Cognitive function in post-cardiac intensive care: patient characteristics and impact of multidisciplinary cardiac rehabilitation.

New/worsening cognitive and physical impairments following critical care pose significant problems. Multidisciplinary cardiac rehabilitation (CR) can improve physical function after cardiac intensive care (CIC). This observational study aimed to evaluate cognitive function in patients participating in multidisciplinary CR and to identify correlates of impaired cognitive function after CIC. We analyzed 111 consecutive patients admitted to our comprehensive care ward at least 7 days after CIC and assessed factors associated with cognitive function using the Functional Independence Measure (FIM). Patients were stratified into two groups based on the median FIM-Cognitive scores: impaired (n = 56) and preserved cognition (n = 55) groups. Multiple logistic regression analysis identified age [odds ratio (OR) 1.06; 95% confidence interval (CI) 1.00-1.13; p = 0.042], Mini-Nutrition Assessment-Short Form (MNA-SF; OR 0.73; 95% CI 0.56-0.95; p = 0.017), and FIM-Physical scores (OR: 0.94; 95% CI 0.90-0.99; p = 0.012) as significant and independent factors associated with impaired cognition. The median length of hospital stay was 28 (interquartile range: 18, 43) days. The FIM-Cognitive and FIM-Physical scores significantly increased from admission to discharge [32.0 (27.0, 35.0) vs. 34.0 (29.0, 35.0) points; p < 0.001; 67.0 (53.0, 75.0) vs. 85.0 (73.5, 89.0) points; p < 0.001, respectively]. On subgroup analysis within the impaired cognition group, increased FIM-Cognitive scores positively and significantly correlated with increased FIM-Physical scores (ρ = 0.450; p = 0.001). Multiple linear regression analysis identified atrial fibrillation (AF; ß = - 0.29; p = 0.016), ln(glycated hemoglobin; HbA1c) (ß = 0.29; p = 0.018), and ln(high-sensitivity C-reactive protein; hs-CRP) (ß = - 0.26; p = 0.034) as significant and independent factors correlated with increased FIM-Cognitive scores. In conclusion, advanced age, low MNA-SF score, and FIM-Physical score were independent factors associated with impaired cognition in post-CIC patients. Multidisciplinary CR improved both physical and cognitive functions, and AF, HbA1c, and hs-CRP were independent factors correlated with increased FIM-Cognitive score.

Isolated Right Ventricular Stress (Takotsubo) Cardiomyopathy.

A 79-year-old woman was admitted with a left femoral neck fracture and she immediately developed circulatory shock. Echocardiography showed a markedly enlarged right ventricle (RV) with systolic ballooning of the mid-ventricular wall and preserved contractility of the apex. The left ventricular (LV) motion was normal. Multi-detector-row computed tomography showed severe congestion of the contrast media in the right atrium with no forward flow to RV, but no pulmonary embolism. She was successfully treated with percutaneous veno-arterial extracorporeal membrane oxygenation. This case presented with acute, profound, but reversible RV dysfunction triggered by acute stress in a manner similar to that seen in LV stress cardiomyopathy.

Pre-procedural peripheral endothelial function is associated with increased serum creatinine following percutaneous coronary procedure in stable patients with a preserved estimated glomerular filtration rate.

BACKGROUND: Worsening renal function, indicated by increased serum creatinine (SCr), is a common complication of percutaneous coronary procedures. Risk factors for increased SCr overlap with coronary risk factors involved in endothelial dysfunction. We hypothesized that endothelial dysfunction, measured using the reactive hyperemia peripheral arterial tonometry index (RHI), can predict periprocedure-increased SCr. METHODS: RHI was assessed before elective coronary procedures in 316 consecutive stable patients with a preserved estimated glomerular filtration rate (eGFR, >60mL/min/1.73m2). SCr was measured before and 2 days after procedures. RESULTS: There was no significant correlation between natural logarithmic transformations of RHI (Ln-RHI) and basal Ln-eGFR. Periprocedure increase in SCr was observed in 148 (47%) patients. The increased SCr group had significantly lower Ln-RHI [0.48 (0.36, 0.62) vs. 0.59 (0.49, 0.76), p<0.001]. Multivariate linear regression analysis identified body mass index (BMI) (ß=0.148, p=0.005) and Ln-RHI (ß=-0.365, p<0.001) as significant determinants of percent changes in SCr. Multivariate logistic regression analysis identified Ln-RHI (per 0.1) [odds ratio (OR) 0.672, 95% confidence interval (95% CI) 0.586-0.722; p<0.001], Ln-B-type natriuretic peptide (OR: 1.484, 95% CI: 1.130-1.974; p=0.004), current smoking (OR: 2.563, 95% CI: 1.379-4.763, p=0.003), BMI (OR: 1.113, 95% CI: 1.031-1.203; p=0.007), coronary intervention (OR: 1.736, 95% CI: 1.036-2.909; p=0.036), and Ln-hemoglobin A1c (OR: 6.728, 95% CI: 1.093-41.392, p=0.040) as independent determinants of increased SCr. Receiver-operating characteristics curve analysis showed that Ln-RHI correlated significantly with increased SCr (area under the curve, 0.684, 95% CI: 0.626-0.742, p<0.001). The optimum cut-off point of Ln-RHI for the periprocedure increased SCr was 0.545. CONCLUSIONS: Pre-procedure measurement of endothelial function by RHI is an effective strategy to assess the patient's risk conditions for worsening renal function after percutaneous coronary procedures.

Staging laparoscopy for advanced gastric cancer: significance of preoperative clinicopathological factors.

PURPOSE: Although the use of staging laparoscopy (SL) for detecting peritoneal metastasis (P) and determining peritoneal lavage cytology (CY) is widespread in advanced gastric cancer, an indication for SL based on preoperative clinicopathological factors is controversial. METHODS: From May 2006 to September 2015, 120 patients with advanced gastric cancer with primary tumors ≥5 cm and/or with bulky regional lymph nodes (bulky N) underwent SL for assessment of P/CY status. Clinicopathological factors were analyzed retrospectively to determine their influence on peritoneal spread (P1 and/or CY1). An additional analysis of 379 consecutive patients with clinically T2 or deeper gastric cancer in the same time period was carried out to confirm the SL results. RESULTS: Peritoneal spread was confirmed by SL in 54 cases (45%). The presence of type-4 tumors (n = 38, p < 0.0001) and diffuse-type tumors (n = 85, p = 0.04) correlated significantly with peritoneal spread. These two factors were also correlated significantly with increased peritoneal spread in a subgroup analysis among patients with tumors with bulky N (n = 44). The additional analysis of 379 patients showed results consistent with the SL results. The frequency of peritoneal spread was 78% among type-4 tumors, 47% among diffuse-type tumors ≥5 cm, and 38% among diffuse-type tumors with bulky N, whereas among intestinal-type tumors, it was 18% in tumors ≥5 cm and 13% among tumors with bulky N. CONCLUSIONS: Among tumors ≥5 cm or with bulky N, type-4 tumors and diffuse-type tumors had a high potential for peritoneal spread and patients with such tumors were considered more suitable candidates for SL.

Lipid profile associated with coronary plaque regression in patients with acute coronary syndrome: Subanalysis of PRECISE-IVUS trial.

BACKGROUND AND AIMS: Although dual low-density lipoprotein cholesterol (LDL-C)-lowering therapy (DLLT) with statin-ezetimibe combination showed clinical benefit in patients with acute coronary syndrome (ACS) confirming "the lower, the better," the underlying mechanisms of DLLT are still unknown. METHODS: PRECISE-IVUS trial evaluated the effects of DLLT on IVUS-derived coronary atherosclerosis and lipid profile, compared with atorvastatin monotherapy, quantifying the coronary plaque response in 100 ACS patients. We explored the potential predictors of plaque regression. RESULTS: Lower total cholesterol, LDL-C, triglyceride, remnant-like particles cholesterol, and stronger reduction of small dense LDL-C and cholesterol absorption markers were observed in patients with plaque regression compared to those with progression. Multivariate analysis revealed that achieved LDL-C was the strongest predictor for coronary plaque regression (95% CI: 0.944-1.000, p = 0.05), followed by age (95% CI: 0.994-1.096, p = 0.09). CONCLUSIONS: Incremental LDL-C lowering by DLLT was associated with stronger coronary plaque regression, reconfirming that lowering LDL-C to levels below previous targets provided additional clinical benefit.

Synergistic effect of ezetimibe addition on coronary atheroma regression in patients with prior statin therapy: Subanalysis of PRECISE-IVUS trial.

BACKGROUND: The IMPROVE-IT trial showed that the clinical benefit of statin/ezetimibe combination appeared to be pronounced in patients with prior statin therapy. We hypothesized that the antiatherosclerotic effect of atorvastatin/ezetimibe combination was pronounced in patients with statin pretreatment. METHODS: In the prospective, randomized, controlled, multicenter PRECISE-IVUS trial, 246 patients undergoing intravascular ultrasound-guided percutaneous coronary intervention were randomized to atorvastatin/ezetimibe combination or atorvastatin alone. The dosage of atorvastatin was uptitrated with a treatment goal of lowering low-density lipoprotein cholesterol to below 70 mg/dl in both groups. Serial volumetric intravascular ultrasound was performed at baseline and 9-12 month follow-up to quantify the coronary plaque response in 202 patients. We compared the intravascular ultrasound endpoints in all subjects, stratified by the presence or absence of statin pretreatment. RESULTS: The baseline low-density lipoprotein cholesterol level (100.7 ± 23.1 mg/dl vs. 116.4 ± 25.9 mg/dl, p < 0.001) and lathosterol (55 (38 to 87)) µg/100 mg total cholesterol vs. 97 (57 to 149) µg/100 mg total cholesterol, p < 0.001) was significantly lower, and campesterol/lathosterol ratio (3.9 (2.4 to 7.4) vs. 2.6 (1.5 to 4.1), p < 0.001) was significantly increased in patients with statin pretreatment. Contrary to the patients without statin pretreatment (-1.3 (-3.1 to -0.1)% vs. -0.9 (-2.3 to 0.9)%, p = 0.12), the atorvastatin/ezetimibe combination showed a significantly stronger reduction in delta percent atheroma volume, compared with atorvastatin alone, in patients with statin pretreatment (-1.8 (-3.6 to -0.3)% vs. -0.1 (-1.6 to 0.8)%, p = 0.002). CONCLUSION: Compensatory increase in cholesterol absorption observed in statin-treated patients might attenuate the inhibitory effects of statins on coronary plaque progression. A low-dose statin/ezetimibe combination might be a promising option in statin-hyporesponder.

Advanced peripheral microvascular endothelial dysfunction and polyvascular disease in patients with high cardiovascular risk.

BACKGROUND: Polyvascular disease (PolyVD) refers to the coexistence of coronary artery disease (CAD), peripheral arterial disease (PAD), and/or cerebrovascular disease (CVD), and carries a high risk of cardiovascular mortality. Endothelial dysfunction plays a crucial role in cardiovascular pathophysiology. This study investigated the association between PolyVD and the presence of microvascular endothelial dysfunction. METHODS: Consecutive stable patients (n=533) with diabetes mellitus and/or multiple cardiovascular risk factors were enrolled. Peripheral microvascular endothelial function in the finger microvasculature was assessed using the reactive hyperemia peripheral arterial tonometry index (RHI), and ankle-brachial index was measured for diagnosis of lower-extremity PAD prior to coronary angiography. Diagnosis of CVD was based on clinical symptoms, carotid ultrasound, and magnetic resonance imaging. PolyVD was defined as two or more coexisting vascular diseases from CAD, lower-extremity PAD, and CVD. RESULTS: Natural logarithmic transformations of RHI (Ln-RHI) were significantly attenuated in 93 patients with PolyVD (0.44±0.20) compared with those in 440 patients without PolyVD (0.56±0.19; p<0.001) or in 299 patients with a single vascular disease (0.54±0.19; p<0.001). There was an independent correlation between Ln-RHI (per 0.1) and the presence of PolyVD in all high-risk patients [odds ratio (OR): 0.724; 95% confidence interval (CI): 0.610-0.859; p<0.001] and one or more vascular diseases (OR: 0.724; 95% CI: 0.605-0.867, p<0.001). Receiver-operating characteristics curve analysis showed that Ln-RHI correlated significantly with PolyVD (area under the curve, 0.682, 95% CI: 0.625-0.740, p<0.001). The optimum cut-off point of Ln-RHI for the existence of PolyVD was 0.479. CONCLUSIONS: Microvascular endothelial dysfunction is significantly associated with the presence of PolyVD. Severe impairment of endothelial function in peripheral microvasculature may be an important pathophysiological component of PolyVD.

Prognostic Significance of Peripheral Microvascular Endothelial Dysfunction in Heart Failure With Reduced Left Ventricular Ejection Fraction.

BACKGROUND: Endothelial dysfunction plays a crucial role in heart failure (HF), but the association between peripheral microvascular endothelial function assessed by reactive hyperemia peripheral arterial tonometry (RH-PAT) and prognosis remains unknown in HF with reduced left ventricular (LV) ejection fraction (HFREF). We prospectively investigated the association between peripheral microvascular endothelial function and HF-related near-future cardiovascular outcomes in HFREF patients. METHODS AND RESULTS: The 362 HFREF patients (LVEF <50%) were followed for HF-related events (composite of cardiovascular death and HF hospitalization) up to 3 years. A natural logarithmic-scaled RH-PAT index (Ln-RHI) was obtained for each patient. A total of 82 HF-related events were recorded. The lower-RHI group (Ln-RHI ≤0.49, median) experienced a higher rate of HF-related events compared with the higher-RHI group by Kaplan-Meier analysis (30.9% vs. 14.4%, log-rank test: P<0.001). Multivariable Cox hazard analysis identified Ln-RHI as an independent predictor for HF-related events (per 0.1, hazard ratio: 0.84, 95% confidence interval: 0.75-0.95, P=0.005). Adding Ln-RHI to the Meta-analysis Global Group in Chronic HF risk score (MAGGICs) and Seattle Heart Failure Model (SHFM), powerful prognostic predictors of HF, significantly improved the net reclassification index (MAGGICs: 20.11%, P=0.02, SHFM: 24.88%, P<0.001), and increased the C-statistics for prediction of HF-related events (MAGGICs+Ln-RHI: from 0.612 to 0.670, SHFM+Ln-RHI: from 0.662 to 0.695). CONCLUSIONS: Peripheral microvascular endothelial dysfunction assessed by RH-PAT was associated with future HF-related events in HFREF.

Impact of Dual Lipid-Lowering Strategy With Ezetimibe and Atorvastatin on Coronary Plaque Regression in Patients With Percutaneous Coronary Intervention: The Multicenter Randomized Controlled PRECISE-IVUS Trial.

BACKGROUND: Despite standard statin therapy, a majority of patients retain a high "residual risk" of cardiovascular events. OBJECTIVES: The aim of this study was to evaluate the effects of ezetimibe plus atorvastatin versus atorvastatin monotherapy on the lipid profile and coronary atherosclerosis in Japanese patients who underwent percutaneous coronary intervention (PCI). METHODS: This trial was a prospective, randomized, controlled, multicenter study. Eligible patients who underwent PCI were randomly assigned to atorvastatin alone or atorvastatin plus ezetimibe (10 mg) daily. Atorvastatin was uptitrated with a treatment goal of low-density lipoprotein cholesterol (LDL-C) <70 mg/dl. Serial volumetric intravascular ultrasound was performed at baseline and again at 9 to 12 months to quantify the coronary plaque response in 202 patients. RESULTS: The combination of atorvastatin/ezetimibe resulted in lower levels of LDL-C than atorvastatin monotherapy (63.2 ± 16.3 mg/dl vs. 73.3 ± 20.3 mg/dl; p < 0.001). For the absolute change in percent atheroma volume (PAV), the mean difference between the 2 groups (-1.538%; 95% confidence interval [CI]: -3.079% to 0.003%) did not exceed the pre-defined noninferiority margin of 3%, but the absolute change in PAV did show superiority for the dual lipid-lowering strategy (-1.4%; 95% CI: -3.4% to -0.1% vs. -0.3%; 95% CI: -1.9% to 0.9% with atorvastatin alone; p = 0.001). For PAV, a significantly greater percentage of patients who received atorvastatin/ezetimibe showed coronary plaque regression (78% vs. 58%; p = 0.004). Both strategies had acceptable side effect profiles, with a low incidence of laboratory abnormalities and cardiovascular events. CONCLUSIONS: Compared with standard statin monotherapy, the combination of statin plus ezetimibe showed greater coronary plaque regression, which might be attributed to cholesterol absorption inhibition-induced aggressive lipid lowering. (Plaque Regression With Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound [PRECISE-IVUS]; NCT01043380).

Telmisartan enhances mitochondrial activity and alters cellular functions in human coronary artery endothelial cells via AMP-activated protein kinase pathway.

OBJECTIVE: Mitochondrial dysfunction plays an important role in cellular senescence and impaired function of vascular endothelium, resulted in cardiovascular diseases. Telmisartan is a unique angiotensin II type I receptor blocker that has been shown to prevent cardiovascular events in high risk patients. AMP-activated protein kinase (AMPK) plays a critical role in mitochondrial biogenesis and endothelial function. This study assessed whether telmisartan enhances mitochondrial function and alters cellular functions via AMPK in human coronary artery endothelial cells (HCAECs). METHODS AND RESULTS: In cultured HCAECs, telmisartan significantly enhanced mitochondrial activity assessed by mitochondrial reductase activity and intracellular ATP production and increased the expression of mitochondria related genes. Telmisartan prevented cellular senescence and exhibited the anti-apoptotic and pro-angiogenic properties. The expression of genes related anti-oxidant and pro-angiogenic properties were increased by telmisartan. Telmisartan increased endothelial NO synthase and AMPK phosphorylation. Peroxisome proliferator-activated receptor gamma signaling was not involved in telmisartan-induced improvement of mitochondrial function. All of these effects were abolished by inhibition of AMPK. CONCLUSIONS: Telmisartan enhanced mitochondrial activity and exhibited anti-senescence effects and improving endothelial function through AMPK in HCAECs. Telmisartan could provide beneficial effects on vascular diseases via enhancement of mitochondrial activity and modulating endothelial function through AMPK activation.

Plaque REgression with Cholesterol absorption Inhibitor or Synthesis inhibitor Evaluated by IntraVascular UltraSound (PRECISE-IVUS Trial): Study protocol for a randomized controlled trial.

BACKGROUND: Although the positive association between achieved low-density lipoprotein cholesterol (LDL-C) level and the risk of coronary artery disease (CAD) has been confirmed by randomized studies with statins, many patients remain at high residual risk of events suggesting the necessity of novel pharmacologic strategies. The combination of ezetimibe/statin produces greater reductions in LDL-C compared to statin monotherapy. PURPOSE: The Plaque REgression with Cholesterol absorption Inhibitor or Synthesis inhibitor Evaluated by IntraVascular UltraSound (PRECISE-IVUS) trial was aimed at evaluating the effects of ezetimibe addition to atorvastatin, compared with atorvastatin monotherapy, on coronary plaque regression and change in lipid profile in patients with CAD. METHODS: The study is a prospective, randomized, controlled, multicenter study. The eligible patients undergoing IVUS-guided percutaneous coronary intervention will be randomly assigned to receive either atorvastatin alone or atorvastatin plus ezetimibe (10 mg) daily using a web-based randomization software. The dosage of atorvastatin will be increased by titration within the usual dose range with a treatment goal of lowering LDL-C below 70 mg/dL based on consecutive measures of LDL-C at follow-up visits. IVUS will be performed at baseline and 9-12 months follow-up time point at participating cardiovascular centers. The primary endpoint will be the nominal change in percent coronary atheroma volume measured by volumetric IVUS analysis. CONCLUSION: PRECISE-IVUS will assess whether the efficacy of combination of ezetimibe/atorvastatin is noninferior to atorvastatin monotherapy for coronary plaque reduction, and will translate into increased clinical benefit of dual lipid-lowering strategy in a Japanese population.

Statins combined with exercise are associated with the increased renal function mediated by high-molecular-weight adiponectin in coronary artery disease patients.

BACKGROUND: Statins and exercise therapy are clinically effective in preventing cardiovascular events in patients with coronary artery disease (CAD). The aim of this study was to determine the effects of statins combined with exercise on the renal function of CAD patients. METHODS: We performed a sub-analysis of a clinical trial that determined the 20-week-effects of two statins (rosuvastatin, n=14; atorvastatin, n=14) combined with regular exercise on renal function, as assessed by the estimated glomerular filtration rates (eGFRs) of CAD patients. RESULTS: The combination of statins and exercise therapy increased eGFRs from 61.1±16.6 at baseline to 65.8±16.8ml/min/per 1.73m(2) (p=0.03), increased serum levels of high-molecular-weight (HMW) adiponectin, increased ubiquinol/low-density lipoprotein cholesterol (LDL-C) ratios, and decreased high sensitivity C-reactive protein (hs-CRP). Changes in HMW-adiponectin, ubiquinol/LDL-C ratios and hs-CRP were significantly correlated with changes in eGFR (r=0.597, p=0.001; r=0.437, p=0.02; and r=-0.473, p=0.01, respectively). Treatment-induced increases in HMW-adiponectin independently correlated with the increases in eGFR (ß=0.513, p=0.02) in a multivariate analysis. Both atorvastatin and rosuvastatin combined with regular exercise produced increases in eGFR. The patients treated with rosuvastatin exhibited significant improvements in eGFR. CONCLUSION: Statins combined with exercise significantly increased eGFR in CAD patients, and these improvements in renal function were correlated with increases in HMW-adiponectin levels. The statins-exercise combination treatment may have provided clinical benefits for patients with CAD partly through the improvement in renal function.

Peripheral endothelial function and cardiovascular events in high-risk patients.

BACKGROUND: Endothelial dysfunction is a key component of vascular vulnerability. Reactive hyperemia index (RHI), as assessed by the peripheral arterial tonometry, can noninvasively evaluate endothelial function. This study was designed to determine the additional prognostic value of endothelial function to the Synergy Between PCI With Taxus and Cardiac Surgery Score (SYNTAXsc) and the Framingham Risk Score (FRS) in predicting cardiovascular events in high-risk patients. METHODS AND RESULTS: We undertook a two-center prospective study in 528 stable patients at high-risk for cardiovascular events from the years 2006-2011. The RHI was measured before coronary angiography and coronary complexity was assessed by SYNTAXsc. After optimal therapies including coronary revascularization, there was follow-up with patients until August 2012. Cardiovascular events consist of cardiovascular death, myocardial infarction, unstable angina, ischemic stroke, coronary revascularization, heart failure-induced hospitalization, aortic disease, and peripheral arterial disease. During 1468 person-years of follow-up, 105 patients developed cardiovascular events. Multivariate Cox proportional hazards analysis identified B-type natriuretic peptide (BNP), SYNTAXsc, and RHI as independent cardiovascular event predictors (hazard ratio [95% confidence interval]: natural logarithm of BNP per 0.1: 1.019 [1.002 to 1.037]; P=0.023, SYNTAXsc per tertile: 2.426 [1.825 to 3.225]; P<0.0001, RHI per 0.1: 0.761 [0.673 to 0.859]; P<0.0001). When RHI was added to the FRS, BNP, and SYNTAXsc, net reclassification index was significantly improved (27.5%; P<0.0001), with a significant increase in the C-statistic (from 0.728 [0.679 to 0.778] to 0.766 [0.726 to 0.806]; P=0.031). CONCLUSIONS: Advanced endothelial dysfunction significantly correlated with near future cardiovascular events in high-risk patients. This physiological vascular measurement improved risk discrimination when added to the FRS, BNP, and SYNTAXsc. CLINICAL TRIAL REGISTRATION URL: clinicaltrials.gov (http://www.clinicaltrials.gov). Unique identifier: NCT00737945.

Effects of endothelial dysfunction on residual platelet aggregability after dual antiplatelet therapy with aspirin and clopidogrel in patients with stable coronary artery disease.

BACKGROUND: Dual antiplatelet therapy with aspirin and clopidogrel is widely used in patients with coronary stents. High residual platelet reactivity (high RPR) after dual antiplatelet therapy is associated with increased cardiovascular events. Endothelial function could affect platelet reactivity in vivo. We hypothesized that endothelial dysfunction could be associated with high RPR after dual antiplatelet therapy in patients with stable coronary artery disease. METHODS AND RESULTS: We screened patients with stable coronary artery disease for cytochrome P450 (CYP) 2C19 genotypes and enrolled 103 patients who lacked CYP2C19*2 or *3 loss-of-function allele to minimize the effect of this gene on high RPR. All patients received aspirin (100 mg/d) and clopidogrel (75 mg/d for long-term treatment or a loading dose of 300 mg) before the following tests. Platelet aggregability was assessed as P2Y12 reaction unit using the VerifyNow System. High RPR was defined as P2Y12 reaction unit ≥ 230. Peripheral endothelial function was expressed as reactive hyperemia index using reactive hyperemia peripheral arterial tonometry. Fifty-three patients exhibited high RPR. High RPR patients were significantly older, had higher levels of B-type natriuretic peptide, and were predominantly hypertensive compared with non-high RPR patients. Reactive hyperemia index was significantly lower in high RPR patients (0.46 ± 0.15) compared with non-high RPR patients (0.61 ± 0.18; P<0.001). Linear regression analysis demonstrated significant negative correlation between reactive hyperemia index and P2Y12 reaction unit (r=-0.32; P=0.001). Multivariable logistic regression analysis identified reactive hyperemia index as an independent and significant determinant of high RPR (odds ratio, 0.55; 95% confidence interval, 0.39-0.78; P=0.001). CONCLUSIONS: In patients with stable coronary artery disease, endothelial function was significantly impaired in high RPR patients. Endothelial dysfunction is independently correlated with high RPR after dual antiplatelet therapy. CLINICAL TRIAL REGISTRATION URL: http://www.umin.ac.jp/ctr. Unique identifier: UMIN000008239.

Successful diet and exercise therapy as evaluated on self-assessment score significantly improves endothelial function in metabolic syndrome patients.

BACKGROUND: Simple office-based counseling for diet and exercise does not appear to positively affect success rates in metabolic syndrome (MetS) patients. The utility of the lifestyle modification self-assessment score (Self-AS) in the improvement of endothelial function by office-based counseling for patients with MetS was investigated. METHODS AND RESULTS: Patients with MetS (n=207) and age- and sex-matched individuals without MetS (n=124) were enrolled in this cross-sectional study. Endothelial function was assessed using reactive hyperemia-peripheral arterial tonometry index (RHI). Patients with MetS had significant endothelial dysfunction compared with those without MetS (RHI, 0.502±0.178 vs. 0.614±0.229; P<0.001). Seventy MetS patients participating in the prospective interventional study received simple office-based lifestyle modification counseling that was accompanied by Self-AS questionnaire after 10 months. RHI was significantly improved following lifestyle modifications (from 0.452±0.136 to 0.547±0.202, P<0.001). Reductions in waist circumference (R(2)=0.094, P=0.01) and increased high-density lipoprotein cholesterol (R(2)=0.227, P<0.001) independently correlated with improved RHI. Self-AS significantly correlated with changes in waist circumference (r=-0.57, P<0.001) and RHI (r=0.30, P=0.02). Patients with a good achievement of lifestyle modifications (higher Self-AS) had significant improvement in endothelial function compared with those with lower scores (% change in RHI, +48.7±61.6 vs. +7.8±35.1, P=0.001). CONCLUSIONS: Good achievement of lifestyle modifications as evaluated on Self-AS significantly improved endothelial function with concomitant reductions in waist circumferences in MetS patients.

Basal and ischemia-induced transcardiac troponin release into the coronary circulation in patients with suspected coronary artery disease.

BACKGROUND: Cardiac troponin is a specific biomarker for cardiomyocyte necrosis in acute coronary syndromes. Troponin release from the coronary circulation remains to be determined because of the lower sensitivity of the conventional assay. We sought to determine basal and angina-induced troponin release using a highly sensitive troponin assay. METHODS AND RESULTS: The cardiac troponin T levels in serum sampled from the peripheral vein (PV), the aortic root (AO), and the coronary sinus (CS) were measured in 105 consecutive stable patients with coronary risk factor(s) and suspected coronary artery disease (CAD) and in 33 patients without CAD who underwent an acetylcholine provocation test. At baseline, there was a significant increase in the troponin levels from AO [9.0 (6.4, 13.1) pg/mL for median (25(th), 75(th) percentiles)] to CS [10.3 (7.3, 15.5) pg/mL, p<0.001] in 96 (91.4%) patients and the difference was 1.1 (0.4, 2.1) pg/mL, which reflected basal transcardiac troponin release (TTR). TTR was positively correlated with PV levels (r = 0.22, p = 0.03). Male sex, left ventricular hypertrophy determined by echocardiography, T-wave inversion, and CAD correlated with elevated TTR defined as above: median, 1.1 pg/mL. A significant increase in TTR was noted in 17 patients with coronary spasms [0.6 (0.2, 1.2) pg/mL, p<0.01] but not in 16 patients without spasms [0.0 (-0.5, 0.9) pg/mL, p = 0.73] after the acetylcholine provocation. CONCLUSION: Basal TTR in the coronary circulation was observed in most of the patients with suspected CAD and risk factor(s). This sensitive assay detected myocardial ischemia-induced increases in TTR caused by coronary spasms.

Coronary plaque component in patients with vasospastic angina: a virtual histology intravascular ultrasound study.

BACKGROUND: Coronary spasm plays an important role in the pathogenesis of ischemic heart disease. However, tissue components of coronary plaque in patients with vasospastic angina (VSA) have been unknown. This study used virtual histology (VH)-intravascular ultrasound (IVUS) to elucidate the tissue component of spastic coronary arteries and its gender differences in patients with VSA. METHODS: According to acetylcholine provocation tests, the study subjects (42 patients [19 men, 23 women, 61 ± 13 years]) were divided into 2 groups: the VSA group of 26 patients and the non-VSA group of 16 patients. After nitrate injection, IVUS volumetric analysis was done, and the parameters were compared between the groups. RESULTS: Although clinical demographics were almost identical between the groups, VSA group had lower plasma adiponectin level (5.9 ± 3.3 µg/ml vs. 11.2 ± 7.6 µg/ml, p=0.007) and tended to have higher high-sensitivity C-reactive protein (0.15 ± 0.24 mg/dl vs. 0.06 ± 0.04 mg/dl, p=0.1) than non-VSA group. VSA group had diffusely thickened intima (% plaque volume, 34 ± 11% vs. 27 ± 7%, p=0.01) compared with non-VSA group. However, plaque components of patients with VSA were similar with that of non-VSA patients (dense calcium, 4 ± 6% vs. 3 ± 4%; necrotic core, 10 ± 9% vs. 8 ± 6%; fibrofatty, 19 ± 16% vs. 22 ± 11%; and fibrous, 67 ± 16% vs. 67 ± 9%). Although male patients with VSA had atherogenic lipid and metabolic profiles than female VSA patients, there were no significant gender differences in the volumetric IVUS parameters and plaque components. CONCLUSIONS: Compared with non-VSA patients, VSA patients had diffusely thickened fibrous-dominant coronary plaque without gender difference, and that might suggest the role of vasospasm in the development of atherosclerosis.