Michiaki Nagai

The insular cortex and cardiovascular system: a new insight into the brain-heart axis

The classical literature on neurocardiology has focused mainly on the subcortical regions of the central autonomic nervous system. However, recent studies have supported the notion that the cardiovascular system is regulated by cortical modulation. Modern neuroimaging data, including positron emission tomography and functional magnetic resonance imaging, have revealed that a network consisting of the insular cortex, anterior cingulate gyrus, and amygdala plays a crucial role in the regulation of central autonomic nervous system. Because the insular cortex is located in the region of the middle cerebral arteries, its structure tends to be exposed to a higher risk of cerebrovascular disease. The insular cortex damage has been associated with arrhythmia, diurnal blood pressure variation disruption (eg, a non-dipper or riser pattern), myocardial injury, and sleep disordered breathing, as well as higher plasma levels of brain natriuretic peptide, catecholamine, and glucose. This review article focuses on the role of the insular cortex as a mediator for the cardiovascular system and summarizes current knowledge on the relationships between cerebrovascular disease and cardiovascular system dysregulation. Finally, a hypothesis of the neural network involved in cortical cardiovascular modulation, including modulation of the insular cortex, is provided.

Hypertension and Dementia

Although hypertension is well known as a cause of vascular dementia (VaD), recent findings highlight the role of hypertension in the pathogenesis of Alzheimers disease (AD) as well as mild cognitive impairment (MCI). Recent studies have shown that disruption of diurnal blood pressure (BP) variation is closely associated with cognitive impairment via injury of the small cerebral arteries indicating that long-standing hypertension constitutes a risk of brain matter atrophy or white matter lesions (WMLs). In several clinical trials, BP-lowering with antihypertensive agents was suggested to reduce the risk of dementia or cognitive decline. This review paper focuses on the role of hypertension as a risk factor for cognitive impairment, and summarizes current knowledge on the relationships between ambulatory BP monitoring (ABPM) and cognitive impairment. Finally, an overview of the impact of antihypertensive therapy on dementia prevention is provided.

Ambulatory blood pressure as an independent determinant of brain atrophy and cognitive function in elderly hypertension

Objective Recent studies have demonstrated a relationship between brain atrophy and hypertension. Systolic hypertension in the elderly has been found to be a risk factor for cognitive impairment. We studied the relationship of ambulatory blood pressure with brain atrophy and cognitive function. Methods We performed ambulatory blood pressure monitoring and brain magnetic resonance imaging in 55 unmedicated elderly hypertensive patients (72.7 ± 6.0 years old). The volume of total brain matter was measured using an intensity contour-mapping algorithm. Cognitive function was assessed by mini-mental state examination score. Results Total brain matter volume and cognitive function were significantly correlated (r = 0.314, P = 0.02). Total brain matter volume was significantly negatively correlated with age (r = −0.365, P = 0.006), 24-h systolic blood pressure (r = −0.343, P = 0.01), awake systolic blood pressure (r = −0.278, P = 0.04) and sleep systolic blood pressure (r = −0.491, P = 0.0001), and significantly positively correlated with male sex (r = 0.493, P = 0.0001), body mass index (r = 0.282, P = 0.04) and nocturnal systolic blood pressure dipping (r = 0.323, P = 0.02). Mini-mental state examination score was significantly negatively correlated with age (r = −0.277, P = 0.04) and sleep systolic blood pressure (r = −0.360, P = 0.007), and significantly positively correlated with nocturnal systolic blood pressure dipping (r = 0.402, P = 0.002). In multiple linear regression analysis adjusted for age, sex, and body mass index, sleep systolic blood pressure (P = 0.009) was more significantly negatively associated with total brain matter volume than was either 24-h (P = 0.035) or awake (P = 0.020) systolic blood pressure. Conclusions In elderly hypertensive patients, absolute ambulatory systolic blood pressure level (particularly during sleep) and nocturnal dipping in systolic blood pressure were strong indicators of brain matter volume and cognitive function.

Visit-to-visit blood pressure variations: New independent determinants for carotid artery measures in the elderly at high risk of cardiovascular disease

Recently, visit-to-visit variability in systolic blood pressure (SBP) has been shown to be a predictor of stroke. In this study, we investigated the relationship of visit-to-visit blood pressure (BP) variations (based on 12 visits once a month) with intima-media thickness (IMT) and stiffness in common carotid artery among the 201 high-risk elderly (female 75%) at cardiovascular disease. Max-IMT was significantly positively correlated with age, smoking, renin-angiotensin system inhibitor use, coefficient of variation (CV), and delta (maximum-minimum) in SBP, and CV in diastolic BP (DBP) but was significantly negatively correlated with female, high-density lipoprotein (HDL), and minimum in SBP. Stiffness parameter β was significantly positively correlated with age, standard deviation (SD), CV, maximum, and delta in SBP, and SD, CV, and delta in DBP but was significantly negatively correlated with smoking, HDL, average, and minimum in DBP. In a multiple regression analysis, delta SBP (P < .001) was associated with max-IMT independently of average SBP. CV (P < .05) and delta (P < .05) in SBP, and CV (P < .001) and delta (P < .01) in DBP were associated with stiffness parameter β independently of average BP. In the high-risk elderly, exaggerated visit-to-visit BP fluctuations were significant indicators for carotid artery atherosclerosis and stiffness independently of average BP.

Sleep Duration as a Risk Factor for Cardiovascular Disease- a Review of the Recent Literature

Sleep loss is a common condition in developed countries, with evidence showing that people in Western countries are sleeping on average only 6.8 hour (hr) per night, 1.5 hr less than a century ago. Although the effects of sleep deprivation on our organs have been obscure, recent epidemiological studies have revealed relationships between sleep deprivation and hypertension (HT), coronary heart disease (CHD), and diabetes mellitus (DM). This review article summarizes the literature on these relationships. Because sleep deprivation increases sympathetic nervous system activity, this increased activity serves as a common pathophysiology for HT and DM. Adequate sleep duration may be important for preventing cardiovascular diseases in modern society.

Visit-to-visit blood pressure variations: new independent determinants for cognitive function in the elderly at high risk of cardiovascular disease.

Objective: Recently, visit-to-visit blood pressure (BP) variability has been shown to be associated with silent cerebral injury and stroke. However, the relationships between visit-to-visit BP variation and cognitive function are not clear. Methods: The cognitive function was evaluated using a mini-mental state examination (MMSE) and global deterioration scale (GDS) in 201 elderly patients at high risk of cardiovascular disease (CVD) (79.9 ± 6.4 years old; women 75%). Based on 12 visits (once a month), visit-to-visit BP variability (expressed as the SD and coefficient of variation), maximum BP, minimum BP, and &dgr; (maximum − minimum) BP were measured. Results: The MMSE score had significant negative correlations with coefficient of variation and &dgr; in SBP, and &dgr;DBP. The GDS score had significant positive correlations with coefficient of variation and &dgr; in SBP, and &dgr;DBP. Low MMSE score (<24) had significant positive correlations with coefficient of variation and &dgr; in SBP, and &dgr;DBP. High GDS score (>3) had significant positive correlations with coefficient of variation and &dgr; in SBP, and &dgr;DBP. In a multiple linear regression analysis adjusted for confounders, coefficient of variation (P < 0.001) and &dgr; (P < 0.001) in SBP had significant negative associations with the MMSE score. The &dgr;SBP (P < 0.05) had significant positive association with the GDS score. The coefficient of variation and &dgr; in SBP had significant positive associations with low MMSE score (P < 0.01, P < 0.01, respectively) and high GDS score (P < 0.05, P < 0.001, respectively). Conclusions: In the high-risk elderly, exaggerated visit-to-visit BP fluctuations were significant indicators for cognitive impairment.

Visit-to-visit blood pressure variability in the elderly: Associations with cognitive impairment and carotid artery remodeling

OBJECTIVE Recently, visit-to-visit blood pressure (BP) variability has been shown to be associated with vascular remodeling and cognitive dysfunction. However, there have been no studies that focused on the relationship between visit-to-visit BP variability and cognitive dysfunction in relation to vascular remodeling. In this study, we investigated the relationships among visit-to-visit BP measures, carotid artery remodeling and cognitive function in the elderly at high risk of cardiovascular disease. METHODS The cognitive function was evaluated using a Mini-Mental State Examination (MMSE) and global deterioration scale (GDS) in 201 elderly subjects at high risk of cardiovascular disease (79.9 ± 6.4 years old; female 75%). Based on 12 visits (once a month), visit-to-visit BP variability (expressed as the coefficient of variation [CV] and as delta [maximum--minimum] BP) were measured. Carotid ultrasound was performed to measure intima-media thickness (IMT) and the stiffness parameter β. RESULTS The patients having both high delta systolic BP (SBP) and high IMT had significantly higher prevalence of low MMSE score than those with both low delta SBP and low IMT (p < 0.05), and the patients having both high delta SBP and high stiffness parameter β also had significantly higher prevalence of low MMSE score than those with both low delta SBP and low stiffness parameter β (p < 0.01). In the logistic regression analysis adjusted for age, calcium channel blocker use, low density lipoprotein, average heart rate, and average SBP level, a significant interaction was found between delta SBP and stiffness parameter β for the low MMSE score (p < 0.05). CONCLUSIONS In the high risk elderly, exaggerated visit-to-visit BP variability and advanced carotid artery remodeling have a synergetic association with cognitive dysfunction.

Sleep Duration and Insomnia in the Elderly: Associations With Blood Pressure Variability and Carotid Artery Remodeling

BACKGROUND Recent studies have shown that short and long sleep durations and insomnia are associated with increased home-measured blood pressure (BP) variability, which in turn has a relationship with arterial stiffness. However, the determinants for visit-to-visit systolic blood pressure (SBP) variability have rarely been investigated in relation to sleep duration, insomnia, and carotid arterial stiffness. METHOD The subjects were 201 elderly individuals (79.9±6.4 years old) with one or more cardiovascular risks. Based on 12 visits, visit-to-visit BP variability (expressed as a coefficient of variation [CV]) and δ (maximum - minimum) BP were measured. Self-reported sleep duration and insomnia questionnaires were used to classify the patients according to sleep duration period and insomnia status. RESULTS After multivariable adjustment, long sleep duration (≥ 9 hours per night) had significant positive associations with SBP δ (P < 0.05), while persistent insomnia had significant positive associations with SBP CV (P < 0.05) and δ (P < 0.01). Additionally, significant interactions were found in terms of long sleep duration by carotid artery stiffness parameter β (P < 0.05), persistent insomnia by intima-media thickness (P < 0.01), and persistent insomnia by stiffness parameter β (P < 0.05) for SBP δ. CONCLUSION In elderly patients at high risk for cardiovascular disease, long sleep duration as well as persistent insomnia were significantly associated with higher visit-to-visit BP variability. Long sleep duration and persistent insomnia each had synergetic interactions with carotid artery stiffness and with visit-to-visit BP variability.

Effects of Nighttime Single‐Dose Administration of Vasodilating vs Sympatholytic Antihypertensive Agents on Sleep Blood Pressure in Hypertensive Patients With Sleep Apnea Syndrome

Obstructive sleep apneas syndrome (OSAS) is associated with nocturnal hypertension with higher sleep blood pressure (BP) and its variability, both of which increase cardiovascular risk. In this crossover design study, the effect of nighttime single‐dose administration of vasodilating (nifedipine 40 mg) vs sympatholytic (carvedilol 20 mg) antihypertensive agents on sleep BP in 11 hypertensive OSAS patients was evaluated. The authors recently developed a trigger sleep BP monitor with an oxygen‐triggered function that initiates BP measurement when oxygen desaturation falls. The BP‐lowering effects of nifedipine on the mean (P<.05) and minimum sleep systolic BPs (SBPs) (P<.01) were stronger than those of carvedilol. Sleep SBP surge (difference between the hypoxia‐peak SBP measured by oxygen‐triggered function and SBPs within 30 minutes before and after the peak SBP) was only significantly reduced by carvedilol (P<.05). The nighttime dosing of both vasodilating and sympatholytic antihypertensive drugs is effective to reduce sleep BP but with different BP‐lowering profiles.

Visit-to-visit blood pressure variability, silent cerebral injury, and risk of stroke.

Apart from the well-known role of hypertension in cerebrovascular disease, visit-to-visit blood pressure (BP) variability is emerging as an independent risk factor for stroke. Although the underlying mechanism is not fully understood, artery remodeling is thought to be closely involved in the relationship between visit-to-visit BP variability and stroke. This review article summarizes the recent literature on these topics. Silent cerebral injury is considered to serve as a common pathophysiology in the relationship of visit-to-visit BP variability with cognitive impairment and stroke. Here we review visit-to-visit BP variability, some comparisons of the effects of antihypertensive agents on visit-to-visit BP variability, and an issue regarding the impact of these agents on stroke.