Aya Ebihara

Evidence for association between paraoxonase gene polymorphisms and atherosclerotic diseases

Paraoxonase 1 (PON1) is proposed to have an anti-atherogenic action. Two polymorphisms at the PON1 (M/L55 and Q/R192) have been shown to be associated with coronary artery disease (CAD). This conclusion is not drawn universally, however, and specific ethnic characteristics may be important determinants in this association. Recently two homologues of PON1 - PON2 and PON3 - were identified and Sanghera et al. demonstrated C/S311 polymorphism at PON2 was associated with the risk of CAD. Within that context, we investigated the association between the aforementioned three polymorphisms and CAD and ischemic stroke in a Japanese population. The study population included 431 control subjects, 210 CAD patients, and 235 ischemic stroke patients. Genotype distributions and allele frequencies of M/L55 and C/S311 were similar among the control and patient groups, whereas the R192 allele frequency was significantly higher (P<0.001) in CAD (75%) and ischemic stroke (76%) patients than in control subjects (65%). When confounding influences of other risk factors were controlled for by multivariate analysis, R192 remained an independent risk determinant (additive model: OR (95% CI), P value CAD: 2.01 (1.45-2.79), 0.0001; ischemic stroke: 1.84 (1.34-2.52), 0.0002 (three genotypes into calculation)). Taken together, our data indicate that the Q/R192 is principally associated with both CAD and ischemic stroke in Japanese.

Angiogenic Effects of Adrenomedullin in Ischemia and Tumor Growth

Adrenomedullin (AM) is a novel vasodilating peptide involved in the regulation of circulatory homeostasis and implicated in the pathophysiology of cardiovascular disease. We tested the hypothesis that AM also possesses angiogenic properties. Using laser Doppler perfusion imaging, we found that AM stimulated recovery of blood flow to the affected limb in the mouse hind-limb ischemia model. AM exerted this effect in part by promoting expression of vascular endothelial growth factor (VEGF) in the ischemic limb, and immunostaining for CD31 showed the enhanced flow to reflect increased collateral capillary density. By enhancing tumor angiogenesis, AM also promoted the growth of subcutaneously transplanted sarcoma 180 tumor cells. However, heterozygotic AM knockout mice (AM+/−) showed significantly less blood flow recovery with less collateral capillary development and VEGF expression than their wild-type littermates. Similarly, mice treated with AM22-52, a competitive inhibitor of AM, showed reduced capillary development, and growth of sarcoma 180 tumors was inhibited in AM+/− and AM22-52–treated mice. Notably, administration of VEGF or AM rescued blood flow recovery and capillary formation in AM+/− and AM22-52–treated mice. In cocultures of endothelial cells and fibroblasts, AM enhanced VEGF-induced capillary formation, whereas in cultures of endothelial cells AM enhanced VEGF-induced Akt activation. These results show that AM possesses novel angiogenic properties mediated by its ability to enhance VEGF expression and Akt activity. This may make AM a useful therapeutic tool for relieving ischemia; conversely, inhibitors of AM could be useful for clinical management of tumor growth.

Protective Effects of Endogenous Adrenomedullin on Cardiac Hypertrophy, Fibrosis, and Renal Damage

BACKGROUND Adrenomedullin (AM) is a novel vasodilating peptide thought to have important effects on cardiovascular function. The aim of this study was to assess the activity of endogenous AM in the cardiovascular system using AM knockout mice. METHODS AND RESULTS Mice heterozygous for an AM-null mutation (AM+/-) and their wild-type littermates were subjected to aortic constriction or angiotensin II (Ang II) infusion. The resultant cardiovascular stress led to increases in heart weight/body weight ratios, left ventricular wall thickness, and perivascular fibrosis, as well as expression of genes encoding angiotensinogen, ACE, transforming growth factor-beta, collagen type I, brain natriuretic peptide, and c-fos. In addition, renal damage characterized by decreased creatinine clearance with glomerular sclerosis was noted. In all cases, the effects were significantly more pronounced in AM+/- mice. Hearts from adult mice subjected to aortic constriction showed enhanced extracellular signal-regulated kinase (ERK) activation, as did cardiac myocytes from neonates treated acutely with Ang II. Again the effect was more pronounced in AM+/- mice, which showed increases in cardiac myocyte size, protein synthesis, and fibroblast proliferation. ERK activation was suppressed by protein kinase C inhibition to a greater degree in AM+/- myocytes. In addition, treatment of cardiac myocytes with recombinant AM suppressed Ang II-induced ERK activation via a protein kinase A-dependent pathway. CONCLUSIONS Endogenous AM exerts a protective effect against stress-induced cardiac hypertrophy via protein kinase C- and protein kinase A-dependent regulation of ERK activation. AM may thus represent a useful new tool for the treatment of cardiovascular disease.

Speckle tracking global strain rate E/E' predicts LV filling pressure more accurately than traditional tissue Doppler E/E'.

Background: The ratio of early diastolic transmitral flow velocity (E) to tissue Doppler (TD) mitral annular early diastolic velocity (E/E′VEL‐TD) has been widely used for the noninvasive assessment of LV diastolic filling pressures. However, it has been reported that E/E′VEL‐TD is not accurate particularly when being applied to patients with advanced heart failure. Methods: Fifty‐six ICU patients with decompensated heart failure underwent simultaneous echocardiography and PCWP measurements. Patients with elevated PCWP (n = 41) were compared with patients normal PCWP (n = 15) as well as age‐matched healthy controls (n = 32). In the apical 4‐chamber view, the ratio of E to speckle tracking (ST) mitral annular velocity (E/E′VEL‐ST) and early diastolic global LV longitudinal strain rate (E/E′SR‐ST) were evaluated as new surrogate markers of elevated PCWP. Results: Correlations with PCWP were observed for speckle tracking derived E/E′VEL‐ST (r = 0.40,P = 0.002) and E/E′SR‐ST (r = 0.56, P < 0.001), although the traditional E/E′VEL‐TD did not show a significant correlation (r = 0.23, P = 0.082). Compared with controls, patients with elevated PCWP had significant increases in all variables. The best cutoff values and diagnostic accuracies for identifying elevated PCWP were E/E′VEL‐TD>12 (Sensitivity/Specificity/area under the ROC curve: 0.58/0.90/0.78), E/E′VEL‐ST > 14 (0.60/0.85/0.80), and E/E′SR‐ST > 93 (0.80/0.88/0.89). Conclusion: Speckle tracking derived E/E′SR‐ST may be a robust surrogate marker of elevated LV filling pressure. In ICU patients, E/E′SR‐ST showed better correlation with PCWP and higher diagnostic accuracy than the tissue Doppler approach. (Echocardiography 2012;29:404‐410)

Prognostic impact of left ventricular noncompaction in patients with Duchenne/Becker muscular dystrophy — Prospective multicenter cohort study☆ , ☆☆

BACKGROUND The reported prevalence of left ventricular noncompaction (LVNC) varies widely and its prognostic impact remains controversial. We sought to clarify the prevalence and prognostic impact of LVNC in patients with Duchenne/Becker muscular dystrophy (DMD/BMD). METHODS We evaluated the presence of LNVC in patients with DMD/BMD aged 4-64 years old at the study entry (from July 2007 to December 2008) and prospectively followed-up their subsequent courses (n=186). The study endpoint was all-cause death and the presence of LVNC was blinded until the end of the study (median follow-up: 46 months; interquartile range: 41-48 months). RESULTS There were no significant differences in baseline characteristics between patients with LVNC (n=35) and control patients without LVNC (n=151), with the exception of LV function. Patients with LVNC showed, in comparison with patients without LVNC, a significant negative correlation between age and LVEF (R=-0.7 vs. R=-0.4) at baseline; and showed a significantly greater decrease in absolute LVEF (-8.6 ± 4.6 vs. -4.3 ± 4.5, p<0.001) during the follow-up. A worse prognosis was observed in patients with LVNC (13/35 died) than in patients without LVNC (22/151 died, Log-rank p<0.001). Multivariate Cox analysis revealed that LVNC is an independent prognostic factor (relative hazard 2.67 [95% CI: 1.19-5.96]). CONCLUSION LVNC was prevalent in patients with DMD/BMD. The presence of LVNC is significantly associated with a rapid deterioration in LV function and higher mortality. Neurologists and cardiologists should pay more careful attention to the presence of LVNC.

Reproducibility and Diagnostic Accuracy of Three-Layer Speckle Tracking Echocardiography in a Swine Chronic Ischemia Model

Background: The subendocardial myocardium normally has higher systolic strain than the subepicardial myocardium and can be damaged first in face of ischemia. We investigated the reproducibility and feasibility of novel three‐layer speckle tracking system and compared the diagnostic accuracy with experienced visual interpretation. Methods: An ameroid constrictor was placed around the proximal left circumflex (LCX) coronary artery in 19 pigs. Four weeks later, subtotal stenosis was confirmed in all pigs by coronary angiogram. Two dead pigs and three pigs with pathological infarction were excluded. Transthoracic left ventricle (LV) short‐axis echocardiograms were recorded at rest before and 4 weeks after the operation. LV posterior wall motion was scored by two experienced doctors and analyzed by the speckle tracking system (n = 14). Results: Strain variables gave reasonable intra/interobserver reproducibility (mean absolute percentage errors = 13/19, intraclass correlation coefficients = 0.97/0.92). All strain variables and visual wall‐motion scores changed significantly during stenosis (P < 0.05). Of all variables, endocardial strains, particularly the circumferential strain demonstrated the highest area under curve (AUC), showing better diagnostic accuracy than experienced visual interpretation (sensitivity 0.93 vs. 0.79, specificity 0.93 vs. 0.73, AUC 0.95 vs. 0.77, P < 0.05). Conclusion: Three‐layer speckle tracking is a feasible and reproducible modality. In particular, endocardial speckle tracking provides incremental value in accurately identifying regional ischemia even in the rest echocardiography. (Echocardiography 2011;28:1148‐1155)

Prediction of coronary artery stenosis using strain imaging diastolic index at rest in patients with preserved ejection fraction.

BACKGROUND Post-ischemic myocardial diastolic stunning persists for a long time after transient ischemia even after systolic function has recovered. We sought to identify coronary artery stenosis in clinical patients using strain imaging diastolic index (SI-DI) at rest. METHODS We retrospectively examined 85 patients with suspected coronary artery disease and preserved ejection fraction (EF; >50%) who underwent both echocardiography and coronary angiography. Speckle tracking strains were measured in 3 apical views and parasternal left ventricular (LV) short-axis views at the papillary muscle level. LV segments with inadequate image quality and deficit segments in the movie were excluded by the blinded observer. After strain analysis, LV segments were classified into no stenosis (≤ 50%), mild stenosis (51-75%), and severe stenosis (>75%) groups on the bases of the coronary angiogram. RESULTS SI-DI decreased significantly in severe stenosis segments (p<0.05, ANOVA), but none of the peak strains showed significant difference. The area under the curve for predicting severe stenosis in radial, longitudinal, and transverse SI-DI was 0.72, 0.74, and 0.80, respectively. A cut-off value of 49 for transverse SI-DI can predict LV segments with severe stenosis with sensitivity of 0.79 and specificity of 0.73. A screening cut-off value of 63 for transverse SI-DI shows sensitivity of 0.95 and specificity of 0.50. CONCLUSION SI-DI at rest is a novel marker in predicting coronary stenosis even in patients with preserved EF. This index can be used to screen patients with suspected coronary artery disease in routine echocardiography and does not require stress provocation.

Value of live 3D transoesophageal echocardiography in the diagnosis of mitral valve lesions

We experienced a case in which live 3D transoesophageal echocardiography (TEE) was found much more valuable than 2D TEE in assessing mitral lesions in circumferential direction and making surgical plans for mitral valve prolapse.

Prognostic impact of venous thromboembolism in patients with Duchenne muscular dystrophy: Prospective multicenter 5-year cohort study

Please cite this article as: Kimura Koichi, Morita Hiroyuki, Daimon Masao, Kawata Takayuki, Nakao Tomoko, Lee Seitetsu L., Hirokawa Megumi, Ebihara Aya, Nakajima Takashi, Ozawa Tetsuo, Yonemochi Yosuke, Aida Izumi, Motoyoshi Yasufumi, Mikata Takashi, Uchida Idai, Komori Tetsuo, Kitao Ruriko, Nagata Tetsuya, Takeda Shin’ichi, Komaki Hirofumi, Segawa Kazuhiko, Takenaka Katsu, Komuro Issei, Prognostic Impact of Venous Thromboembolism in Patients with Duchenne Muscular Dystrophy: Prospective Multicenter 5-Year Cohort Study, International Journal of Cardiology (2015), doi: 10.1016/j.ijcard.2015.04.244

Multiple coronary artery fistulae with biventricular hypertrophy.

Here, we report a case of multiple coronary artery fistulae with biventricular hypertrophy. The initial diagnosis of multiple coronary artery fistulae, draining into the left as well as the right ventricle, was made by standard transthoracic 2-dimensional and Doppler echocardiography. Later, multiple coronary fistulae communicating with the left ventricle through persistent sinusoids were diagnosed by coronary angiography.