Ken Harada

Impact of omega-3 polyunsaturated fatty acids on coronary plaque instability: An integrated backscatter intravascular ultrasound study

OBJECTIVE To assess the impact of omega-3 polyunsaturated fatty acids (ω3 PUFAs) on coronary plaque instability. METHODS Serum content of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) was measured in 336 of 368 consecutive patients suspected of having coronary artery disease who underwent coronary angiography. Conventional and integrated backscatter intravascular ultrasound (IB-IVUS) parameters were analyzed in 116 patients with 128 coronary plaques, using a 43-MHz (motorized pullback 0.5mm/s) intravascular catheter (View It, Terumo Co., Japan). Lipid-rich plaques were classified into two categories according to their components. RESULTS Patients with acute coronary syndrome had significantly lower levels of ω3 PUFAs (especially of EPA and DPA) than those without it. IB-IVUS analyses showed that ω3 PUFAs correlated inversely with % lipid volume and positively with % fibrous volume. Patients with low EPA levels, low DPA levels, and low DHA levels had a significantly higher % lipid volume (p=0.048, p=0.008, and p=0.036, respectively) and a significantly lower % fibrous volume (p=0.035, p=0.008, and p=0.034, respectively) than those with high levels of these fatty acids. Even after adjustment for confounders, the presence of both low EPA and low DPA levels proved to be an independent predictor for lipid-rich plaques in any of the two categories. CONCLUSIONS A lower serum content of ω3 PUFAs (especially of EPA and DPA) was significantly associated with lipid-rich plaques, suggesting the contribution to the incidence of acute coronary syndrome.

Cardiac 64-Multislice Computed Tomography Reveals Increased Epicardial Fat Volume in Patients With Acute Coronary Syndrome

Inflammatory cytokines released from epicardial fat around coronary arteries may modulate the coronary arteries and promote coronary atherosclerosis. We assessed the hypothesis that epicardial fat volume (EFV) is increased in patients with acute coronary syndrome (ACS). EFV was measured in 80 Japanese patients hospitalized for ACS using 64-multislice computed tomography. The ACS group included 51 patients with ST-segment elevated myocardial infarction and 29 patients with non-ST-segment elevated myocardial infarction. All patients underwent emergency coronary angioplasty and 64-multislice computed tomographic scanning during hospitalization. The control group included 90 consecutive outpatients with suspected ACS whose coronary computed tomographic results were normal. EFV was larger in patients with ACS than in the control group (117 ± 47 vs 95 ± 33 ml, p <0.001). Multivariate regression analysis showed that EFV was associated with age, body mass index, and visceral fat area in the control group. However, these correlations did not appear in the ACS group. Multivariate logistic regression analysis showed that EFV >100 ml was independently associated with ACS (odds ratio 2.84, 95% confidence interval 1.17 to 6.87, p = 0.021). Receiver operator characteristic analysis determined a cut-off value of 100.3 ml with a sensitivity of 75% and a specificity of 60% for ACS (area under the curve 0.692, 95% confidence interval 0.596 to 0.777, p <0.001). Compared to subcutaneous adipose tissue, epicardial adipose tissue showed inflammatory cell infiltrates on a micrograph. In conclusion, the present study demonstrated significantly increased EFV in patients with ACS. A large amount of epicardial fat may be a risk factor for ACS.

Relation of functional and morphological changes in mitochondria to myocardial contractile and relaxation reserves in asymptomatic to mildly symptomatic patients with hypertrophic cardiomyopathy

AIMS To examine the relation between mitochondrial dysfunction and myocardial contractile and relaxation reserves in hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS Thirty HCM patients (LVEF >or=60%) underwent biventricular cardiac catheterization analysis both at rest and during atrial pacing as well as myocardial (99m)Tc-sestamibi scintigraphy at rest to calculate washout rate. Endomyocardial biopsy specimens were obtained for quantitative mRNA analysis and electron microscopy. The HCM patients were divided into two groups-group A: normal force-frequency relation and a pressure half-time (T(1/2)) of <30 ms (n = 15); group B: abnormal force-frequency relation or T(1/2) of >or=30 ms (n = 15). The (99m)Tc-sestamibi washout rate was significantly correlated with T(1/2) for all patients (r = 0.74, P < 0.01) and was also significantly greater in group B (29.2 +/- 6.3%) than in group A (19.3 +/- 3.1%). The abundance of mRNAs for mitochondrial electron transport-related enzymes was significantly higher in group A than in group B. Mitochondria showed a greater variation in size and were more disorganized in group B than in group A. CONCLUSION Mitochondria showed functional impairment and morphological disorganization in the left ventricle of HCM patients without baseline systolic dysfunction. These mitochondrial changes were associated with impaired myocardial contractile and relaxation reserves.

Accuracy of 64-slice multidetector computed tomography for classification and quantitation of coronary plaque: Comparison with integrated backscatter intravascular ultrasound

BACKGROUND Noninvasive assessment of coronary plaque is important for coronary risk stratification. Whereas integrated backscatter intravascular ultrasound (IB-IVUS) has proven effective for analysis of the tissue components of coronary plaque, plaque assessment by 64-slice multidetector computed tomography (MDCT) has not been established. We therefore evaluated the accuracy of MDCT compared with IB-IVUS for identification of coronary plaque components and determination of plaque volume. METHODS Thirty-one sites in 17 coronary vessels (7 left anterior descending, 5 left circumflex, and 5 right coronary arteries) with substantial stenosis were visualized by both 64-slice MDCT and IB-IVUS. Coronary plaque was evaluated by MDCT and the findings were compared with those of IB-IVUS at the same sites and for the same vessel lengths. Plaque was classified as low-attenuated, fibrous, or calcified, and the volume of each plaque component and total plaque volume were calculated. RESULTS Total plaque volume per vessel determined by MDCT was significantly correlated with that determined by IB-IVUS (r=0.704, P<0.05, n=17). However, the volumes of individual plaque components determined by the two approaches were not correlated. The predominant plaque morphology as determined by the two approaches was consistent in 12 of the 17 vessels (70.6%), whereas calcified and low-attenuated plaques were overestimated by MDCT in the remaining vessels. CONCLUSIONS MDCT is a promising approach for noninvasive detection of different types of coronary plaque and may therefore contribute to coronary risk stratification. The ability of MDCT to determine the volume of individual plaque components, however, is limited.

Mechanism of Diastolic Stiffening of the Failing Myocardium and Its Prevention by Angiotensin Receptor and Calcium Channel Blockers

Objective: To investigate the mechanism responsible for the increased cardiac stiffness associated with hypertensive heart failure in Dahl salt-sensitive (DS) rats and the effects of treatment with the combination of a calcium channel blocker [azelnidipine (AZE)] and angiotensin II type 1 receptor blocker [olmesartan (OLM)]. Methods: DS rats fed a high-salt diet from 7 weeks of age were treated (or not) from 12 to 19 weeks of age with the vasodilator hydralazine, OLM plus AZE, or the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin. Rats fed a low-salt diet served as controls. Results: Treatment with OLM plus AZE attenuated changes in the expression of collagen isoforms and a decrease in the ratio of elastin to collagen in the left ventricle and prevented the increase in myocardial stiffness and diastolic dysfunction in DS rats in a manner independent of the hypotensive effect of these drugs. Such treatment also inhibited the expression and activation of elastolytic proteases (including cathepsins S and K and metalloproteinases-2, -9, and -12), NADPH oxidase-dependent superoxide production, and inflammatory changes in the failing myocardium. All these effects were mimicked by treatment with apocynin. Conclusions: The changes in collagen isoform expression and the decrease in the elastin to collagen ratio in the failing myocardium likely account for the increase in diastolic stiffness in this model of hypertensive heart failure. Administration of angiotensin receptor and calcium channel blockers prevented these changes in a manner independent of the hypotensive effect of these drugs by inhibiting the increase in elastolytic activity induced by activation of NADPH oxidase.

Epicardial fat volume correlates with severity of coronary artery disease in nonobese patients

Objective It has been reported that epicardial adipose tissue could locally modulate the coronary artery functions through secretion of proinflammatory and anti-inflammatory cytokines. Epicardial fat tissue is further implicated in the pathogenesis of coronary artery disease (CAD) because of its proximity to the adventitia of the major epicardial coronary arteries. We investigated the relationship between epicardial fat volume (EFV) and severity of CAD in nonobese patients using 64-slice multidetector computed tomography (MDCT). Methods One hundred and forty nonobese patients (BMI <25 kg/m2) were enrolled. EFV and visceral fat area were measured by MDCT. Patients were classified according to the plaque components (noncalcified, mixed and calcified) and severity of CAD. Inflammatory biomarkers were also measured, and compared with each CT parameter. Results EFV was significantly correlated with the extent or severity of CAD. Patients with noncalcified or mixed plaque had a greater EFV than those with calcified plaque. Log-transferred high sensitivity C-reactive protein (CRP) was significantly correlated with EFV (r = 0.24, P = 0.04). Adiponectin level was significantly inversely correlated with visceral fat area (r = 0.38, P = 0.0001). Conclusion Increased EFV is associated with more severe CAD and noncalcified or mixed coronary plaques in nonobese patients.

Impact of Insulin Resistance on Post-Procedural Myocardial Injury and Clinical Outcomes in Patients Who Underwent Elective Coronary Interventions With Drug-Eluting Stents

OBJECTIVES This study sought to evaluate the associations between homeostatic indexes of insulin resistance (HOMA-IR) and post-procedural myocardial injury and clinical outcome after a percutaneous coronary intervention (PCI) with a drug-eluting stent. BACKGROUND Insulin resistance increases the risk of cardiovascular events. However, the association between insulin resistance and clinical outcome after coronary intervention is unclear. METHODS We evaluated 516 consecutive patients who underwent elective PCI with drug-eluting stents. Blood samples were collected from venous blood after overnight fasting, and fasting plasma glucose and insulin levels were measured. HOMA-IR was calculated according to the homeostasis model assessment. Post-procedural myocardial injury was evaluated by analysis of troponin T and creatine kinase-myocardial band isozyme levels hours after PCI. Cardiac event was defined as the composite endpoint of cardiovascular death, myocardial infarction, and any revascularization. RESULTS With increasing tertiles of HOMA-IR, post-procedural troponin T and creatine kinase-myocardial band levels increased. In the multiple regression analysis, HOMA-IR was independently associated with troponin T elevation. During a median follow-up of 623 days, patients with the highest tertiles of HOMA-IR had the highest risk of cardiovascular events. The Cox proportional hazard models identified HOMA-IR as independently associated with worse clinical outcome after adjustment for clinical and procedural factors. CONCLUSIONS These results indicated the impact of insulin resistance on post-procedural myocardial injury and clinical outcome after elective PCI with drug-eluting stent deployment. Evaluation of insulin resistance may provide useful information for predicting clinical outcomes after elective PCI.

Impact of chronic kidney disease on the incidence of peri-procedural myocardial injury in patients undergoing elective stent implantation

BACKGROUND It is well known that chronic kidney disease is a strong independent predictor of adverse outcomes after percutaneous coronary intervention in patients with ischemic heart disease. Recently, peri-procedural myocardial injury has been associated with adverse cardiac events. The aim of this study was to investigate the relationship between renal function and peri-procedural myocardial injury in patients undergoing elective stent implantation. METHODS This study comprised 273 consecutive patients who underwent elective stent implantation. They were divided into two groups: estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m(2) and eGFR ≥60 mL/min/1.73m(2). Peri-procedural TnT levels higher than three times the normal limit were defined as peri-procedural myocardial injury. RESULTS Patients with eGFR <60 mL/min/1.73m(2) showed a higher incidence of peri-procedural myocardial injury compared to patients with eGFR ≥60 mL/min/1.73m(2) (4.3 versus 20.9%, P < 0.0001). Even after a multivariate adjustment, the eGFR level predicted peri-procedural myocardial injury [odds ratio 0.92, 95% confidence interval (CI): 0.89-0.95, P < 0.0001]. Total stent length was also an independent predictor of peri-procedural myocardial injury (odds ratio 1.09, 95% CI: 1.02-1.16, P = 0.009). Using a receiver-operating curve analysis, eGFR level of 62.1 mL/min/1.73m(2) (sensitivity 93.3%, specificity 57.2%) was the best value (area under the curve = 0.803) to maximize the power of eGFR levels in predicting peri-procedural myocardial injury. CONCLUSIONS Patients with eGFR <60 mL/min/1.73m(2) were strongly associated with peri-procedural myocardial injury after elective stent implantation. Therefore, eGFR may be a simple and convenient predictor of peri-procedural myocardial injury.

Impact of abdominal and epicardial fat on the association between plasma adipocytokine levels and coronary atherosclerosis in non-obese patients

OBJECTIVE Ectopic fat accumulation is associated with coronary artery disease. Visceral adipose tissue has paracrine and systemic effects and is a source of adipocytokines. It has been implicated in the pathogenesis of coronary atherosclerosis; however, nothing is known about whether increases in epicardial fat have the same effect on coronary atherosclerosis as increases in abdominal visceral fat. METHODS We examined 216 consecutive patients suspected to have coronary artery disease. Individuals with acute coronary syndrome and inadequate computed tomography (CT) imaging were excluded. We enrolled 164 patients (65 ± 10 years old; 70% men; body mass index [BMI], 23.8 ± 3.6 kg/m(2)). The plasma concentrations of adiponectin, interleukin-6 (IL-6), plasminogen activator inhibitor-1, and vascular endothelial growth factor were measured. The characteristics of coronary plaque, abdominal visceral fat area, and epicardial fat volume (EFV) were determined by 64-slice CT imaging. RESULTS EFV was greater in subjects with noncalcified plaque than in those with no plaque or with calcified plaque (126 ± 39 mL vs. 98 ± 34 mL and 97 ± 45 mL, respectively; P = 0.010). EFV was significantly correlated with BMI, triglycerides, and the triglyceride/high-density lipoprotein cholesterol ratio (r = 0.51, 0.19, and 0.20, respectively) but not with plasma levels of adipocytokines. The plasma adiponectin and IL-6 concentration was significantly correlated with abdominal visceral fat area in coronary plaque patients (r = -0.49 and 0.20). CONCLUSIONS In non-obese Japanese patients, epicardial fat may have unique mechanisms affecting the development of coronary atherosclerosis, which is different from abdominal visceral fat.

Prognostic impact of concurrence of metabolic syndrome and chronic kidney disease in patients undergoing coronary intervention: Involvement of coronary plaque composition

BACKGROUND AND PURPOSE Metabolic syndrome (MetS) and chronic kidney disease (CKD) have both been reported as risk factors for cardiovascular events. The aim of this study was to assess the synergistic effect of MetS and CKD on atherosclerotic plaque and cardiovascular outcomes. METHODS AND SUBJECTS A total of 545 consecutive patients who underwent percutaneous coronary intervention (PCI) were divided into 4 groups based on the presence or absence of MetS and CKD. MetS was defined using the criteria of the Adult Treatment Panel III of the US National Cholesterol Education Program. CKD was defined as an estimated glomerular filtration rate of <60ml/min/1.73m(2). We analyzed the incidence of major adverse cardiac events (MACE), including cardiovascular death, nonfatal myocardial infarction, target lesion revascularization, and revascularization for new lesions. We also assessed coronary plaque characteristics of 204 patients using integrated backscatter intravascular ultrasound (IB-IVUS). RESULTS MACE occurred more frequently in patients with both MetS and CKD (51.4%) than in the other groups, during the follow-up period (log-rank p<0.001). In the IB-IVUS analyses, patients with both MetS and CKD exhibited greater plaque burden (p=0.003) with higher lipid content (p=0.048) compared to the other groups. In Cox analysis, both MetS and CKD proved to be independent predictors of MACE even after adjustment for confounding factors (p=0.018). CONCLUSIONS Comorbidity of MetS and CKD is an independent predictor of adverse cardiovascular outcomes in patients undergoing coronary intervention, an effect that may be attributed to coronary plaque instability.