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 7 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.

Circ J 2009; 73: 732 -740 alcium-channel blockers (CCBs), especially those of the L-type dihydropyridine (DHP) subclass, are widely used to treat hypertension because they are better able to lower blood pressure (BP) than are other types of antihypertensive agents. 1 The DHP CCBs (dCCBs) complement the BP-lowering ability in both salt-sensitive and salt-resistant forms of hypertension (HT), and elderly patients generally respond well to dCCBs. 2 Recently, a number of trials, including VALUE, 3 ALLHAT, 4 ASCOT, 5 Syst-Eur, 6 and STONE, 7 and most correctly performed metaanalyses have demonstrated that dCCBs effectively reduce the incidence of stroke events in older patients with HT 6,7 and could be the preferred agents for treating HT in patients with ischemia heart diseases because of their vasodilatory effects on the coronary arteries. 3,8,9 Moreover, dCCBs demonstrate additive effects on BP reduction by most other kinds of antihypertensive agents, especially angiotensin-Iconverting enzyme inhibitors, angiotensin-II-receptor blockers, β-blockers, and thiazide diuretics, with few sideeffects. 2,10 Because of these advantages of dCCBs, several groups that establish international guidelines have recently endorsed them as an initial therapy option in patients with essential HT (EHT), and as an important component of most multidrug regimens for BP control according to a Japanese guideline (JSH2004). 11 However, the response of BP to dCCBs differs among individuals, so, to lower BP more effectively, determining an individual's sensitivity to a dCCB before prescribing it would be useful.Recent studies indicate that the heterogeneity of a patient's responses to antihypertensive treatment is, at least in part, genetically determined. 12 This finding underscores the role of pharmacogenetic research to identify either functional genetic variations or variations inherited in linkage disequilibrium (LD) with these variations as markers to enable more individualized evaluation and selection of agents for treating HT in each drug class. 13 In Japan, more than a dozen dCCBs, particularly DHP derivatives, are available for clinical use. These DHP derivatives bind to receptors on the α1 subunits of DHP-sensitive voltage-gated (L-type) calcium channels to exert their antihypertensive effects and are believed to play a central role in the excitation-contraction coupling for cardiac and (Received August 11, 2008; revised manuscript received October 27, 2008; accepted November 12, 2008; released online February 17, 2009 Fumiki Yoshihara, MD; Satoko Nakamura, MD; Hajime Nakahama, MD; Toshiyuki Miyata, PhD*; Yuhei Kawano, MD Background: The response of blood pressure (BP) to L-type dihydropyridine calcium-channel blockers (dCCBs) differs among individuals. Methods and Results:A pharmacogenomic analysis was undertaken in 161 patients with essential hypertension who were treated with dCCBs to study whether genetic polymorphisms of the calcium channel α1C and α1D subunit genes, CACNA1C and CACNA1D, are associated with the antihyper...

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.

IntroductionThiazide diuretics (TZDs) have been most widely used as a first line antihypertensive drug (1,2). Recently, the ALLHAT study confirmed the usefulness of TZDs for the reduction of blood pressure (BP) and cardiovascular diseases in comparison with newer antihypertensive drugs, including Ca channel blockers (CCBs) such as amlodipine and angiotensin converting enzyme inhibitors (ACEIs) such as lisinopril in about 40,000 hypertensive patients with high risk factors (3). TZDs are not only effective as a monotherapy for hypertension, but are also very useful for combination therapy with other antihypertensive drugs (4). Moreover, the use of a TZD as a drug therapy for hypertension, which is a chronic and lifelong disease, would be very good from the viewpoint of the cost of drugs, because TZDs are the cheapest of all antihypertensive drugs. However, the response of BP to TZDs differs among individuals, and TZDs often induce side effects, such as hypokalemia and lipid, glucose and uric acid metabolism abnormalities (4). Therefore, it would be useful to determine the individual sensitivity to a TZD before prescribing it.Regarding previous findings about gene polymorphisms that influence TZD-sensitivity, Turner et al. (5) reported that the β3-subunit of the G protein (GNB3) C825T polymorphism was related to the antihypertensive effect of a TZD in Caucasian and African-American subjects with essential hypertension (EHT). Glorioso et al. (6) also demonstrated that the α-adducin (ADD1) Gly460Trp polymorphism is the gene conferring susceptibility to the antihypertensive effect of TZDs in Italian hypertensives. This ADD1 Gly460Trp polymorphism was also suggested to confer susceptibility to saltsensitivity in Caucasians and Asians with EHT (7).Mutations of causative genes have recently been detected in several monogenic electrolyte disorders, such as mutations in the thiazide-sensitive Na-Cl cotransporter (TSC) gene for Gitelman syndrome (8, 9), the WNK1 and 4 genes for Gordon syndrome (pseudohypoaldosteronism type II) (10) and the mineral corticoid receptor (MLR) for pseudohypoaldosteronism type I (PHA I) (11). TZDs are commonly effective for treating Gitelman syndrome and Gordon syndrome. We also focused on the Na /Ca 2 exchanger gene (NCX1), because its impairment was recently reported in mesangial cells from salt-sensitive hypertensive rats (12). TZDs are known to be effective for salt-sensitive hypertension. It is also known that the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) are activated in response to changes in circulating blood volume after TZD administration. Therefore, it is expected that gene polymorphisms related to the RAAS and SNS might be involved in the antihypertensive effect of TZDs. The present study investigated the gene polymorphism influencing the TZD-sensitivity by analyzing mainly single nucleotide polymorphisms (SNPs) of several water-electrolyte-related genes, including GN3B, ADD1, TSC, MLR, NCX1, WNK1, WNK4 and RAAS-and SNS-related genes, to antici...

Masked hypertension has been drawing attention recently because this condition is often seen in untreated and treated individuals and is associated with target organ damage and a poor cardiovascular prognosis. Although masked hypertension is defined as normal office blood pressure with elevated ambulatory or home blood pressure, there are several subtypes. Morning hypertension is the most common form of masked hypertension, and is caused by natural circadian variation, evening alcohol consumption, and the use of short-acting antihypertensive drugs. Daytime hypertension may be caused by lifestyle factors such as habitual smoking and mental or physical stress. Nighttime hypertension is seen in various conditions that produce non-dipping status, including a high salt intake, renal dysfunction, obesity, sleep apnea, and autonomic failure. Advanced target organ damage such as increases in the left ventricular mass, carotid artery intima-media thickness, and urinary albumin excretion, is often present both in untreated and treated subjects with masked hypertension. In our study, the presence of the reverse white-coat effect is independently associated with those indices of organ damage among treated hypertensive patients. It is important to identify individuals with masked hypertension, to evaluate them with including the search for the subtype, and to treat each patient appropriately according to the cause of this condition.