Tokihisa Nagai

Silent cerebral microbleeds associated with arterial stiffness in an apparently healthy subject

Silent cerebral microbleeds (MBs) are a common finding in stroke patients, especially those with intracerebral hemorrhage, and are thought to be a marker of future cerebral hemorrhage. Clinically, two distinct forms of MBs have been documented, those observed with either or both stroke or small vessel disease (SVD) and those associated with cerebral amyloid angiopathy. We investigated a possible association between MBs and arterial stiffness in a general population. Subjects were 443 apparently healthy individuals with a mean age of 67.1±8.1 years. The presence of MBs, lacunar infarcts and periventricular hyperintensity (PVH) was determined by 3-tesla magnetic resonance imaging. Carotid intima-media thickness (IMT) was measured by ultrasonography. Arterial stiffness was evaluated by brachial-to-ankle pulse wave velocity (baPWV), and the Framingham stroke risk score (FSRS) was obtained as an integrated cerebrovascular risk factor. The prevalence of MBs was 5.0%. Both baPWV and FSRS were significantly higher in subjects with MBs (1820±308 vs. 1645±325 cm/s, P=0.014 and 12.1±8.6 vs. 8.9±7.5%, P=0.047, respectively). Odds ratio of a high baPWV, defined as ⩾1500 cm/s, for the presence of MBs was 6.05 even after correction for confounding parameters, including age and hypertension. This association with high baPWV remained irrespective of MBs location, whether strictly located in the lobes or in the basal ganglia and infratentorial regions. These findings indicate an association between arterial stiffness and the presence of MBs. Assessment of arterial stiffness may be useful in identifying subjects at high risk for the presence of MBs.

Abdominal fat, adipose-derived hormones and mild cognitive impairment: the J-SHIPP study.

Background/Aim: Lower body weight in later life has been shown to be associated with dementia. However, abdominal fat distribution under conditions of mild cognitive impairment (MCI) and the possible involvement of leptin and adiponectin in MCI have not been fully investigated. Methods: We analyzed 517 middle-aged-to-elderly community-dwelling persons. Abdominal subcutaneous fat and visceral fat areas were determined using computed tomography, and plasma leptin and adiponectin concentrations were measured in fasting samples. MCI was assessed using the Japanese version of the MCI screening method. Results: In men, the abdominal subcutaneous fat area was significantly lower in participants with MCI than in those with normal cognitive function [median (interquartile range): 107.4 (85.9, 133.1) cm2 vs. 136.4 (93.1, 161.4) cm2; p = 0.002]. Logistic regression analyses with confounding factors including age and abdominal subcutaneous fat area showed that a 10 mg/l increase in plasma adiponectin had a protective effect against the development of MCI in men (odds ratio: 0.46; 95% CI: 0.20–0.97; p = 0.041). In contrast, MCI was not found to be associated with abdominal fat area or adipose-derived hormones in women. Conclusion: Reduced amounts of subcutaneous fat and low levels of plasma adiponectin were found to be associated with MCI in men.

Association of central systolic blood pressure with intracerebral small vessel disease in Japanese.

BACKGROUND Recent studies have reported the association between advanced arterial stiffness and brain small vessel diseases (SVDs). Two possible hemodynamic mechanisms, increases in central blood pressure (BP) and pulsatile flow load to the brain, have been speculated to link arterial stiffness and SVD. The carotid flow augmentation index (AI) has been proposed as an index of pulsatile flow to the brain. We compared its association with brain SVD with that of central BP in a general population. METHODS Subjects were 500 individuals free from symptomatic cardiovascular diseases with a mean age of 66.9 +/- 8.4 years. Brachial-ankle pulse wave velocity (baPWV) was measured as an index of arterial stiffness. Carotid flow AI was obtained by Doppler ultrasonography. The presence of silent cerebral lacunar infarcts (SCI) was determined as a manifestation of SVD by 3-tesla magnetic resonance imaging (MRI). Second peak radial systolic BP (SBP2) and pulse pressure (PP2) were used as estimates of central BP. RESULTS baPWV was significantly associated with radial BP2 (r = 0.55, P < 0.0001) but not with carotid flow AI (r = 0.03, P = 0.51). Radial BPs and baPWV, but not flow AI, were significantly higher in subjects with SCI. Radial SBP2 had higher odds ratio for the presence of SCI than brachial SBP, PP, and radial PP2. Logistic regression analysis showed that radial SBP2, but not flow AI, was independently related to the presence of SCI. CONCLUSION These findings indicate that the SBP2, an estimate of central SBP, is significantly associated with the presence of SVD in an apparently healthy general population.

Leptin in Sarcopenic Visceral Obesity: Possible Link between Adipocytes and Myocytes

The combination of sarcopenia, age-related loss of muscle strength and mass, and obesity has been recognized as a new category of obesity among the elderly. Given that leptin has been hypothesized to be involved in the pathogenesis of sarcopenic obesity, we investigated the relationship between plasma leptin levels and thigh muscle sarcopenia and visceral obesity. Thigh muscle cross-sectional area (CSA) and visceral fat area were measured using computed tomography as indices for muscle mass and visceral fat, respectively, in 782 middle-aged to elderly subjects (303 men and 479 women), participating in a medical check-up program. Visceral obesity was defined as visceral fat area >100 cm2, and sarcopenia was defined as < (one standard deviation − mean of thigh muscle CSA/body weight of young subjects [aged <50 years]). Thigh muscle CSA was significantly and negatively associated with plasma levels of leptin in both men (β = -0.28, p<0.0001) and women (β = -0.20, p<0.0001), even after correcting for other confounding parameters, including age, body weight, body height, visceral fat area, blood pressure, homeostatic model assessment index, and high sensitive C reactive protein. Subjects were divided into four groups based on presence or absence of sarcopenia or visceral obesity. Plasma levels of leptin were higher in subjects with sarcopenic visceral obesity than in those with either sarcopenia or visceral obesity alone. These findings indicate that sarcopenic visceral obesity is a more advanced, and suggest that leptin may link visceral obesity and sarcopenia.

Arterial stiffness in sarcopenic visceral obesity in the elderly: J-SHIPP study

Aging is associated with dramatic changes in body composition. Agerelated loss ofmusclemass and strength, known as sarcopenia, is amajor concern in an aged society, especially because sarcopenia in the legs leads to serious functional impairments such as postural instability, falling, fracture, frailty and death, including cardiovascular diseases [1]. The combination of sarcopenia and obesity is another concern in an aged society. Furthermore, sarcopenic obesity, especially sarcopenic visceral obesity, results in both functional and metabolic abnormalities. In our previous studies, we found that sarcopenic visceral obesity is associated with postural instability [2] and leptin resistance manifested by higher plasma leptin concentrations [3]. Arterial stiffness underlies numerous pathological conditions and increases the risk of cardiovascular events. Recently, we showed that sarcopenia in the thigh muscle is associated with higher arterial stiffness, indexed by brachial-ankle pulsewave velocity, in middle-aged to elderly men [4]. Thereafter, similar findings have also been reported [5,6]. Because obesity is associated with arterial stiffness [7], we hypothesize that visceral obesity and sarcopenia independently affect arterial stiffness. Subjects in this study were independent middle-aged to elderly persons recruited from among consecutive visitors to the Anti-Aging Center at Ehime University Hospital from March 2006 to December 2009. Among the 1276 consecutive subjects who were initially approached, we studied 1024 who agreed with the study aims and protocols, and gave written consent to all procedures. These subjects had no history of symptomatic cardiovascular events including peripheral arterial diseases, stroke, coronary heart disease, and congestive heart failure. The study was approved by the Ethics Committee of Ehime University Graduate School of Medicine. The authors of this article have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [8]. Femoral muscle cross-sectional area (CSA) was measured using computed tomography (CT; LightSpeed VCT; GE Healthcare, Tokyo, Japan) at the mid-thigh, measured as the midpoint from the inguinal crease to the proximal pole of the patella [2,3]. The visceral fat area was measured using CT at the level of the umbilicus. CT images were obtained with aminimal slicewidth of 5 mm and analyzed using OsiriX software (OsiriX Foundation, Geneva, Switzerland). Visceral obesity was defined as a visceral fat area N100 cm in men and women, according to the Japanese criterion defining metabolic syndrome. Since thigh muscle CSA showed a strong association with bodyweight (BW) (r=0.71 inmen; r=0.66 inwomen), thighmuscle CSAwas corrected by body weight (CSA/BW) as a sarcopenic index of muscle mass per BW. Sarcopenia was defined as having a CSA/BW within one standard deviation value of the CSA/BW distribution in subjects aged b50 years [3,4]. Brachial-ankle pulse wave velocity (baPWV) as an index of arterial stiffness was measured using a volume-plethysmographic apparatus (form PWV/ABI; Omron Healthcare Co. Ltd., Kyoto, Japan). Because body composition profiles differ between men and women, the following analyses were performed in men and women separately. Clinical characteristics of the study population are shown in Table 1. The values of baPWVwere significantly and positively related to visceral fat area and inversely related to thigh muscle CSA in both men and women (Fig. 1). We further investigated whether thigh muscle CSA and visceral fat area are associated with baPWV independently or if there are other confounding parameters by multiple regression analyses (Table 2). The visceral fat areawas positively associated with baPWV in men and women, and thigh muscle CSA was negatively related to baPWV in men. Interestingly, inclusion of plasma levels of leptin into the model eliminated the effect of thigh muscle CSA in men. The combined effect of thigh sarcopenia and visceral obesity was evaluated in four groups based on the presence or absence of either or both thigh muscle sarcopenia and visceral obesity (Fig. 2). Subjects with visceral obesity had a significantly higher baPWV than that in the control group in men and women. Men with sarcopenic visceral obesity had the highest baPWV among the four groups.

Postural Instability Is Associated with Brain Atrophy and Cognitive Impairment in the Elderly: The J-SHIPP Study

Background/Aims: Mobility impairment in older adults has been suggested to be a marker of subclinical structural and functional brain abnormalities. We investigated a possible association between static postural instability and brain abnormalities and cognitive decline. Methods: The study subjects were 390 community residents without definitive dementia (67 ± 7 years old) and 21 patients with Alzheimer’s disease (AD). Brain atrophy was measured by MRI. Results: The mobility of the posturography-measured center of gravity (COG) was positively associated with the temporal horn area (THA; r = 0.260; p < 0.001). Subjects who could not stand on one leg for >40 s (n = 102) showed a significantly larger THA (22 ± 18 vs. 14 ± 11 × 10–2 cm2; p < 0.001). Multiple regression analysis identified COG path length (β = 0.118; p = 0.032) and one-leg standing time (β = 0.176; p = 0.001) as independent determinants of THA. Mild cognitive impairment (MCI) subjects (n = 61) had a significantly enlarged THA compared to that of normal cognitive subjects (22 ± 16 vs. 16 ± 13 × 10–2 cm2; p = 0.002). AD patients showed a more enlarged THA (78 ± 55 × 10–2 cm2). Subjects with cognitive decline showed a significantly shorter one-leg standing time (normal: 50 ± 17 s; MCI: 42 ± 21 s; AD: 18 ± 20s; p < 0.001). Conclusion: Reduced postural stability was an independent marker of brain atrophy and pathological cognitive decline in the elderly.

Increased Expression of Angiotensin Converting Enzyme 2 in Conjunction with Reduction of Neointima by Angiotensin II Type 1 Receptor Blockade

Angiotensin converting enzyme 2 (ACE2), a newly recognized homolog of ACE that converts angiotensin II (Ang II) to angiotensin-1–7 (Ang-(1–7)), is found in vascular smooth muscle cells. Expression of ACE2 may be a local determinant of vascular Ang-(1–7) production and, when increased, may augment the increasingly recognized protective effects of this peptide within injured tissues. We previously showed that treatment with the angiotensin II type 1 (AT1) receptor blocker (ARB) olmesartan increased aortic ACE2 and Ang-(1–7) in conjunction with improved vascular remodeling in spontaneously hypertensive rats (SHR). In the present study, we investigated balloon injury–related ACE2 in the vasculature by determining the effect of sustained AT1 blockade on ACE2 protein expression in the carotid arteries of 12-week-old male SHR treated with either vehicle (n=5) or 10 mg/kg olmesartan (n=5) in drinking water for 14 days. Olmesartan treatment caused a 61% reduction in the cross-sectional area of the neointima, from 0.27±0.01 mm2 in vehicle-treated rats to 0.11±0.01 mm2 in olmesartan-treated rats. In contrast, olmesartan treatment had no effect on the medial area of injured or uninjured carotid arteries compared to that in vehicle-treated rats. Quantitative analysis of ACE2 immunostaining intensity in the carotid artery of SHR was significantly greater (p<0.05) in the neointima of olmesartan-treated SHR compared to that in vehicle-treated animals. In contrast, ACE2 immunostaining intensity was not quantitatively different in uninjured carotid arteries of olmesartan and vehicle-treated animals. These studies suggest that changes in ACE2 within the vascular system of SHR are regulated by a factor other than arterial pressure.

Postprandial hypotension as a risk marker for asymptomatic lacunar infarction.

Objective: Increasing blood pressure (BP) variability is reported to be a cardiovascular risk factor. However, the clinical implications of postprandial hypotension (PHYPO), a commonly observed BP variability in elderly persons, are poorly understood. Here, we investigated the possible associations between postprandial BP decline and asymptomatic cerebral damage in community residents. Methods: Study participants consisted of 1308 general community residents (65 ± 9 years old). Postprandial BP change was calculated from SBP measured just before and 30 min after lunch. PHYPO was defined as a decline in SBP of more than 20 mmHg. The presence of asymptomatic cerebrovascular damage was evaluated by brain MRI. Results: Prevalence of lacunar infarction was significantly higher in participants with PHYPO (P = 0.004). A postprandial decline in SBP was linearly increased with the number of lacunar lesions (none, n = 1200, −3.4± 11.3 mmHg; one lesion, n = 82, −5.2 ± 11.8; two lesions, n = 18, −6.9 ± 11.5; three lesions, n = 7, −13.4 ± 11.3; and four lesions, n = 1, −27; P = 0.012). Although participants with PHYPO were older (P < 0.001) and had higher preprandial BP (P < 0.001) and faster pulse wave velocity (P = 0.001), multivariate analysis adjusted for these covariates indicated that postprandial BP decline was an independent determinant for the number of lacunar infarctions (P = 0.004). No significant associations were observed with grade of periventricular hyperintensity or frequency of microbleeds. These relationships were also found in an analysis based on central BP, whereas no superiority was seen in the analysis based on central BP. Conclusion: Postprandial BP decline is an overlooked risk marker for asymptomatic lacunar infarction in community residents.

Clinical usefulness of the second peak of radial systolic blood pressure for estimation of aortic systolic blood pressure

Central aortic blood pressure (BP), obtained from radial arterial waveform using the transfer function method (TFM), has been shown to have prognostic value independently of brachial BP. In this study, the relationship between peripheral systolic BP (SBP) and aortic SBP was evaluated. We further investigated whether TFM-derived aortic SBP can be estimated by information obtained from the radial waveform. The radial waveform was analysed to obtain the first peak of radial SBP (SBP1), second peak of radial SBP (SBP2), radial augmentation index (AI) (radial (SBP2−DBP)/(SBP1−DBP) × 100 and aortic SBP and AI using TFM in 233 subjects in the supine position. Measurements were repeated after changing position to the prone position. The constructed equation was validated in 149 community residents with different backgrounds. Radial SBP2 was closer to TFM-derived aortic SBP compared with brachial SBP. TFM-derived aortic SBP was approximated by the equation: aortic SBP=18.9—radial SBP2−0.03 × HR—0.214 × radial AI (r2=0.992). The equation was also applicable to predicting aortic SBP in the prone position as well as in different populations (mean difference between predicted aortic SBP and TFM-derived aortic SBP: −0.01±1.34 and 1.05±1.47 mm Hg, respectively). Radial arterial waveform analysis can be used for estimation of TFM-derived aortic SBP.

Association of Postural Instability With Asymptomatic Cerebrovascular Damage and Cognitive Decline The Japan Shimanami Health Promoting Program Study

Background and Purpose— Asymptomatic cerebral small-vessel disease (cSVD) in elderly individuals are potent risk factors for stroke. In addition to common clinical risk factors, postural instability has been postulated to be associated with cSVD in older frail patients. Here, we conducted a cross-sectional study to understand the possible link between postural instability and asymptomatic cSVD further, namely periventricular hyperintensity, lacunar infarction, and microbleeds, as well as cognitive function, in a middle-aged to elderly general population (n=1387). Methods— Postural instability was assessed based on one-leg standing time (OLST) and posturography findings. cSVD was evaluated by brain magnetic resonance imaging. Mild cognitive impairment was assessed using a computer-based questionnaire, and carotid intima-media thickness as an index of atherosclerosis was measured via ultrasonography. Results— Frequency of short OLST, in particular <20 s, increased linearly with severity of cSVD (lacunar infarction lesion: none, 9.7%; 1, 16.0%; >2, 34.5%; microbleeds lesion: none, 10.1%; 1, 15.3%; >2, 30.0%; periventricular hyperintensity grade: 0, 5.7%; 1, 11.5%; >2, 23.7%). The association of short OLST with lacunar infarction and microbleeds but not periventricular hyperintensity remained significant even after adjustment for possible covariates (lacunar infarction, P=0.009; microbleeds, P=0.003; periventricular hyperintensity, P=0.601). In contrast, no significant association was found between posturographic parameters and cSVD, whereas these parameters were linearly associated with OLST. Short OLST was also significantly associated with reduced cognitive function independent of covariates, including cSVD (P=0.002). Conclusions— Postural instability was found to be associated with early pathological changes in the brain and functional decline, even in apparently healthy subjects.