, p=0.018) in the dominant model. After full adjustment for all confounding factors, only one polymorphism (69901A>C) was found to be associated with carotid atherosclerosis in the dominant model (p=0.028). Multiple logistic regression analysis showed that one SNP (66292C>G) was significantly associated with chronic kidney disease (CKD: estimated creatinine clearance <60 mL/min) in the recessive model (p=0.0006). Our results suggest that genetic variations in XDH contribute partly to hypertension and its complications, including atherosclerosis and CKD.

Association of genetic polymorphisms of ACADSB and COMT with human hypertension.

Objectives Genetically hypertensive rats provide an excellent model to investigate the genetic mechanisms of hypertension. We previously identified three differentially expressed genes, Acadsb (short/branched chain acyl-CoA dehydrogenase), Comt (catecholamine-O-methyltransferase), and Pnpo (pyridoxine 5′-phosphate oxidase), in hypertensive and normotensive rat kidneys as potential susceptibility genes for rat hypertension. We examined the association of human homologues of these genes with human hypertension. Methods We sequenced three genes using samples from 48 or 96 hypertensive patients, identified single nucleotide polymorphisms, and genotyped them in a population-based sample of 1818 Japanese individuals (771 hypertensive individuals and 1047 controls). Results After adjustments for age, body mass index, present illness (hyperlipidaemia, diabetes mellitus), and lifestyle (smoking, alcohol consumption), multivariate logistic regression analysis revealed that −512A>G in ACADSB was associated with hypertension in women (AA vs AG + GG: odds ratio = 0.70, 95% confidence interval = 0.53–0.94). This single nucleotide polymorphism was in tight linkage disequilibrium with −254G>A. Furthermore, −1187G>C in COMT was associated with hypertension in men (GG vs CG + CC: odds ratio = 0.69, 95% confidence interval = 0.52–0.93) and was in tight linkage disequilibrium with 186C>T. After adjustments described above, −512 A>G and −254G>A in ACADSB were associated with variations in systolic blood pressure. ACADSB was in tight linkage disequilibrium with MGC35392 across a distance of 18.3 kb. COMT was not in linkage disequilibrium with any adjacent genes. Analysis indicated that two haplotypes of COMT were significantly associated with hypertension in men. Conclusion Our study suggests the possible involvement of genetic polymorphisms in ACADSB and COMT in essential hypertension in the Japanese population.

Protective effects of an angiotensin II receptor blocker and a long-acting calcium channel blocker against cardiovascular organ injuries in hypertensive patients.

The purpose of this study is to compare the long-term effects of an angiotensin II receptor blocker (ARB) and a long-acting calcium channel blocker (CCB) on left ventricular geometry, hypertensive renal injury and a circulating marker of collagen synthesis in hypertensive patients. Patients with essential hypertension (24 men and 19 women; age, 37–79 years) were treated with a long-acting CCB, amlodipine (AML; 2.5–7.5 mg once daily) for 6 months. Then, AML was switched to an ARB, candesartan (CS; 4–12 mg once daily), in 22 patients (CS group), while AML was continued in the remaining 21 patients for another 6 months (AML group). At the end of each treatment period, ambulatory blood pressure monitoring (ABPM), echocardiography and sampling of blood and urine were performed. The average office blood pressure during the latter period was comparably controlled in the AML and the CS groups (AML: 130±8/87±7 mmHg; CS: 133±11/88±7 mmHg), while the average systolic blood pressure of 24-h ABPM was significantly lower in the AML than in the CS group (127±9 vs. 133 ±14 mmHg, p<0.05). Consequently, the left ventricular mass index was significantly decreased in the AML group (102±18 to 92±12 g/m2, p<0.05), while the change was insignificant in the CS group (103±25 to 98±21 g/m2). On the other hand, plasma procollagen I C-terminal peptide (PICP), a marker of collagen synthesis, was lowered by CS (86±21 to 70±21 ng/ml, p<0.01), but was not significantly affected by AML (80±127 to 74±91 ng/ml). CS reduced urinary albumin excretion (57±123 to 26±33 mg/g creatinine, p<0.05), but AML did not bring about significant changes (85±27 to 73±19 mg/g creatinine). The results suggested that long-acting CCBs are effective in improving left ventricular hypertrophy by controlling 24-h blood pressure, while ARBs possess protective effects against cardiovascular fibrosis and renal injury beyond their antihypertensive effects.

Effects of alcohol restriction on ambulatory blood pressure, heart rate, and heart rate variability in Japanese men

We investigated the effects of alcohol restriction on ambulatory blood pressure (BP), heart rate, and heart rate variability in 33 Japanese male volunteers (37 +/- 1 years, mean +/- SE), who were all habitual drinkers. Subjects were told either to keep their usual drinking habits for 3 weeks (usual alcohol period), or to reduce alcohol intake by at least half of their usual drinking amount (reduced alcohol period). The ambulatory BP, heart rate, and electrocardiographic R-R intervals were measured during a 24-h period with a portable recorder on the last day of each period. A power spectral analysis of R-R intervals was performed to obtain the low-frequency (LF) and high-frequency (HF) components. The percentage of differences between adjacent normal R-R intervals >50 msec (pNN50) was also calculated. The amount of ethanol intake was significantly reduced from 70 +/- 5 mL/day in the usual alcohol period to 19 +/- 3 mL/day in the reduced alcohol period (P < .0001). The daytime systolic BP was significantly lower in the reduced alcohol period than in the usual alcohol period by 4 +/- 1 mm Hg (P < .05). The daytime and nighttime heart rate was significantly lower in the reduced alcohol period than in the usual alcohol (P < .001 for each). The pNN50 and the HF component were significantly higher in the reduced alcohol period than in the usual alcohol period (P < .0001 for each). The LF/HF ratio was significantly lower in the reduced period than in the usual period (P < .01). These results demonstrate that 3-week alcohol restriction produced reductions in ambulatory systolic BP, heart rate, and the index of sympathovagal balance, and augmentations of parasympathetic indices of heart rate variability in Japanese male drinkers.

Urinary excretion of liver fatty acid-binding protein in health-check participants

BackgroundMessenger RNA of liver fatty acid-binding protein (L-FABP) is expressed in proximal tubules of the kidney, and a certain amount is excreted into urine. We analyzed factors relating to the urinary L-FABP excretion in health-check participants.MethodsWe measured L-FABP in the first morning urine by ELISA in 715 men and 193 women 30–79 years of age who entered a 2-day hospitalized health checkup program. In addition to the routine physical examination and laboratory tests, plasma high-sensitivity C-reactive protein (HSCRP) was assayed.ResultsIn 150 healthy subjects, urinary L-FABP averaged 3.6 ± 0.2 µg/g creatinine, whereas the values were significantly increased in patients with hypertension (5.2 ± 0.4, P = 0.010), diabetes mellitus (5.5 ± 0.5, P < 0.001), and chronic hepatitis (5.8 ± 1.0, P = 0.022). Urinary L-FABP excretion was significantly greater in women than in men when the value was related to creatinine. In regression analysis in men, urinary L-FABP was positively correlated with fasting plasma glucose (r = 0.103, P = 0.033) and plasma HSCRP (r = 0.135, P = 0.006).ConclusionsIt is suggested that renal production and urinary excretion of L-FABP are increased in situations in which arteriosclerosis is promoted, such as hypertension, diabetes mellitus, and cardiovascular inflammation.

Effects of Valsartan on the Progression of Chronic Renal Insufficiency in Patients with Nondiabetic Renal Diseases

The present study tested the effects of valsartan, an angiotensin II receptor blocker, on the progression of renal insufficiency in patients with nondiabetic renal diseases. The study subjects were 22 patients with nondiabetic renal diseases whose serum creatinine (Cr) ranged from 1.5 to 3.0 mg/dl. Valsartan (40–80 mg) or placebo was given once daily for 1 year each in a random crossover manner. In both periods, antihypertensive medications were titrated when the blood pressure was not lower than 140/90 mmHg. Blood sampling and urinalysis were performed bimonthly throughout the study periods. The average blood pressure was comparable between the valsartan and the placebo periods (130±9/86 ±6 vs. 131±8/86±6 mmHg). Serum Cr significantly increased from 1.9±0.5 to 2.3±0.8 mg/dl (p<0.001) during the placebo period, but the change was insignificant in the valsartan period (2.1±0.6 to 2.2±0.9 mg/dl). The slope of decrease in the reciprocal of serum Cr was steeper in the placebo period than in the valsartan period (−0.064 ±0.070/year vs. −0.005±0.050/year, p<0.01). During the valsartan period, urinary protein excretion was less than that during the placebo period (0.75±0.73 vs. 1.24±0.92 g/g Cr, p<0.001). Serum K was significantly higher in the valsartan period than in the placebo period (4.6±0.5 vs. 4.4±0.5 mEq/l, p<0.05); however, no patients discontinued taking valsartan as a result of hyperkalemia. It is possible that long-term treatment with an angiotensin II receptor blocker, valsartan, is effective at retarding the deterioration of renal function in patients with nondiabetic renal disease by a mechanism independent of blood pressure reduction.

COMPARISON OF THE EFFECTS OF AMLODIPINE AND LOSARTAN ON 24-HOUR AMBULATORY BLOOD PRESSURE IN HYPERTENSIVE PATIENTS

Effects of amlodipine (AML), a long-acting calcium antagonist, and losartan (LOS), an angiotensin II receptor antagonist, on 24-hr blood pressure profile were compared in 15 patients with essential hypertension. After 4 weeks of placebo period, the patients were treated with AML or LOS in a random cross-over design for 12–16 weeks each. Either drug was given once daily at 0800 and the doses were titrated so that the office blood pressure was reduced lower than 140/90 mmHg. At the end of each period, 24-hr blood pressure was monitored. Average office blood pressure was lowered from 158 ± 2/ 98 ± 2 mmHg to 134 ± 1/87 ± 1 mmHg by AML and 134 ± 2/88 ± 1 mmHg by LOS. Average 24-hr blood pressure was also reduced from 144 ± 3/ 92 ± 2 mmHg to 131 ± 2/84 ± 2 mmHg by AML and 135 ± 3/85 ± 2 mmHg by LOS. The averaged 24-hr systolic blood pressure was significantly lower in AML than in LOS (p < 0.05). Then, the 24-hr blood pressure was analyzed for four segments; morning (0530–0900 h), daytime (0930–1800 h), evening (1830–2300 h) and night (2330–0500 h). Although the daytime blood pressure was comparable between AML and LOS, systolic blood pressure in the evening and morning hours were lower in AML than in LOS (133 ± 2 vs. 138 ± 3 mmHg, p < 0.01; 129 ± 3 vs. 134 ± 4, p < 0.05). Trough to peak ratio of antihypertensive effect on systolic blood pressure was significantly greater in AML than in LOS (62 ± 5% vs. 55 ± 4%, p < 0.05). Either drug did not cause reflective increase in pulse rate over 24 hours. These results suggest that both AML and LOS are equally effective in lowering daytime blood pressure without eliciting reflex tachycardia, however, the antihypertensive effect of AML lasts longer than that of LOS. Such information seems important to achieve 24-hr blood pressure control using these drugs.

Non‐invasive Monitoring of Hemodynamic Changes During Hemodialysis by the Use of a Newly Developed Admittance Cardiograph

Abstract:  Only a little information is available for the evaluation of the complex hemodynamic changes that occur during hemodialysis. Recently, we developed the transthoracic electrical admittance cardiograph for repeated measurements of cardiac output, and monitored hemodynamic changes during hemodialysis by the use of this device. We measured cardiovascular hemodynamic and autonomic parameters non‐invasively during 210 min of hemodialysis in 19 chronic hemodialysis patients who for more than 2 months had no history of cardiovascular collapses during hemodialysis. Blood pressure was monitored every 10 min using a cuff‐oscillometric device (TM‐2425; A & D, Tokyo, Japan). Cardiac output was monitored on a beat‐by‐beat basis by a newly developed electrical admittance cardiograph (NICOVIEW PA1100; NEC, Tokyo, Japan). Electrocardiogram R‐R intervals were also monitored by the TM‐2425. Power spectral analysis of R‐R intervals was performed to obtain the low‐frequency (LF; 0.05–0.15 Hz) and the high‐frequency (HF; 0.15–0.40 Hz) components based on an autoregressive model. Change in circulatory blood volume was also monitored by a CRIT‐LINE (In‐Line Diagnostics, Riverdale, UT, USA). Although blood volume declined significantly by 16.3 ± 1.4% (mean ± SE) during hemodialysis (P < 0.0001), mean blood pressure did not change significantly. Heart rate increased significantly from the initial values of 76.3 ± 3.4–86.4 ± 4.9 beats/min (P = 0.03). Cardiac output and stroke volume decreased significantly from 4.47 ± 0.30 to 2.91 ± 0.32 L/min (P < 0.0001), and from 57.0 ± 3.7 to 33.9 ± 3.1 mL (P < 0.0001), respectively. Total peripheral vascular resistance increased significantly from 1940 ± 146 to 3117 ± 280 dyne × s × cm5 (P < 0.0001). The LF component did not show significant change, while the HF component decreased significantly (P = 0.007), and the LF/HF ratio increased significantly (P = 0.03). These results suggest that a reduction in parasympathetic nerve activity and sympathetic nerve activation and a marked increase in total peripheral vascular resistance are responsible for the maintenance of blood pressure during hemodialysis in chronic hemodialysis patients. The admittance cardiograph seems to be one of the best options for serial measurements of cardiac output.