Mayu Nishio

Atherosclerotic and Thrombogenic Neointima Formed Over Sirolimus Drug-Eluting Stent: An Angioscopic Study

OBJECTIVES We sought to examine by angioscopy the neointima formation and thrombogenic potential of the neointima after deployment of a drug-eluting stent (DES). BACKGROUND Late stent thrombosis after DES implantation, a major safety concern, has been associated with poor strut coverage by neointima. Intracoronary angioscopy provides a method for visual evaluation of stent coverage by neointima and detection of thrombus in the stented coronary segment. METHODS Patients undergoing implantation of a sirolimus DES (n = 57) were serially examined by angioscopy immediately after (baseline) and again at 10 months (follow-up) after implantation. The angioscopic color grade of the neointima from white to yellow was assessed in a semiquantitative manner. Stent coverage was classified into not covered (Grade 0), covered by a thin layer (Grade 1), or buried under neointima (Grade 2). The thrombogenic potential of the neointima was evaluated by the prevalence of thrombus on the neointima. RESULTS The maximum yellow color grade of the neointima within DES-implanted lesions increased significantly from baseline to follow-up (1.4 +/- 1.1 vs. 1.9 +/- 0.6, p = 0.0008). Even among lesions without yellow color at baseline, yellow color was detected in 94% (17 of 18) of lesions at follow-up. The prevalence of thrombus was significantly higher on the yellow than on the white neointimal areas. Thrombus was detected on yellow and/or Grade-0/1 neointima, but never on the white Grade-2 neointima. CONCLUSIONS Sirolimus DES promoted formation of atherosclerotic yellow neointima in the stent-implanted lesion at 10-month follow-up. Thrombus was detected more often on the yellow area than on the white area and was never detected where a stent was buried under white neointima. These data suggest that the increased potential risk of late stent thrombosis in DES lesions may be due to the newly formed yellow neotima and cholesterol-laden plaque.

Noninvasive Assessment of Wall Distensibility With the Evaluation of Diastolic Epicardial Movement

BACKGROUND Left ventricular (LV) wall stiffening plays an important role in the development of heart failure with preserved ejection fraction (HFpEF). Based on the linear elastic theory, we hypothesized that the evaluation of epicardial movement during diastole is helpful for the noninvasive assessment of LV wall distensibility. METHODS AND RESULTS Based on the linear elastic theory, the epicardial movement index (EMI) was calculated on the echocardiogram as: [see text.] We calculated diastolic wall strain (DWS) as follows to examine whether DWS substitutes for EMI: [see text.] The animal study using hypertensive Dahl salt-sensitive rats, HFpEF model, and normotensive Dahl rats showed the significant and inverse correlation of EMI or DWS with myocardial stiffness constant. Preload alteration did not affect EMI or DWS. In the clinical study, the HFpEF patients had lower EMI and DWS than the normal volunteers and the asymptomatic patients with LV hypertrophy. CONCLUSIONS The evaluation of epicardial movement may be useful in noninvasively assessing wall distensibility in the absence of LV systolic dysfunction.

ACE inhibitor and angiotensin II type 1 receptor blocker differently regulate ventricular fibrosis in hypertensive diastolic heart failure.

Background Promoted myocardial stiffening has a crucial role in the transition to overt diastolic heart failure (DHF) in hypertensive hearts and is attributed to progressive ventricular fibrosis. Previous studies revealed the effects of an angiotensin II type 1 receptor blocker (ARB) and an angiotensin-converting enzyme inhibitor (ACEI) on the synthesis and degradation of collagens in the other phenotype of heart failure, systolic heart failure, which has a different pathophysiology; however, little is known about their effects in DHF. Objective To investigate effects of an ACEI and an ARB on the regulatory system of ventricular fibrosis in hypertensive DHF. Design and methods Dahl salt-sensitive rats fed a diet containing 8% NaCl from age 7 weeks (DHF model) were divided into three groups: six untreated rats, six rats treated with a subdepressor dose of an ARB, candesartan cilexetil (1 mg/kg per day), from age 8 weeks, and six rats treated with a subdepress or dose of an ACEI, temocapril hydrochloride (0.2 mg/kg per day), from age 8 weeks. Six Dahl salt-sensitive rats fed on normal chow served as controls. Data were collected when animals were aged 20 weeks. Results The administration of an ARB or an ACEI inhibited ventricular fibrosis to the same degree. The ACEI decreased the level of type I collagen mRNA, but the decrease was less than that induced by the ARB. The difference in collagen synthesis was probably cancelled out by that in degradation: both in-vitro and in-situ zymography showed that gelatinase activity was greater in the rats treated with the ACEI than in those treated with the ARB. Conclusions An ARB and an ACEI inhibited ventricular fibrosis through different mechanisms in hypertensive DHF.

Beneficial effects of bisoprolol on the survival of hypertensive diastolic heart failure model rats.

β‐blocker therapy is an established therapeutic strategy for systolic heart failure. However, its benefits in diastolic heart failure (DHF) are controversial.

Therapeutic effects of angiotensin II type 1 receptor blocker at an advanced stage of hypertensive diastolic heart failure.

Objective Angiotensin II type 1 receptor blocker (ARB) is increasingly prescribed for the treatment of systolic heart failure with a growing body of clinical evidence. The roles of ARB, however, remain to be clarified in the treatment of diastolic heart failure (DHF), particularly at its advanced stage. This experimental study investigated the effects of ARB administered at an advanced stage of hypertensive DHF. Methods Dahl salt-sensitive rats fed an 8% NaCl diet from age 7 weeks represent overt DHF at age 20 weeks, as noted in previous studies (hypertensive DHF model). The DHF model rats were randomly divided into two groups at age 17 weeks when left ventricular diastolic dysfunction, hypertrophy, fibrosis, macrophage infiltration and reactive oxygen species generation were already augmented; six rats treated for 3 weeks with a subdepressor dose of ARB (olmesartan 0.6 mg/kg per day), and six untreated rats. Results The 3-week administration of ARB significantly decreased the left ventricular end-diastolic pressure in association with attenuation of left ventricular hypertrophy, fibrosis and diastolic dysfunction. Macrophage infiltration was attenuated with decreased gene expression of transforming growth factor-β1 and monocyte chemoattractant protein-1 in the left ventricular myocardium of the ARB-treated rats. The production of reactive oxygen species also decreased with NADPH oxidase activity. Conclusions ARB provides beneficial effects in hypertensive DHF independent of its antihypertensive effects even if initiated at an advanced stage. The beneficial effects are at least partly attributed to the attenuation of inflammatory changes and oxidative stress through the suppression of cytokine and chemokine production and of NADPH oxidase activity.

Cardiac steroidogenesis and glucocorticoid in the development of cardiac hypertrophy during the progression to heart failure.

Background Elevated plasma glucocorticoid level is an independent predictor of increased mortality risk in chronic heart failure, but local biosynthesis and pathophysiological roles of glucocorticoids in the heart remain unclear. Methods Dahl salt-sensitive rats on high-salt diet and mice with transthoracic aortic banding (TAC) operation (TAC mice), both of which finally represent heart failure, were assessed at compensatory hypertrophic stage. As a model of cardiac-specific activation of steroidogenesis, α-myosin heavy chain–steroidogenic acute regulatory protein transgenic mice were used. Results In hypertrophied hearts of Dahl salt-sensitive rats and TAC mice, the gene expressions of steroidogenic acute regulatory protein and CYP11A, rate limiting factors of steroid biosynthesis, were significantly upregulated and cardiac corticosterone level was increased compared with age-matched control. Although transgenic mice represented no morphological changes at basal condition, TAC induced greater increases in a ratio of left ventricular weight to body weight (4.8 ± 0.2 vs.4.3 ± 0.1 mg/g, P < 0.05) and left ventricular corticosterone level (104.5 ± 13.3 vs. 69.8 ± 3.8 pg/mg, P < 0.05) in the transgenic mice than in littermates. In neonatal cardiomyocytes, corticosterone increased atrial natriuretic peptide expression, protein synthesis and cell surface area, and provided the additive hypertrophic effects on phenylephrine-induced hypertrophied myocytes. These effects were prevented by glucocorticoid receptor blockade but not by mineralocorticoid receptor blockade. Conclusion In hypertrophied hearts, cardiac steroidogenesis was activated with an increase in cardiac glucocorticoid level. Glucocorticoid had potential of augmenting cardiac hypertrophy via glucocorticoid receptor even under the activation of α-adrenoceptor-mediated hypertrophic signaling. Cardiac steroidogenesis system and local glucocorticoid may play important roles in the development of hypertrophy and the progression to heart failure.

The Utility of Carotid Ultrasonography in Identifying Severe Coronary Artery Disease in Asymptomatic Type 2 Diabetic Patients Without History of Coronary Artery Disease

OBJECTIVE Although many studies have shown that carotid intima-media thickness (IMT) is associated with coronary artery disease (CAD), it remains inconclusive whether assessment of carotid IMT is useful as a screening test for asymptomatic but severe CAD in diabetic patients. RESEARCH DESIGN AND METHODS A total of 333 asymptomatic type 2 diabetic patients without history of CAD underwent exercise electrocardiogram or myocardial perfusion scintigraphy for detection of silent myocardial ischemia, and those whose test results were positive were subjected to coronary computed tomography angiography or coronary angiography. The ability of carotid IMT to identify severe CAD corresponding to treatment with revascularization was examined by receiver-operating characteristic (ROC) curve analyses. RESULTS Among the 333 subjects, 17 were treated with revascularization. A multiple logistic regression analysis showed that maximum IMT was an independent predictor of severe CAD even after adjustment for conventional risk factors. ROC curve analyses revealed that the addition of maximum IMT to conventional risk factors significantly improved the prediction ability for severe CAD (from area under the curve, 0.67 to 0.79; P = 0.039). The greatest sensitivity and specificity were obtained when the cut-off value of maximum IMT was set at 2.45 mm (pretest probability, 5%; posttest probability, 11%; sensitivity, 71%). When we applied age-specific cut-off values, the sensitivity of screening further increased in both the nonelderly (pretest probability, 6%; posttest probability, 10%; sensitivity, 100%) and the elderly subjects (pretest probability, 5%; posttest probability, 15%; sensitivity, 100%). CONCLUSIONS Our study suggests that carotid maximum IMT is useful for screening asymptomatic type 2 diabetic patients with severe CAD equivalent to revascularization.

Detection of disrupted plaques by coronary CT: comparison with angioscopy

Background Disrupted plaques are the major cause of acute coronary syndrome (ACS). Although the detection of vulnerable plaques by coronary CT (CCT) has been examined and reported, there has been no report on the detection of disrupted plaques by CCT. Objectives To test the ability of CCT to detect disrupted coronary plaques. Methods 32 consecutive patients with suspected ischaemic heart disease who underwent successful coronary angioscopic examination and CCT were analysed. Yellow plaques of colour grade 1−3 and disrupted yellow plaques were examined by angioscopy. CCT findings (low attenuation, positive remodelling and ring-like enhancement) were examined for each site of yellow plaques. Results In the 32 patients, 65 yellow plaques were detected. Higher-colour-grade yellow plaques and disrupted yellow plaques had a significantly higher incidence of CCT findings: low attenuation (grade 1 vs grade 2 vs grade 3, 18% vs 59% vs 69%; non-disrupted vs disrupted, 36% vs 66%), positive remodelling (24% vs 59% vs 75%; 33% vs 75%), and ring-like enhancement (0% vs 19% vs 25%; 6% vs 44%). Positive and negative predictive values for ring-like enhancement to detect disrupted plaque were 88% and 63%, respectively; those for the combined CCT findings (low attenuation, positive remodelling and ring-like enhancement) to detect disrupted plaque were 90% and 58%, respectively. Conclusion CCT findings were associated with disrupted plaques confirmed by angioscopy. Ring-like enhancement had a high positive predictive value for detecting disrupted plaque.

Noninvasive Assessment of Diastolic Function in Subjects With Preserved Left Ventricular Ejection Fraction: Usefulness of Color Kinetic Imaging

BACKGROUND Noninvasive assessment of left ventricular (LV) diastolic function is not established in patients with preserved ejection fraction. We investigated a relation between diastolic function and diastolic wall dynamics. METHODS AND RESULTS In the animal study, data were collected in hypertensive Dahl salt-sensitive rats, a diastolic heart failure (DHF) model (n = 35), and normotensive Dahl rats (n = 26). In the clinical study, echocardiography was conducted in 26 diabetic patients with normal ejection fraction and 10 age-matched controls. The diastolic index of color-encoded images (color kinesis diastolic index [CK-DI]) was calculated as the ratio of LV cavity area expansion during the first 30% of diastolic filling time to that during the whole diastolic filling period. In the DHF model, the E/A ratio of the transmitral flow velocity curves was pseudonormalized with the development of heart failure, but CK-DI was not. CK-DI, not E/A, was significantly and inversely correlated with the time constant of LV relaxation. Angiotensin receptor blocker improved LV relaxation in the DHF model and increased CK-DI, but not E/A. The diabetic patients showed lower CK-DI than the controls, although E/A was not different. CONCLUSION Color-encoded imaging is useful in evaluating LV diastolic function. The prevalence of LV diastolic dysfunction may have been clinically underestimated by the transmitral flow velocity curves.

Difference of Clinical Characteristics between Hypertensive Patients with and without Diastolic Heart Failure: The Roles of Diastolic Dysfunction and Renal Insufficiency

Clinical characteristics were compared between hypertensive patients with and without heart failure in the absence of reduced ejection fraction (EF) to gain insights into the effects of renal insufficiency on the prevalence of diastolic heart failure. Study subjects consisted of 691 hypertensive patients with an EF > 40%. Patients with serum creatinine >2.5 mg/dL were excluded from the study. The Framingham heart failure criteria were met by 198 patients, and competing risks of the prevalence of heart failure were analyzed. The multiple logistic regression analysis revealed that obesity, female gender, creatinine clearance (CCr), and a ratio of transmitral E velocity to early diastolic mitral annular velocity (E/E′)>15 were independently associated with the prevalence of heart failure with preserved EF. Patients with 60≤CCr<90 mL/min represented higher E/E′ ratio and lower E′ velocity than the patients with CCr≥90 mL/min, although there was no difference in the prevalence of heart failure between the two groups. These indices were not different between the patients with 60≤CCr<90 mL/min and CCr<60 mL/min, although the prevalence of heart failure was higher in the patients with CCr<60 mL/min. The hemoglobin concentration was significantly decreased and the brachial-ankle pulse wave velocity was significantly elevated in patients with CCr<60 mL/min. Thus, progressive left ventricular diastolic dysfunction and renal insufficiency are competing risks of the prevalence of diastolic heart failure in hypertensive patients. Renal insufficiency may exert its effects through the modulation of extracardiac factors such as anemia and arterial stiffening rather than through the promotion of diastolic dysfunction.