Toyofumi Yoshii

Clinical significance of global two-dimensional strain as a surrogate parameter of myocardial fibrosis and cardiac events in patients with hypertrophic cardiomyopathy

AIMS Late gadolinium enhancement (LGE) on contrast-enhanced magnetic resonance imaging (MRI) in hypertrophic cardiomyopathy (HCM) has been reported to be associated with myocardial fibrosis and cardiac events. In patients with HCM, two-dimensional (2D) strain can identify subclinical global systolic dysfunction despite normal left ventricular (LV) chamber function. Therefore, this study tested the hypothesis that global 2D strain could detect subtle myocardial fibrosis and serve as a novel prognostic parameter in HCM patients. METHODS AND RESULTS Echocardiography and MRI were performed in 48 consecutive patients with HCM and normal chamber function. We measured global longitudinal strain (GLS) in apical two-chamber, four-chamber, and long-axis views using speckle-tracking analysis. The extent of LGE (%LGE = LGE volume/total LV volume) and LV mass index were calculated by MRI using Simpsons rule and custom software. All patients were followed up for major cardiac events. Global longitudinal strain in patients with LGE was significantly lower than that without LGE (-11.8 ± 2.8 vs. -15.0 ± 1.7%, P < 0.001). Multivariate analysis showed that GLS was an independent predictor of %LGE (standard coefficient = 0.627, P < 0.001). During a mean follow-up period of 42 ± 12 months, five patients had cardiac events. When the patients were stratified based on the median level of GLS (-12.9%), all events were observed in the worse GLS group (P = 0.018). CONCLUSION These results suggest that global 2D strain might provide useful information on myocardial fibrosis and cardiac events in HCM patients with normal chamber function.

Eplerenone With Valsartan Effectively Reduces Atherosclerotic Lesion by Attenuation of Oxidative Stress and Inflammation

Objective—Angiotensin II contributes to atherogenesis, mainly through oxidative stress and inflammation. Recent data suggest that aldosterone is implicated in some effects of angiotensin II. We hypothesized that aldosterone could directly contribute to oxidative stress and atherosclerotic lesion formation. Methods and Results—Male apolipoprotein E–deficient mice 6 weeks of age were placed on a normal diet or 1.25% high-cholesterol diet. After 6 weeks of the high-cholesterol diet, a marked increase in atherosclerotic lesion formation was observed in the aorta, accompanied by significant elevation of plasma cholesterol level. Production of superoxide anion and expression of NAD(P)H oxidase subunit p47phox, tumor necrosis factor-α, and monocyte chemoattractant protein-1 in the aorta were increased with the high-cholesterol diet. Eplerenone (1.67 g/kg in high-cholesterol diet) did not affect blood pressure or plasma cholesterol but decreased the atherosclerotic area by nearly 70% (P<0.05), associated with attenuation of oxidative stress and inflammatory response. Valsartan (0.5 mg/kg per day) also decreased the atherosclerotic lesion, whereas coadministration of valsartan and eplerenone further decreased it. Moreover, aldosterone (0.1 &mgr;mol/L) enhanced NADPH oxidase activity in cultured vascular smooth muscle cells. Conclusions—These results suggest that aldosterone may play a critical role in atherogenesis subsequent to oxidative stress in part independent of angiotensin II–mediated signaling, and that eplerenone could prevent atherosclerosis by attenuating oxidative stress and inflammation.

Regression of Atherosclerosis by Amlodipine via Anti-Inflammatory and Anti-Oxidative Stress Actions

We examined whether amlodipine, an L-type calcium channel blocker (CCB), has an inhibitory effect on oxidative stress and inflammatory response, and thereby atherosclerosis, in apolipoprotein E–deficient (ApoEKO) mice. Adult male ApoEKO mice (6 weeks of age) were fed a high-cholesterol diet (HCD) for 8 or 10 weeks with or without oral administration of amlodipine (3 mg/kg/day) for 10 weeks or for only the last 2 weeks of the HCD. After HCD feeding, atherosclerotic lesion formation, in situ superoxide production and nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity were evaluated in the proximal aorta. The expressions of NADPH oxidase subunits (p47phox and rac-1), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) were determined with immunohistochemistry and quantitative real-time reverse-transcription polymerase chain reaction. After 8 to 10 weeks of HCD administration to ApoEKO mice, marked atherosclerotic lesion formation was observed in the proximal aorta. In the atherosclerotic lesion, superoxide production, the expression of NADPH oxidase subunits, and NADPH oxidase activity were enhanced, and the expressions of MCP-1, ICAM-1, and VCAM-1 were increased. These changes were suppressed in mice that were treated with amlodipine for 10 weeks concomitant with HCD administration, with no significant change in blood pressure and plasma cholesterol level. We also observed that treatment with amlodipine for only the last 2 weeks regressed the atherosclerotic lesions with a decrease in oxidative stress and vascular inflammation. Inhibition of the atherosclerotic lesion area and lipid area in the proximal aorta by amlodipine was correlated with its inhibitory actions on oxidative stress, inflammation and the production of adhesive molecules. These results suggest that amlodipine not only inhibits atherosclerotic lesion formation, but also regresses atherosclerosis, and that these effects are at least partly due to inhibition of oxidative stress and inflammatory response.

Attenuation of inflammatory vascular remodeling by angiotensin II type 1 receptor-associated protein.

To explore the role of angiotensin II Type 1 receptor–associated protein (ATRAP) in vascular remodeling, we developed transgenic mice for mouse ATRAP cDNA and examined remodeling after inflammatory vascular injury induced by polyethylene cuff placement. In ATRAP transgenic (ATRAP-Tg) mice, ATRAP mRNA was increased 3- to 4-fold in the heart, aorta, and femoral artery. ATRAP-Tg mice showed no significant change in body weight, systolic blood pressure, heart rate, and heart/body weight ratio. However, cell proliferation and neointimal formation in the injured artery were attenuated in ATRAP-Tg mice. The increase in NADPH oxidase activity and the expression of p22phox, a reduced nicotinamide-adenine dinucleotide/reduced nicotinamide-adenine dinucleotide phosphate oxidase subunit, after cuff placement was also attenuated in ATRAP-Tg mice. Moreover, activation of extracellular signal–regulated kinase, signal transducer and activator of transcription 1, and signal transducer and activator of transcription 3 after cuff placement was significantly reduced in ATRAP-Tg mice. Pressor response and cardiac hypertrophy induced by angiotensin II infusion and pressure overload were also attenuated in ATRAP-Tg mice. These results suggest that ATRAP plays an important role in vascular remodeling as a negative regulator.

Effect of combination of calcium antagonist, azelnidipine, and AT1 receptor blocker, olmesartan, on atherosclerosis in apolipoprotein E-deficient mice

Objective Angiotensin II type 1 receptor blockers (ARB) are widely recognized to have a vasculoprotective effect. Accumulating data have revealed that calcium antagonists also retard atherosclerosis. We examined the possibility that combination therapy of ARB and calcium antagonists could more effectively prevent atherosclerosis than monotherapy. Methods and results We observed a marked increase in the atherosclerotic area, associated with the exaggerated expression of nicotinamide adenine dinucleotide (phosphate), reduced form [NAD(P)H] oxidase subunits (p22phox and p47phox) and superoxide anion production, in the aorta of apolipoprotein E-deficient mice maintained on a 1.25% high-cholesterol diet for 10 weeks. A calcium antagonist, azelnidipine, at a dose of 1 mg/kg a day or an ARB, olmesartan, at a dose of 3 mg/kg a day, significantly inhibited these parameters, with no change in systolic blood pressure and the blood cholesterol level. Moreover, the co-administration of lower doses of azelnidipine (0.1 mg/kg a day) and olmesartan (1 mg/kg a day) significantly inhibited the atherosclerotic area and oxidative stress, whereas azelnidipine or olmesartan alone at these doses did not affect these parameters. Furthermore, we observed similar inhibitory effects of azelnidipine or olmesartan on angiotensin II-induced NADPH oxidase activity and Akt activity in cultured vascular smooth muscle cells. Conclusion These results suggest that the co-administration of calcium antagonists and ARB synergistically blunts oxidative stress at least partly through the inhibition of Akt activity and enhances the beneficial effects of these drugs on atherosclerosis compared with monotherapy.

Right Ventricular Pacing from the Septum Avoids the Acute Exacerbation in Left Ventricular Dyssynchrony and Torsional Behavior Seen with Pacing from the Apex

OBJECTIVE The study objective was to compare the left ventricular (LV) dyssynchrony and torsional behavior between right ventricular apical (RVA) and right ventricular septal (RVS) pacing. METHODS Forty-six patients with symptomatic sick sinus syndrome and preserved LV function were assigned to 2 groups: RVA (n = 23) and RVS (n = 23). Echocardiographic study including two-dimensional speckle tracking imaging was performed in the AAI and DDD modes. RESULTS Mean QRS width during DDD mode was significantly longer with RVA pacing than with RVS pacing. Dyssynchrony, torsion, and untwisting rate during DDD mode were significantly worse with RVA than with RVS pacing. In patients with RVA pacing, there was an increase in longitudinal dyssynchrony from AAI to DDD mode that significantly correlated with the deterioration of untwisting rate. CONCLUSION In bradyarrhythmic patients with preserved LV function, RVS pacing resulted in a reduced LV dyssynchrony and better torsional behavior than RVA pacing.

The differences in left ventricular torsional behavior between patients with hypertrophic cardiomyopathy and hypertensive heart disease.

BACKGROUND The aim of this study was to investigate the differences in left ventricular (LV) twisting behavior between patients with hypertrophic cardiomyopathy (HCM) and hypertensive heart disease (HHD). METHODS Forty-four patients with HCM (mean age, 63±15 years), 35 patients with HHD (mean age, 63±13 years) and 20 age and sex-matched control subjects were evaluated. After a standard echocardiographic examination, LV twist and twisting velocity profiles from apical and basal short-axis images were analyzed using two-dimensional speckle tracking imaging. RESULTS LV diastolic and systolic dimensions, and ejection fraction were not significantly different among the groups. LV mass index and early diastolic mitral annular velocity were not significantly different between the HCM and HHD groups. The peak torsion in the HCM and HHD groups was significantly greater than that in the control group. The peak untwisting velocity in the HCM group was comparable with that in the control group. However, when the peak untwisting velocity was corrected by peak torsion, this ratio was significantly decreased in the HCM group compared with the values in the HHD and control groups. The time to peak untwisting velocity in the HCM group was significantly longer than the values in the HHD and control groups. CONCLUSIONS These results suggest that enhanced peak torsion in HCM may improve untwisting behavior, but this mechanism fails to fully compensate for impaired untwisting behavior compared with HHD.

Impact of type 2 diabetes on serial changes in tissue characteristics of coronary plaques: an integrated backscatter intravascular ultrasound analysis

AIMS Several studies have demonstrated that type 2 diabetes mellitus (T2DM) is associated with accelerated atherosclerosis, which results in an increased risk of coronary vascular events. However, serial changes in plaque characteristics have not been reported in vivo. We evaluated the progression of coronary atherosclerosis in patients with T2DM using an integrated backscatter intravascular ultrasound (IB-IVUS) examination. METHODS AND RESULTS Forty-two T2DM and 48 non-diabetic patients who underwent percutaneous coronary intervention were enrolled in the study. Non-culprit 20-mm length coronary lesions with mild-to-moderate stenosis were measured using a 40-MHz (motorized pullback of 0.5 mm/s) IVUS catheter. IVUS examinations were performed on one target lesion in each patient. Six months later, a follow-up IVUS examination was repeated in the same coronary segment imaged at the baseline examination. T2DM patients demonstrated a greater total plaque volume (TPV; 139 ± 53 vs. 114 ± 45 mm(3), P = 0.02) and total lipid volume (TLV; 67 ± 26 vs. 55 ± 30 mm(3), P = 0.039) at the baseline examination. The progression of TPV (8.6 ± 15.4 vs. -2.2 ± 16.0%, P < 0.01) and TLV (10.8 ± 28.8 vs. -2.5 ± 20.0%, P < 0.05) from the baseline was observed in T2DM patients, but not in non-diabetic patients. The increase in TLV was blunted in T2DM patients who achieved HbA1c levels of <6.5%. CONCLUSION Accelerated plaque progression with an increase in the lipid-rich component of non-culprit plaques was observed in T2DM, despite the use of standard medical treatment. Better glycaemic control ameliorated the worsening of plaque characteristics in T2DM.

Carotid arterial circumferential strain by two-dimensional speckle tracking: a novel parameter of arterial elasticity

Recently, the development of two-dimensional speckle-tracking (2DST) technology has allowed the direct measurement of the elastic parameters of the carotid arterial wall. The aims of this study were to determine the feasibility of measuring peak circumferential strain (CS) of the carotid arterial wall using 2DST and to compare this value with conventional arterial stiffness parameters in subjects with and without hypertension. The study included 90 healthy subjects and 40 age-and sex-matched patients with hypertension. The short-axis view of the right common carotid artery was recorded. The CS in the posterior region of the carotid artery was calculated by 2DST using special software and corrected by the following equation: ɛcirc=ln (systolic blood pressure/diastolic blood pressure)/CS. We simultaneously measured the stiffness index β (β) at the same location and the brachial-ankle pulse wave velocity (baPWV). Sixty randomly selected healthy subjects were used to assess the inter/intra-observer variability of ɛcirc and β. In healthy subjects, ɛcirc was significantly correlated with β, age and baPWV. These correlations were slightly better than the corresponding correlations of β with age and baPWV. The hypertensive patients had a significantly larger ɛcirc than the healthy subjects (0.112±0.074 vs. 0.066±0.029/%, P<0.001). The inter/intra-observer variability for ɛcirc was significantly lower than that for β. Our data suggest that the measurement of carotid ɛcirc using 2DST is feasible and has better reproducibility than conventional carotid arterial stiffness.

Coronary Spastic Angina Induced by Anticholinesterase Medication for Myasthenia Gravis A Case Report

Myasthenia gravis (MG) is characterized by weakness of skeletal muscles because of a decrease in the number of available acetylcholine receptors at neuromuscular junctions. Anticholinesterase medication is widely used to treat MG, but muscarinic side effects sometimes appear and limit the drug usage. To their knowledge, the authors present the first case of coronary spastic angina quite possibly induced by anticholinesterase medica tion to treat MG. The appearance of coronary spastic angina in the present case is likely mediated through the increase of acethylcholine by anticholinesterase medication.