Akiko Noda

Mineralocorticoid Receptor Antagonism Attenuates Cardiac Hypertrophy and Failure in Low-Aldosterone Hypertensive Rats

Chronic elevation of plasma aldosterone contributes to heart failure. Mineralocorticoid receptor (MR) antagonism is cardioprotective in such a setting, but whether such protection occurs in the presence of low-aldosterone concentrations remains unclear. We investigated whether MR blockade attenuates cardiac hypertrophy and failure in rats with salt-sensitive hypertension. Dahl salt-sensitive (DS) rats fed a high-salt diet from 7 weeks develop concentric left ventricular (LV) hypertrophy secondary to hypertension at 12 weeks followed by heart failure at 19 weeks (DS-CHF). DS rats on such a diet were treated with a non-antihypertensive dose of the selective MR antagonist eplerenone from 12 to 19 weeks. Renin activity and aldosterone concentration in plasma were decreased in DS-CHF rats compared with controls. LV hypertrophy and fibrosis, as well as macrophage infiltration around coronary vessels, were apparent in DS-CHF rats. The amounts of mRNAs for 11&bgr;-hydroxysteroid dehydrogenase type 1, MR, monocyte chemoattractant protein 1, and osteopontin were increased in these hearts. Treatment of DS-CHF rats with eplerenone inhibited these changes in gene expression, as well as coronary vascular inflammation and heart failure. Eplerenone attenuated both the decrease in the ratio of reduced to oxidized glutathione and the increase in NADPH oxidase activity apparent in DS-CHF rat hearts. MR blockade with eplerenone thus resulted in attenuation of LV hypertrophy and failure, without an antihypertensive effect, in rats with low-aldosterone hypertension. The beneficial cardiac effects of eplerenone are likely attributable, at least in part, to attenuation of myocardial oxidative stress and coronary vascular inflammation induced by glucocorticoid-activated MRs.

Discrimination of Nonobstructive Hypertrophic Cardiomyopathy From Hypertensive Left Ventricular Hypertrophy on the Basis of Strain Rate Imaging by Tissue Doppler Ultrasonography

Background—The differentiation of hypertrophic cardiomyopathy (HCM) from hypertensive left ventricular hypertrophy (H-LVH) on the basis of morphological information obtained by conventional echocardiography is occasionally problematic. We investigated whether strain rate (SR) imaging derived from tissue Doppler imaging (TDI) is able to discriminate HCM from H-LVH. Methods and Results—Conventional echocardiography and TDI were performed with 34 patients with LVH and 16 reference subjects. Mean values of systolic strain (&egr;sys), peak systolic SR, and early diastolic SR obtained from 8 left ventricular (LV) segments were calculated. LV pressures were recorded simultaneously in the patients. Patients were diagnosed with HCM (n=20) or H-LVH (n=14) on the basis of conventional echocardiography and endomyocardial biopsy findings. Multivariate analysis revealed that septum/posterior wall thickness ratio (P=0.00013) and &egr;sys (P<0.0001) were each able to discriminate HCM from H-LVH. A &egr;sys cutoff value of −10.6% discriminated between HCM and H-LVH with a sensitivity of 85.0%, specificity of 100.0%, and predictive accuracy of 91.2%. The combination of the septum/posterior wall thickness ratio and &egr;sys discriminated HCM from H-LVH with a predictive accuracy of 96.1%. The &egr;sys parameter was significantly correlated with pulmonary arterial wedge pressure, LV end-diastolic pressure, the peak positive first derivative of LV pressure, and the time constant of LV pressure decay. Conclusions—SR imaging is able to discriminate HCM from H-LVH, with &egr;sys reflecting myocardial contractile and lusitropic properties.

Mineralocorticoid Receptor Antagonism Ameliorates Left Ventricular Diastolic Dysfunction and Myocardial Fibrosis in Mildly Symptomatic Patients With Idiopathic Dilated Cardiomyopathy: A Pilot Study

Background— Mineralocorticoid receptor antagonism reduces mortality associated with heart failure by mechanisms that remain unclear. The effects of the mineralocorticoid receptor antagonist spironolactone on left ventricular (LV) function and chamber stiffness associated with myocardial fibrosis were investigated in mildly symptomatic patients with idiopathic dilated cardiomyopathy (DCM). Methods and Results— Twenty-five DCM patients with a New York Heart Association functional class of I or II were examined before and after treatment with spironolactone for 12 months. LV pressures and volumes were measured simultaneously, and LV endomyocardial biopsy specimens were obtained. Serum concentrations of the carboxyl-terminal propeptide (PIP) and carboxyl-terminal telopeptide (CITP) of collagen type I were measured. The patients were divided into 2 groups on the basis of the serum PIP/CITP ratio (≤35, group A, n=12; >35, group B, n=13), an index of myocardial collagen accumulation. LV diastolic chamber stiffness, the collagen volume fraction, and abundance of collagen type I and III mRNAs in biopsy tissue were greater and the LV early diastolic strain rate (tissue Doppler echocardiography) was smaller in group B than in group A at baseline. These differences and the difference in PIP/CITP were greatly reduced after treatment of patients in group B with spironolactone, with treatment having no effect on these parameters in group A. The collagen volume fraction was significantly correlated with PIP/CITP, LV early diastolic strain rate, and LV diastolic chamber stiffness for all patients before and after treatment with spironolactone. Conclusions— Spironolactone ameliorated LV diastolic dysfunction and reduced chamber stiffness in association with regression of myocardial fibrosis in mildly symptomatic patients with DCM. These effects appeared limited, however, to patients with increased myocardial collagen accumulation.

Continuous positive airway pressure improves daytime baroreflex sensitivity and nitric oxide production in patients with moderate to severe obstructive sleep apnea syndrome.

Individuals with obstructive sleep apnea syndrome (OSAS) are at high risk for cardiovascular morbidity and mortality. The effects of OSAS severity and nocturnal continuous positive airway pressure (CPAP) on daytime baroreflex sensitivity (BRS) and nitric oxide (NO) production were investigated in OSAS patients. Fifty-one consecutive males with OSAS and 29 age-matched healthy men underwent the Valsalva test and standard polysomnography. Patients with an apnea-hypopnea index (AHI) of ≥20 episodes per hour were randomized to receive CPAP treatment for 3 months (n=14) or no such treatment (n=19). The BRS index measured from the overshoot phase (phase IV) of the Valsalva maneuver and plasma NO concentration were significantly lower, whereas the AHI, oxygen desaturation time, arousal index, percentage of sleep stage 1, and systolic blood pressure were significantly greater, in patients with an AHI of ≥20/h than in those with an AHI of <20/h or in controls. The 24-h urinary excretion of norepinephrine was significantly reduced and the plasma NO concentration was significantly increased after one night of CPAP. The BRS index for phase IV and the Valsalva ratio were significantly increased in the CPAP group after the 3-month treatment period but remained unchanged in the non-CPAP group of OSAS patients. The daytime BRS index and NO production were thus inversely related to the severity of OSAS, and successful CPAP treatment improved these parameters in patients with moderate to severe OSAS. CPAP may therefore reduce the risk of cardiovascular complications due to endothelial dysfunction or increased sympathetic activity.

Elastolytic Cathepsin Induction/Activation System Exists in Myocardium and Is Upregulated in Hypertensive Heart Failure

Cathepsins are cysteine proteases that participate in various types of tissue remodeling. However, their expressions during myocardial remodeling have not been examined. In this study, we investigated their expressions in the left ventricular (LV) myocardium of rats and humans with hypertension-induced LV hypertrophy or heart failure (HF). Real-time PCR and immunoblot analysis revealed that the abundance of cathepsin S mRNA or protein in the LV tissues was greater in rats or humans with HF than in those with hypertrophy or in control subjects. Immunostaining showed that cathepsin S was localized predominantly to cardiac myocytes and coronary vascular smooth muscle cells, but also overlapped in part with macrophages. Elastic lamina fragmentations significantly increased in the LV intramyocardial coronary arteries of HF rats. The amount of elastolytic activity in the extract of the LV myocardium was markedly increased for HF rats compared with controls, and this activity was mostly because of cathepsin S. Although the amount of elastin mRNA was increased in the LV myocardium of HF rats, the area of interstitial elastin was not. The expression of interleukin 1β was increased in the LV myocardium of HF rats, and this cytokine was found to increase the expression and activity of cathepsin S in cultured neonatal cardiomyocytes. These results suggest that cathepsin S participates in pathological LV remodeling associated with hypertension-induced HF. This protease is, thus, a potential target for therapeutics aimed at preventing or reversing cardiac remodeling.

Influence of Nasal Resistance on Initial Acceptance of Continuous Positive Airway Pressure in Treatment for Obstructive Sleep Apnea Syndrome

Background: Continuous positive airway pressure (CPAP) is considered as the standard therapy for obstructive sleep apnea syndrome (OSAS), but some patients with OSAS are unable to accept CPAP due to nasal obstruction and poor nasal airflow. Objectives: We assessed the influence of nasal resistance before beginning CPAP treatment on the initial acceptance of CPAP in OSAS patients. Methods: The study subjects comprised 77 patients (74 males, 3 females) with primary OSAS, all of whom received CPAP treatment with nasal masks. Before trials, all subjects underwent overnight polysomnography, and nasal resistance was measured with active anterior rhinomanometry in the seated position on the first day of CPAP trial. Results: The CPAP treatment was accepted by 56 patients after the initial trials with overnight polysomnography. Body mass index, the number of apnea/hypopnea episodes per hour (apnea/hypopnea index; AHI), and the number of episodes per hour with an oxygen desaturation of >3% (oxygen desaturation index) were significantly higher (p < 0.01) and nasal resistance was lower (p = 0.003) in patients who accepted CPAP than in those who did not. Logistic regression analysis, with patient age, body mass index, Epworth sleepiness scale score, AHI, oxygen desaturation index, and nasal resistance before CPAP treatment as explanatory variables, showed that nasal resistance (OR + 0.1 Pa/cm3/s: 1.48; p = 0.002) and AHI (OR + 1 event/h: 0.93; p = 0.003) were significant factors for CPAP non-acceptance. Conclusions: Nasal resistance before the beginning of CPAP treatment has a significant effect on the acceptance of CPAP in OSAS patients, and hence, could be a predictive parameter for the initial acceptance of CPAP.

Myocardial velocity gradient as a noninvasively determined index of left ventricular diastolic dysfunction in patients with hypertrophic cardiomyopathy.

OBJECTIVES We investigated the utility of the peak negative myocardial velocity gradient (MVG) derived from tissue Doppler imaging (TDI) for evaluation of diastolic dysfunction in patients with hypertrophic cardiomyopathy (HCM). BACKGROUND Hypertrophic cardiomyopathy is characterized by impaired diastolic function with abnormal stiffness and prolonged relaxation. However, it remains difficult to evaluate these defects noninvasively. METHODS Both TDI and conventional echocardiography were performed in 36 patients with HCM and in 47 control subjects. Left ventricular (LV) pressure was measured simultaneously in all HCM patients and in 26 controls. RESULTS The peak negative MVG occurred soon after the isovolumic relaxation period during the initial phase of rapid filling (auxotonic relaxation). It was significantly smaller in HCM patients than in control subjects (2.32 +/- 0.52/s vs. 4.82 +/- 1.15/s, p < 0.0001); the cutoff value for differentiation between all HCM patients and 47 normal individuals was determined as 3.2/s. Both the left ventricular end-diastolic pressure (LVEDP) (19.6 +/- 6.1 mm Hg vs. 6.5 +/- 1.7 mm Hg, p < 0.0001) and the time constant of LV pressure decay during isovolumic diastole (tau) (44.0 +/- 6.7 ms vs. 32.1 +/- 5.5 ms, p < 0.0001) were increased in HCM patients compared with controls. The peak negative MVG was negatively correlated with both LVEDP (r = -0.75, p < 0.0001) and tau (r = -0.58, p < 0.0001). CONCLUSIONS A reduced peak negative MVG reflects both prolonged relaxation and elevated LVEDP. The peak negative MVG might thus provide a noninvasive index of diastolic function, yielding unique information about auxotonic relaxation in patients with HCM.

Daytime sleepiness and automobile accidents in patients with obstructive sleep apnea syndrome.

Abstract We evaluated the rate of automobile accidents and daytime sleepiness using the Epworth sleepiness scale (ESS) in 44 patients with obstructive sleep apnea syndrome (OSAS). We defined the automobile accident score as a sum of two points for every one automobile accident and one point for every near‐miss accident. Automobile accidents and near‐misses were found in 54.5% and 50.0% in patients with OSAS. Automobile accident score was significantly correlated with the ESS score (r= 0.56, P < 0.01). Our findings suggest that ESS score may be useful in detecting patients with the potential risk of automobile accidents associated with daytime sleepiness.

Poor sleep quality impairs cognitive performance in older adults.

The prevalence of insomnia increases with age. Short sleep duration is associated with deficits in cognitive performance. We hypothesized that short sleep duration and sleep quality influence cognitive performance in older adults. The study included 78 adults aged 60 years and over (72.2 ± 5.9 years). Total sleep time and sleep efficiency (total sleep time/time in bed × 100) were calculated using actigraphy. We evaluated cognitive performance with the continuous performance test‐identical pairs and the number‐back test. Sleep apnea was evaluated overnight with a portable home monitoring system. The accuracy of the 0‐back test significantly decreased in participants with total sleep time less than 5 h compared with those with total sleep time greater than 7 h, but there was no significant difference in continuous performance test‐identical pairs between the two groups. Participants with sleep efficiency <85% showed a significant decrease in 0‐ and 1‐back test accuracy compared with those with sleep efficiency ≥85%. There were no significant differences in the accuracy of number‐back tests and continuous performance test‐identical pairs between apnea–hypopnea index ≥15 h−1 and apnea–hypopnea index <15 h−1 groups, or among lowest SpO2 ≥ 90%, lowest 80–90%, and lowest SpO2 < 80% groups. Age, total sleep time and sleep efficiency were significantly correlated with accuracy on the 0‐back test. Age and sleep efficiency were significantly correlated with accuracy on the 1‐back test. Multiple regression analysis revealed that total sleep time was independently correlated with accuracy on the 0‐back test, while age was independently correlated with accuracy on the 1‐back test. Our findings suggest that sleep duration and sleep quality may play a role in cognitive performance in older adults.

Effects of nasal surgery on sleep quality in obstructive sleep apnea syndrome with nasal obstruction.

Background The purpose of this study was to evaluate the effects of nasal surgery on nasal resistance, sleep apnea, and sleep quality in adult male patients with obstructive sleep apnea syndrome (OSAS). A prospective study was performed in OSAS patients who underwent isolated nasal surgery in a tertiary referral center. Methods During the 3-year study period, 49 OSAS patients suffering from symptomatic nasal obstruction/impaired nasal breathing underwent the standard polysomnography before and after surgery. Polysomnography along with measures of nasal resistance and daytime sleepiness (the Epworth sleepiness scale [ESS] scores) were reviewed also. Results Surgery decreased the nasal resistance (0.55 ± 0.37 Pa/cm3 per second versus 0.17 ± 0.19 Pa/cm3 per second; p < 0.001) and ESS scores (11.7 ± 4.1 versus 3.3 ± 1.3; p < 0.001), without changes in the apnea-hypopnea index (AHI; 44.6 ± 22.5 versus 42.5 ± 22.0). Surgery increased nadir oxygen saturation (76.2 ± 10.9% versus 78.8 ± 8.1%; p < 0.01), shortened apnea–hypopnea duration (averaged/maximum; 33.5 ± 7.3/61.1 ± 46.0 versus 28.8 ± 7.4/47.3 ± 36.1 second; p < 0.05/p < 0.01), and improved sleep quality. Conclusion The results suggest that nasal surgery is useful for lowering nasal resistance, ameliorating sleep-disordered breathing, and improving sleep quality and daytime sleepiness in OSAS.