Atsuya Shimizu

Regional white matter lesions predict falls in patients with amnestic mild cognitive impairment and Alzheimer's disease.

OBJECTIVES Preventive strategy for falls in demented elderly is a clinical challenge. From early-stage of Alzheimers disease (AD), patients show impaired balance and gait. The purpose of this study is to determine whether regional white matter lesions (WMLs) can predict balance/gait disturbance and falls in elderly with amnestic mild cognitive impairment (aMCI) or AD. DESIGN Cross-sectional. SETTINGS Hospital out-patient clinic. PARTICIPANTS One hundred sixty-three patients diagnosed with aMCI or AD were classified into groups having experienced falls (n = 63) or not (n = 100) in the previous year. MEASUREMENTS Cognition, depression, behavior and psychological symptoms of dementia, medication, and balance/gait function were evaluated. Regional WMLs were visually analyzed as periventricular hyperintensity in frontal caps, bands, and occipital caps, and as deep white matter hyperintensity in frontal, parietal, temporal, and occipital lobes, basal ganglia, thalamus, and brain stem. Brain atrophy was linearly measured. RESULTS The fallers had a greater volume of WMLs and their posture/gait performance tended to be worse than nonfallers. Several WMLs in particular brain regions were closely associated with balance and gait impairment. Besides polypharmacy, periventricular hyperintensity in frontal caps and occipital WMLs were strong predictors for falls, even after potential risk factors for falls were considered. CONCLUSIONS Regional white matter burden, independent of cognitive decline, correlates with balance/gait disturbance and predicts falls in elderly with aMCI and AD. Careful insight into regional WMLs on brain magnetic resonance may greatly help to diagnose demented elderly with a higher risk of falls.

Prolongation of Activation‐Recovery Interval over a Preexcited Region before and after Catheter Ablation in Patients with Wolff‐Parkinson‐White Syndrome

Activation‐Recovery Interval in WPW Syndrome. Introduction: Preexisting changes in repolarization properties play an important role in T wave abnormalities (cardiac memory) after ablation in patients with Wolff‐Parkinson‐White (WPW) syndrome. However, no report has provided direct evidence for prolongation of action potential duration (APD) over a preexcited region before and after ablation.

Inverse relation of body-surface activation-recovery interval and recovery time to activation time in normal subjects: stronger correlation and more heterogeneous distribution in activation-recovery interval than in recovery time.

The activation‐recovery interval (ARI), measured directly from the myocardium, has shown a good correlation with the action potential duration (APD) in experiments. APD has been reported to be inversely related to the activation time (AT). However, no studies have examined the correlation between the body‐surface ARI and AT in normal subjects. Fifty normal subjects (25 men and 25 women) were studied to elucidate the relationship between the body‐surface ARI and AT. The body‐surface AT was defined as the duration between the QRS onset and the minimum dV/dt of the QRS wave, and ARI as the interval between the minimum dV/dt of the QRS wave and the maximum dV/dt of the T wave in each lead of an 87 unipolar lead system. We also measured the recovery time (RT) defined as the duration between the QRS onset and the maximum dV/dt of the T wave. ARI was inversely correlated with AT (r = ‐0.73). RT was also inversely correlated with AT (r = ‐0.61), however, RT had a less heterogeneous distribution than ARI (148 ms vs 159 ms). There were no differences between male and female subjects in the relation between ARI and RT or in the body‐surface distribution of ARI and RT. These findings suggest that the body‐surface ARI may reflect recovery properties over the cardiac surface and that APD may distribute inhomogsneously over the human cardiac surface with a longer RT over an area with a shorter AT. ARI calculated from body‐surface ECG may be a useful noninvasive and repeatedly measurable estimate of APD.

Circulatory power and ventilatory power over time under goal-oriented sequential combination therapy for pulmonary arterial hypertension

Many therapeutic options are available for patients with pulmonary arterial hypertension (PAH). However, little is known about the effects of sequential combination therapy on exercise capacity. Here we monitored exercise capacity by cardiopulmonary exercise testing (CPX) and observed the benefit of using a peak VO2 cutoff of 15 mL/kg/min to guide combination therapy. Thirty patients newly diagnosed with PAH were treated with goal-oriented sequential combination therapy. Endothelin receptor antagonists (ERA) were the first-line treatment, with phosphodiesterase type 5 inhibitors (PDE-5i) as the preferred combination partner. The patients underwent cardiac catheterization at baseline and after 12 months and CPX at baseline and after three, six, and 12 months. Circulatory power (CP) was defined as the product of peak O2 uptake and peak systolic blood pressure (SBP); ventilatory power (VP) was defined as peak SBP divided by the minute ventilation–CO2 production slope. After 12 months, ERA had been administered to 100% of the study patients and PDE-5i to 82%. Mean CP at baseline and after three, six, and 12 months was 1807, 2063, 2248, and 2245 mmHg·min/mL/kg, respectively, and mean VP was 2.93, 3.53, 4.16, and 3.68 mmHg, respectively. CP was greater after 6 months than at baseline (P = 0.047); VP was greater after three months than at baseline (P = 0.019) and further improved at six months compared with three months (P = 0.040). Therefore, repeated CPX assessment, including measurement of CP and VP, can provide useful information regarding the efficacy of goal-oriented treatment for PAH.

Impact of night-time blood pressure on cerebral white matter hyperintensity in elderly hypertensive patients.

Cerebral white matter hyperintensity (WMH) is highly prevalent in the elderly population, and increases the risk of dementia and stroke. We investigated the relationship between ambulatory blood pressure monitoring levels and quantitatively measured WMH volumes among elderly hypertensive patients with well‐controlled blood pressure (BP) to re‐evaluated effective hypertension management methods to prevent the progression of WMH.

Left main coronary artery compression by a dilated main pulmonary artery and left coronary sinus of Valsalva aneurysm in a patient with heritable pulmonary arterial hypertension and FLNA mutation

Left main coronary artery (LMCA) disease due to external compression by a dilated main pulmonary artery (MPA) is an uncommon clinical entity. Here, we describe a 52-year-old woman with pulmonary arterial hypertension (PAH) and anteroseptal old myocardial infarction (OMI). The cause of the OMI was external compression of the LMCA by the dilated MPA and aneurysm of the left coronary sinus of Valsalva. The patient’s sister (aged 56 years) had also been diagnosed with PAH and both women had a novel heterozygous splicing mutation, IVS2-2A > G (c.374-2A > G in NM_001456), in the filamin A (FLNA) gene. To our knowledge, this is the first report of HPAH which is likely to be due to FLNA mutation and compression of the LMCA between a dilated MPA and aneurysm of the left coronary sinus of Valsalva.

Left ventricular diastolic dysfunction is directly associated with cerebral white matter lesions in elderly patients.

Cerebral white matter lesions (WML) have been established to increase with age, and are associated with heightened risks of stroke, cognitive decline and depressive disorder. We previously reported that the severity of left ventricular (LV) diastolic dysfunction is associated with the volume of cerebral WML. However, the analysis could not be carried out by removing the effect of the common or specific risk factors that are known to be involved in the progression of LV diastolic dysfunction and/or cerebral WML, such as age, hypertension, diabetes mellitus, hyperlipidemia, smoking, obesity and so on. Consequently, whether LV diastolic dysfunction is directly associated with cerebral WML remained unclear. Therefore, to clarify this, we carried out a cross-sectional study by conducting further in-depth examination of these risk factors and also by increasing the study population. The study registration period was from April 2010 to October 2013. Participants comprised 133 outpatients between aged 65 and 75 years with normal LV contraction (ejection fraction >50%) and no signs or history of symptomatic heart failure, ischemic heart diseases, atrial fibrillation, stroke, or cognitive dysfunction. We also excluded those patients with ≥50% stenosis in the carotid arteries on ultrasonography with 2-D and Doppler analysis. The volume of cerebral WML was quantified on brain magnetic resonance imaging using a fully automatic segmentation program developed in the Department of Radiology at Leiden University Medical Center (Leiden, the Netherlands), and early diastolic mitral inflow and early diastolic mitral annular tissue velocity (E/E’) ratio, a parameter that indicates the severity of LV diastolic dysfunction, was measured by tissue Doppler echocardiography. A total of 20 4-h systolic and diastolic blood pressure were obtained by ambulatory blood pressure monitoring. In addition, LV ejection fraction, body mass index, estimated glomerular filtration rate, carotid intimal media thickness, and levels of plasma B-type natriuretic peptide, hemoglobin A1c and low density lipoprotein cholesterol were also determined. Values are shown as mean ± standard deviation unless otherwise stated. Data were analyzed using SPSS version 17.0 software (SPSS, Chicago, IL, USA). The study protocol was approved by the ethics/conflict of interest committee at the National Center for Geriatrics and Gerontology. Written informed consent was obtained from all participants before participation. Table A shows the patient characteristics. The results of linear regression analysis between cerebral WML volume and estimated factors are shown in Table B. These results showed that four factors (age, systolic blood pressure, plasma B-type natriuretic peptide and E/E’) had a significant correlation (P < 0.05) with cerebral WML volume. Based on the results, multivariate analysis was carried out in order to clarify the principal factors involved in the increase of the cerebral WML. As a result, E/E’ and age had been shown to be significantly correlated with cerebral WML volume (P < 0.01), with the correlation greater for E/E’ (P = 0.003) than for age (P = 0.03; Table C). The present study clarified the direct association between the severity of LV diastolic dysfunction and the volume of WML in elderly patients even after removing the effects of risk factors that were involved in the progression of LV diastolic dysfunction and/or cerebral WML. The results can be interpreted in two ways. The first interpretation is that a common, but unknown, factor exacerbates both cerebral WML and LV diastolic dysfunction, with this complicating factor being profoundly involved in the onset and progression of both diseases. The second interpretation involves chronic low cardiac output and chronic cerebral ischemia. Some reports in recent years have suggested that cerebral perfusion is impaired in patients with chronic low cardiac output. Thus, considering that cardiac output decreases with the decrease in blood flow into the LV from the left atrium as a result of the progression in LV diastolic dysfunction, and also considering that a chronic decrease in cerebral blood flow is thought to be the primary mechanism underlying cerebral WML formation, the present results can also be interpreted as suggesting that decreased cardiac output elicits chronic cerebral ischemia. Further investigation is necessary to clarify these points. Correspondence: Dr. Manabu Kokubo MD PhD, Department of Cardiology, National Center for Geriatrics and Gerontology, 7-430, Morioka-cho, Obu, Aichi 474-8511, Japan. Email: mkokubo@ncgg.go.jp Geriatr Gerontol Int 2015; 15 (Suppl. 1): 81–85 bs_bs_banner

1027 ANGIOTENSIN RECEPTOR BLOCKERS INHIBIT DE NOVO ONSET OF MALIGNANT TUMORS

Objective: Angiotensin receptor blockers (ARBs) are commonly used anti-hypertensives. We previously reported that high dose of ARB inhibited growth of malignant tumors in mice. While recent meta-analysis of randomized clinical trials indicated no relation between cancer risk and ARBs, some data suggested potential anti-tumor efficacies of ARBs. We performed a retrospective-cohort for the de novo onset of malignant tumors in Japanese hypertensive patients. Methods: Study population consisted of patients without cancer treated for hypertension for >1year, enrolled from January 2003 to December 2008, grouped based on with or without ARB treatment. Kaplan-Meier time event curve was used to predict time to onset, and log-rank test was performed. In each anti-hypertensive agent (ARB, ACEI, CCB, &bgr;-blocker and diuretic drug), incidence rate was calculated using Cox hazard model with 95% confidence interval (CI). Results: Among 3688 patients (2510 in ARB and 1178 in non-ARB group, mean age 60.9), 63 in the ARBs (2.51%) and 47 in the non-ARB group (3.99%) developed de novo tumor (log-rank test p = 0.02). Cox hazard model revealed statistical significance in the inhibition of de novo occurrence of tumors in the ARB group (incidence rate ratio: 0.65, 95% CI 0.45-0.95). Univariate analysis didn’t show any significant inhibiting effects on the de novo tumor by other anti-hypertensive agents. Conclusion: Development of de novo malignant tumors was significantly lower in hypertensive patients receiving ARBs. This phenomenon wasn’t confirmed in other anti-hypertensive regimens. Further prospective study should be needed to examine the effects of ARBs on cancer incidence in Japanese hypertensive patients.

Effects of dronedarone on HERG and KCNQ1/KCNE1 channels

Dronedarone, a noniodinated and methanesulfonanilide derivative of amiodarone, is under evaluation as a potentially less toxic anti-arrhythmic agent alternative to amiodarone. However, effects of this drug on I K r and I K s channels, two major cardiac repolarizing potassium channels, had not been determined yet. To clarify the effects on I K r and I K s , we studied the effects of dronedarone on HERG channels and KCNQ1/KCNE1 channels heterologously expressed in Xenopus Oocytes by 2-electrodes voltage clamp technique. Because I K r channel is coded by HERG gene, and I K s is coded by co-expression of both KCNQ land KCNE1 genes. Dronedarone potently blocked both HERG channel (IC 5 0 : 3.8′1.0 μM, 0 mV, n=3) and KCNQ1/KCNE1 channels (IC 5 0 : 19.1′2.1 μM, 0 mV, n=2). Amiodarone, a structurally similar compound of dronedarone, had already reported not to block KCNQ1/KCNE1 channels. These findings together with previous reports suggest that 1) dronedarone potently inhibits both HERG channels and KCNQ1/ KCNE1 channels. 2) Insertion of methanesulfonanilide compound to dronedarone might result in an inhibitory action on KCNQ1/ KCNE1 channels. 3) Dronedarone might be a potential antiarrhythmic drug.