Akiyoshi Ogimoto

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.

Possible link between large artery stiffness and coronary flow velocity reserve

Background: Population studies have shown that increased large artery stiffness is an independent predictor of cardiovascular events. Experimental studies have shown that a stiff aorta is associated with decreased coronary blood flow. However, a link between large artery stiffness and coronary microvascular function in the clinical setting has not been demonstrated previously. Objective: To evaluate the relationship between large artery stiffness and coronary flow velocity reserve (CFVR). Patients and methods: 102 consecutive subjects (mean (SD) age 62 (10) years) without coronary and peripheral arterial disease were enrolled in the study. After 15 minutes’ rest, measurements were obtained of brachial-ankle pulse wave velocity (baPWV), augmentation index (AIx) from a carotid pulse tracing, and transthoracic echocardiographic measures, including coronary flow velocity in the left anterior descending coronary artery. In addition, coronary flow velocity during hyperaemia was measured during an intravenous infusion of adenosine triphosphate. CFVR was defined as the ratio of hyperaemic to basal coronary velocity. Results: Subjects with decreased CFVR (<2.5; n = 40) had significantly higher baPWV (1848 (369) cm/s vs 1548 (333) cm/s; p<0.001), greater AIx (25.3 (11.0)% vs 16.3 (20.0)%; p = 0.01) and greater pulse pressure (PP) (64 (13) mm Hg vs 54 (13) mm Hg; p<0.001) than those with normal CFVR (⩾2.5; n = 62). Multivariate analysis showed that AIx and PP were independent predictors of CFVR (r =  −0.32, p<0.001 and −0.25, p = 0.02, respectively). Conclusions: The data suggest that large artery stiffening is linked to a reduction of CFVR, which may partially explain the higher cardiac event rate in patients with increased large artery stiffness.

Direct Angiotensin II Type 2 Receptor Stimulation Ameliorates Insulin Resistance in Type 2 Diabetes Mice with PPARγ Activation

Objectives The role of angiotensin II type 2 (AT2) receptor stimulation in the pathogenesis of insulin resistance is still unclear. Therefore we examined the possibility that direct AT2 receptor stimulation by compound 21 (C21) might contribute to possible insulin-sensitizing/anti-diabetic effects in type 2 diabetes (T2DM) with PPARγ activation, mainly focusing on adipose tissue. Methods T2DM mice, KK-Ay, were subjected to intraperitoneal injection of C21 and/or a PPARγ antagonist, GW9662 in drinking water for 2 weeks. Insulin resistance was evaluated by oral glucose tolerance test, insulin tolerance test, and uptake of 2-[3H] deoxy-D-glucose in white adipose tissue. Morphological changes of adipose tissues as well as adipocyte differentiation and inflammatory response were examined. Results Treatment with C21 ameliorated insulin resistance in KK-Ay mice without influencing blood pressure, at least partially through effects on the PPARγ pathway. C21 treatment increased serum adiponectin concentration and decreased TNF-α concentration; however, these effects were attenuated by PPARγ blockade by co-treatment with GW9662. Moreover, we observed that administration of C21 enhanced adipocyte differentiation and PPARγ DNA-binding activity, with a decrease in inflammation in white adipose tissue, whereas these effects of C21 were attenuated by co-treatment with GW9662. We also observed that administration of C21 restored β cell damage in diabetic pancreatic tissue. Conclusion The present study demonstrated that direct AT2 receptor stimulation by C21 accompanied with PPARγ activation ameliorated insulin resistance in T2DM mice, at least partially due to improvement of adipocyte dysfunction and protection of pancreatic β cells.

Determinants of left ventricular untwisting behaviour in patients with dilated cardiomyopathy: analysis by two-dimensional speckle tracking

Background/objective: Left ventricular (LV) untwisting velocity has emerged as a novel index of LV diastolic function since it is thought to be related to LV diastolic suction. However, the pathophysiology of LV untwisting behavior has not been fully investigated. The aim of this study was to investigate the determinants of LV peak untwisting velocity in patients with dilated cardiomyopathy (DCM). Methods: 101 patients with DCM (mean age 60 (SD 13) years) and 50 control subjects were evaluated. After a standard echocardiographic examination, peak torsion and peak untwisting velocity were measured using two-dimensional speckle-tracking imaging. Radial dyssynchrony was assessed by speckle-tracking radial strain analysis. Tissue Doppler derived systolic (Ts-SD) and diastolic (Te-SD) dyssynchrony indices were also assessed. Results: The patients with DCM had significantly smaller peak torsion (p<0.001) and peak untwisting velocity (p<0.001) and greater radial dyssynchrony (p<0.001) and Ts-SD (p<0.001) and Te-SD (p = 0.001) compared with the control subjects. The peak untwisting velocity was correlated with end-systolic volume index (r = 0.524, p<0.001), E/e′ (r = 0.365, p<0.001), radial dyssynchrony (r = 0.578, p<0.001), Ts-SD (p<0.001), Te-SD (p<0.001) and peak torsion (r = −0.635, p<0.001) in patients with DCM. Multivariate analysis revealed that peak torsion, radial dyssynchrony and E/e′ were independent predictors of peak untwisting velocity in patients with DCM (standard coefficient −0.483, p<0.001, 0.330, p<0.001 and 0.241, p = 0.001, respectively). Conclusion: These results suggest that strain-based LV radial dyssynchrony and E/e′ as well as LV torsion are related to diastolic untwisting behaviour in patients with DCM.

Relation Between Angiotensin-Converting Enzyme II Genotype and Atrial Fibrillation in Japanese Patients With Hypertrophic Cardiomyopathy

AbstractAtrial fibrillation (AF) occurs in about 20% of patients with hypertrophic cardiomyopathy (HCM). HCM patients with AF have an increased risk for clinical decline and thromboembolism. In addition, AF is known to be associated with the atrial renin-angiotensin system (RAS). However, the relation between AF and the RAS in HCM has not been investigated. We genotyped the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene in 138 HCM patients (26 with AF, 112 with sinus rhythm). Distribution of the ACE genotypes (DD, ID, and II) among the total HCM patients was 15%, 46%, and 38%. AF was documented in 3 patients with the DD genotype, 7 with the ID genotype, and 16 with the II genotype (P < 0.03 vs. sinus rhythm group). The odds of AF were 3.2-fold greater in patients with the II genotype than in those with the other genotypes (P = 0.009, 95% confidence interval = 1.3–7.8). Kaplan-Meier curves examining the time to the first documented AF event showed a significant difference between genotypes during the follow-up period (mean 116 months, P < 0.05). These findings suggest that the II genotype of the ACE gene is a significant risk factor for AF in patients with HCM.

Possible Role of Angiotensin-Converting Enzyme 2 and Activation of Angiotensin II Type 2 Receptor by Angiotensin-(1–7) in Improvement of Vascular Remodeling by Angiotensin II Type 1 Receptor Blockade

Cross talk between the angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/Ang II type 1 (AT1) receptor axis and the ACE2/Ang-(1–7)/Mas axis plays a role in the pathogenesis of cardiovascular remodeling. Furthermore, possible stimulation of the Ang II type 2 (AT2) receptor by Ang-(1–7) has been highlighted as a new pathway. Therefore, we examined the possibility of whether the ACE2/Ang-(1–7)/Mas axis and Ang-(1–7)/AT2 receptor axis are involved in the inhibitory effects of AT1 receptor blockers on vascular remodeling. Wild-type, Mas-knockout, and AT2 receptor knockout mice were used in this study. Vascular injury was induced by polyethylene-cuff placement around the mouse femoral artery. Some mice were treated with azilsartan, an AT1 receptor blocker, or Ang-(1–7). Neointimal formation 2 weeks after cuff placement was more marked in Mas-knockout mice compared with wild-type mice. Treatment with azilsartan or Ang-(1–7) attenuated neointimal area, vascular smooth muscle cell proliferation, increases in the mRNA levels of monocyte chemoattractant protein-1, tumor necrosis factor-&agr;, and interleukin-1&bgr;, and superoxide anion production in the injured artery; however, these inhibitory effects of azilsartan and Ang-(1–7) were less marked in Mas-knockout mice. Administration of azilsartan or Ang-(1–7) attenuated the decrease in ACE2 mRNA and increased AT2 receptor mRNA but did not affect AT1 receptor mRNA or the decrease in Mas mRNA. The inhibitory effect of Ang-(1–7) on neointimal formation was less marked in AT2 receptor knockout mice compared with wild-type mice. These results suggest that blockade of the AT1 receptor by azilsartan could enhance the activities of the ACE2/Ang-(1–7)/Mas axis and ACE2/Ang-(1–7)/AT2 receptor axis, thereby inhibiting neointimal formation.

Quantitative analysis of myocardial 18F-fluorodeoxyglucose uptake by PET/CT for detection of cardiac sarcoidosis

BACKGROUND Imaging with fluorodeoxyglucose (FDG) PET/CT is used to diagnose patients with cardiac sarcoidosis (CS). However, its specificity is relatively low. We aimed to demonstrate that higher diagnostic specificity for CS can be obtained using quantitative methodology to analyze PET/CT. METHODS A total of 125 consecutive patients with suspected CS were enrolled in the study. After clinical assessment and cardiac imaging studies, the patients underwent FDG PET/CT imaging after eating a low-carbohydrate diet followed by an overnight fast lasting ≥ 18 h. For visual analysis, fusion and maximum intensity projection images were reviewed. For quantitative analysis, the maximum standardized uptake value (SUV max) within the myocardium was obtained. RESULTS Of the 92 patients who met study inclusion criteria, 37 were diagnosed with CS. Myocardial SUV max was significantly higher in patients with CS compared with non-CS patients (9.5 ± 4.8 vs. 3.0 ± 1.7, p < 0.0001). The area under the curve by receiver operating characteristic analysis was 0.960 for SUV max. Using a cut-off value of 4.0, the sensitivity was 97.3% and specificity was 83.6% for diagnosing CS, which is more accurate than visual analysis. Moreover, SUV max was the only significant predictor of CS among 10 clinical and imaging variables. In 18 patients who received steroid therapy with a mean follow-up duration of 6.4 ± 5.2 months, SUV max significantly decreased from 9.8 ± 4.2 to 5.5 ± 3.5 (p = 0.003). CONCLUSION When evaluated by quantification of myocardial SUV max, FDG PET/CT imaging provides high sensitivity and specificity for diagnosing CS.

Serum levels of matrix metalloproteinases and tumor necrosis factor-α in patients with idiopathic dilated cardiomyopathy and effect of carvedilol on these levels

I myocardial matrix metalloproteinase (MMP) activity has been reported to occur in clinical and experimental forms of dilated cardiomyopathy.1–3 Proinflammatory cytokines, such as tumor necrosis factor(TNF), are important regulators of MMP gene expression. Previous experimental studies have shown that TNFstimulates myocardial MMP activity and can lead to degradation of the extracellular matrix in the myocardium.4 However, few clinical studies of the relation between circulating MMP and TNFlevels in idiopathic dilated cardiomyopathy (IDC) have been conducted. Recently, we reported the presence of increased circulating TNFin patients with IDC, and that blockers could reduce the increased circulating TNFlevels in IDC.5,6 The present study further clarifies the relation between circulating levels of MMPs and TNFin patients with IDC. • • • We studied 34 consecutive patients with IDC between January 1999 and December 2001. The diagnosis of IDC was based on patient history, physical examination, electrocardiogram, echocardiogram, and cardiac catheterization. All patients underwent coronary angiography during the study period, and patients with epicardial coronary artery disease were excluded. Patients who had clinical or laboratory evidence of infections, neoplasms, autoimmune disease, or liver or renal dysfunction were also excluded from this study. Ten age-matched subjects who had no evidence of organic cardiac disease and no cardiac dysfunction were retrospectively selected as the control group. All subjects participated in this study after giving informed consent, and the protocol was approved by the Human Investigations Committee of our institution. In 20 patients who were poor responders to treatment with angiotensin-converting enzyme inhibitors or angiotensin II type-1 receptor blockers for 6 months, carvedilol, a nonselective blocker, was administered orally in addition to combination therapy after their hospital admission. In 18 patients with New York Heart Association functional class II or III congestive heart failure, the initial dosage was 2.5 mg twice daily; the doses were increased at weekly intervals for 8 weeks. In 2 patients in New York Heart Association functional class IV, the initial dosage was 1.0 mg twice daily; the doses were increased at weekly intervals for 12 weeks. The target dose was 25 mg/day, considering the weight of patients in this study of 75 kg. If a decrease in systolic blood pressure to 90 mm Hg or a decrease in heart rate at rest to 60 beats/min occurred, increments in dose were discontinued. As a result, the mean final dose of carvedilol was 19.2 mg. Maintenance of final doses was continued for an additional 6 months. Blood samples from patients were collected for measurement before and 6 months after initiation of carvedilol therapy. After bed rest for 30 minutes, peripheral venous blood samples were collected into chilled tubes and immediately centrifuged at 4°C. The serum samples were stored at 80°C until assay. Serum levels of TNFwere measured by enzyme-linked immunosorFrom The Second Department of Internal Medicine, Ehime University School of Medicine, Shigenobu, Onsen-gun, Ehime, Japan. Dr. Ohtsuka’s address is: The Second Department of Internal Medicine, Ehime University School of Medicine, Shigenobu, Onsen-gun, Ehime 7910295, Japan. E-mail: tohtsuka@m.ehime-u.ac.jp. Manuscript received October 24, 2002; revised manuscript received and accepted December 30, 2002. FIGURE 1. Serum levels of TNF, MMP-1, MMP-3, and MMP-9 in 10 age-matched normal control subjects (NC) and in 34 patients with IDC. *p <0.05; **p <0.001 versus control subjects.

Brief report: Takayasu arteritis and ulcerative colitis: High rate of co-occurrence and genetic overlap

Takayasu arteritis (TAK) is a systemic vasculitis affecting large arteries and large branches of the aorta. Ulcerative colitis (UC) is a prevalent autoimmune colitis. Since TAK and UC share HLA–B*52:01 and IL12B as genetic determinants, and since there are case reports of the co‐occurrence of these diseases, we hypothesized that UC is a common complication of TAK. We undertook this study to perform a large‐scale analysis of TAK, both to evaluate the prevalence of concurrent cases of TAK and UC and to identify and estimate susceptibility genes shared between the 2 diseases.

Qualitative and Quantitative Assessment of Adenosine Triphosphate Stress Whole-Heart Dynamic Myocardial Perfusion Imaging Using 256-Slice Computed Tomography

Background The aim of this study was to investigate the correlation of the qualitative transmural extent of hypoperfusion areas (HPA) using stress dynamic whole-heart computed tomography perfusion (CTP) imaging by 256-slice CT with CTP-derived myocardial blood flow (MBF) for the estimation of the severity of coronary artery stenosis. Methods and Results Eleven patients underwent adenosine triphosphate (0.16 mg/kg/min, 5 min) stress dynamic CTP by 256-slice CT (coverage: 8 cm, 0.27 s/rotation), and 9 of the 11 patients underwent coronary angiography (CAG). Stress dynamic CTP (whole–heart datasets over 30 consecutive heart beats in systole without spatial and temporal gaps) was acquired with prospective ECG gating (effective radiation dose: 10.4 mSv). The extent of HPAs was visually graded using a 3-point score (normal, subendocardial, transmural). MBF (ml/100g/min) was measured by deconvolution. Differences in MBF (mean ± standard error) according to HPA and CAG results were evaluated. In 27 regions (3 major coronary territories in 9 patients), 11 coronary stenoses (> 50% reduction in diameter) were observed. In 353 myocardial segments, HPA was significantly related to MBF (P < 0.05; normal 295 ± 94; subendocardial 186 ± 67; and transmural 80 ± 53). Coronary territory analysis revealed a significant relationship between coronary stenosis severity and MBF (P < 0.05; non-significant stenosis [< 50%], 284 ± 97; moderate stenosis [50–70%], 184 ± 74; and severe stenosis [> 70%], 119 ± 69). Conclusion The qualitative transmural extent of HPA using stress whole-heart dynamic CTP imaging by 256-slice CT exhibits a good correlation with quantitative CTP-derived MBF and may aid in assessing the hemodynamic significance of coronary artery disease.