Fractional flow reserve (FFR) has become an increasingly important index for decision making with respect to revascularization of coronary artery stenosis. It is the gold standard to indicate whether a particular stenosis is responsible for inducible ischemia and it is generally accepted that a stenosis with an ischemic value of FFR is responsible for angina pectoris and a worse outcome, and should be revascularized, whereas lesions with a non-ischemic FFR have a more favorable prognosis and can better be treated medically. In this review paper, the background, concept and clinical application of FFR are discussed from a practical point of view. On top of that, some in-depth considerations are given with respect to further possibilities of FFR for examining the coronary circulation, including separate assessment of coronary, myocardial, and collateral blood flows. Finally, a word of caution is given with respect to using resting pressure indexes, which seem attractive because they avoid the need for hyperemia, but negatively affect the accuracy of the measurements. This review can be read as an overview of the state-of-the-art of FFR and as a guide to further reading.  (Circ J 2013; 77: 561–569)

View full abstract

Transient receptor potential canonical (TRPC) proteins assemble to form ion channels that enable influx of calcium and sodium ions into cells. There are 6 TRPC proteins in humans but more TRPC channels may arise through heteromerization among TRPCs and other types of TRP protein. They are widely expressed and have multiple functions throughout the peripheral and central systems of the body. This review summarizes current knowledge of the characteristics of TRPC channels and discusses principles by which the channels operate. Modulators of the channels include lipids, redox factors, and agonists at G-protein and tyrosine kinase receptors. The channels enable coupling between these factors and the calcium ion, which is a master intracellular regulator of multiple cell functions. In the context of this information the review gives specific consideration to TRPC channels in vascular cells, which include endothelial cells, vascular smooth muscle cells, perivascular adipocytes, and cells of the hematopoietic lineage. It is discussed that the channels may have most significance as drivers of change when there is strain or insult in physiology or disease. The TRPC proteins constitute a substantial and important group of calcium-permeable channels. They remain enigmatic but there is increasing understanding of their properties and recognition of their importance in the vasculature as well as in other systems such as the myocardium.  (Circ J 2013; 77: 570–579)

View full abstract

After myocardial infarction (MI), inflammatory cells such as neutrophils, followed by monocytes and macrophages, infiltrate and phagocytose the necrotic tissues, as well as secreting a variety of inflammatory cytokines. The vulnerable myocardium, which consists of necrotic tissue and inflammatory cells, is susceptible to wall stress, resulting in infarct expansion. Subacute cardiac rupture is an extreme form of infarct expansion, whereas ventricular aneurysm is its chronic form and a trigger for subsequent left ventricular (LV) remodeling. Although post-infarction inflammation is essential for the healing process, excessive inflammation could play an important role in the development of LV remodeling. Increase in the C-reactive protein level, which reflects myocardial inflammation, is reported to be a useful predictive marker for cardiac rupture, ventricular aneurysm and LV remodeling. In addition, an increase in peripheral monocyte count is associated with a poor outcome after MI, and an animal study has demonstrated that granulocyte/macrophage-colony stimulating factor induction causes excessive macrophage infiltration in the infarcted area and worsening of LV remodeling. Recently, it was also found that dendritic cells play an important role in controlling excessive inflammation caused by monocytes/macrophages. Thus, inflammation that develops after MI is a double-edged sword, and how to control inflammation to suppress pathological remodeling is an important issue to be considered in developing new treatment for heart failure.  (Circ J 2013; 77: 580–587)

View full abstract

It is now generally recognized that acute coronary syndromes most commonly result from disruption of thin-cap fibroatheroma (TCFA), which is characterized by a large necrotic core with an overlying thin-fibrous cap measuring <65μm. Recent advances in intracoronary imaging modalities have significantly improved the ability to detect TCFA in vivo. Intravascular ultrasound (IVUS) is perhaps the most promising modality that has been used more than 15 years to evaluate atherosclerotic plaque. IVUS has revealed a lot of the clinical evidence regarding vulnerable plaque detection in live humans. Recently, by analyzing the IVUS acoustic signal before demodulation and scan conversion, IVUS radiofrequency analysis can be used to differentiate adjacent smaller areas of atherosclerotic plaque with heterogeneous composition. Coronary angioscopy allows direct visualization of the coronary artery wall and provides detailed information of the luminal surface of plaque, such as color, thrombus or disruption. Optical coherence tomography imaging, recently been introduced for in vivo human imaging, offers a higher resolution than any other available imaging modality, and can visualize a thin fibrous cap measuring <65μm. In this review, we will discuss the features and limitations of each imaging modalities for detecting TCFA.  (Circ J 2013; 77: 588–595)

View full abstract

Background: Risk stratification is important in the management of Brugada syndrome (BrS). Late potentials (LPs) and T-wave amplitude variability (TAV) in high-resolution ambulatory electrocardiography (ECG) were retrospectively investigated. Methods and Results: One hundred and twenty-seven patients diagnosed with BrS on 12-lead ECG were classified into 3 groups: documented ventricular fibrillation (VF)/asystole (n=19), episodes of syncope alone (n=30), and asymptomatic (n=78). Healthy volunteers were enrolled as controls (n=25). In the BrS patients, LPs showed appreciable circadian periodicity; filtered QRS duration (fQRS) and duration of the terminal low-amplitude signal <40μV (LAS40) increased, whereas root mean square voltage of the terminal 40ms of the fQRS (RMS40) decreased at night compared with the day. TAV did not have such a circadian periodicity. LP-positive incidence (night-time) and peak TAV were as follows: VF/asystole>syncope/asymptomatic>control (P<0.001). VF/asystole was discriminated from control at a ratio of 81–84% by night-time LPs (fQRS >116ms, LAS40 >35ms, RMS40 <25μV) or peak TAV (>54μV); VF/asystole was discriminated from syncope/asymptomatic at a ratio of 60–69%, by night-time LPs (fQRS >122ms, LAS40 >42ms, RMS40 <18μV) or peak TAV (>58μV). Combined analysis of LPs and peak TAV increased the discriminant ratio up to 93% and 77%, respectively. Conclusions: Analysis of both LPs and TAV (taking circadian periodicity into account) is useful in identification of high-risk BrS patients.  (Circ J 2013; 77: 610–618)

View full abstract

Background: Prompt diagnosis and management of atrial tachyarrhythmias (ATAs) during catheter ablation of atrial fibrillation (AF) is still challenging. Methods and Results: In 88 patients undergoing catheter ablation of AF, 128 regular ATAs were induced or converted from AF. The coronary sinus activation time (CSAT) around the mitral annulus (MA) was measured as the difference in activation time between the most proximal and distal poles of the coronary sinus (CS) electrodes. Entrainment pacing was performed around the MA, roof area, or cavotricuspid isthmus (CTI) depending on the CSAT result. Mechanisms of tachycardias included macro-reentry around the MA (perimitral atrial flutter [PM-AFL], n=63), roof-dependent AFL (Roof-AFL, n=14), CTI-dependent AFL (CTI-AFL, n=25), and atrial tachycardia (AT, n=26). When the CSAT was ≥45ms, the MA activation sequence was sequential, either proximal to distal or distal to proximal. When the CSAT was <45ms, the MA activation sequence was mainly non-sequential with converging or diverging patterns. CSAT <45ms was highly sensitive in ruling out PM-AFL from other left ATAs. When combined with PPI data from the MA, roof area or CTI, PM-, Roof-, CTI-AFL and AT was successfully differentiated with a high predictive accuracy. Conclusions: A diagnostic algorithm combining CSAT and entrainment pacing is helpful to assess the mechanism of ATAs during catheter ablation of AF.  (Circ J 2013; 77: 619–625)

View full abstract

Background: The aim of this study was to assess the spatial distribution of the origins of adenosine triphosphate (ATP) sensitive focal atrial tachycardias (AT) that have their earliest activation recorded in the His bundle (HB) catheter. Methods and Results: Catheters were placed according to the standard fashion for an electrophysiologic study of supraventricular arrhythmia, namely, high right atrium, HB, coronary sinus, and right ventricle. The ATs with their earliest activation recorded in the HB catheter and that were terminated by rapid injection of ATP (4.3±2.5mg), formed the study group (n=12). After catheter ablation of these ATs, the distances between the successful ablation site and the HB area were measured. Only one successful site was near the HB and the other sites were at the noncoronary sinus of Valsalva (n=6), tricuspid annulus (n=3), right atrial septum (n=1), and left atrial septum (n=1). The average distance between the HB catheter and successful site was 10.4±8.8mm. In 5 of the 12 cases (the 3 tricuspid and 2 septal foci), the distances were greater than 10mm. Conclusions: When ablating ATP-sensitive AT with the earliest activation recorded in the HB catheter, it is important to perform detailed mapping not only around the HB.  (Circ J 2013; 77: 626–631)

View full abstract

Background: In the Japanese Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (J-ROCKET AF) study, rivaroxaban 15mg once daily was given to patients with creatinine clearance (CrCl) ≥50ml/min (preserved renal function), and was reduced to 10mg once daily in patients with CrCl 30–49ml/min (moderate renal impairment). The aim of this subanalysis was to assess the safety and efficacy of the adjusted dose of rivaroxaban compared with warfarin in a cohort with moderate renal impairment. Methods and Results: Compared with patients with preserved renal function, those with moderate renal impairment (22.2% of all randomized patients) had higher rates of bleeding and stroke events irrespective of study treatment. Among those with moderate renal impairment, the principal safety endpoint occurred at 27.76%/year with rivaroxaban vs. 22.85%/year with warfarin (hazard ratio [HR], 1.22; 95% confidence interval [CI]: 0.78–1.91) and the rate of the primary efficacy endpoint was 2.77%/year vs. 3.34%/year (HR, 0.82; 95% CI: 0.25–2.69), respectively. There were no significant interactions between renal function and study treatment in the principal safety and the primary efficacy endpoints (P=0.628, 0.279 for both interactions, respectively). Conclusions: The safety and efficacy of rivaroxaban vs. warfarin were consistent in patients with moderate renal impairment and preserved renal function.  (Circ J 2013; 77: 632–638)

View full abstract

Background: The Cardiac failure, Hypertension, Age, Diabetes, Stroke [Doubled] (CHADS₂) score is a useful scheme for risk stratification of thromboembolism patients, but there is little information about its usefulness for the evaluation of antiarrhythmic drug (AAD) therapy. Methods and Results: This study included 459 paroxysmal atrial fibrillation (AF) patients (309 men, mean age 66±12 years, mean follow-up 50±35 months) and prophylactic efficacy was analyzed on the basis of CHADS₂ score. (1) Survival rates free from AF recurrence at 1, 6, 12 and 24 months were, respectively, 89%, 74%, 63% and 47% in score-0 group (n=152); 92%, 68%, 59% and 48% in score-1 group (n=158); 86%, 64%, 56% and 46% in score-2 group (n=84); 81%, 65%, 51% and 35% in score-3 group (n=43); and 68%, 50%, 36% and 18% in ≥score-4 group (n=22) (P<0.05; score-0, score-1 or score-2 vs. ≥score-4 group). (2) Survival rates free from progression to chronic AF at 12, 36, 60 and 90 months were, respectively, 95%, 93%, 91% and 89% in score-0 group; 97%, 91%, 89% and 88% in score-1 group; 96%, 93%, 88% and 83% in score-2 group; 91%, 74%, 67% and 60% in score-3 group; and 91%, 82%, 68% and 55% in ≥score-4 group (P<0.01; score-0, score-1 or score-2 vs. ≥score-4 group). (3) In multivariate logistic regression analysis adjusted for potentially confounding variables, CHADS₂ score was associated with AF recurrence (odds ratio [OR] 1.45, 95% confidence interval [CI] 1.16–1.81, P<0.001), and progression to chronic AF during AAD therapy (OR 1.64, 95% CI 1.04–2.69, P<0.001). Conclusions: When using a rhythm control strategy, the CHADS₂ score is a useful scheme for predicting the outcome of AAD treatment of patients with paroxysmal AF.  (Circ J 2013; 77: 639–645)

View full abstract

Background: This study compared older men and women with cardiovascular (CV) risk factors in terms of the effects of a 6-month exercise intervention on high-sensitivity C-reactive protein (hsCRP) levels, blood pressure (BP) and other risk factors. Methods and Results: Sixty older (age 61–79) overweight men and 71 such women with 2 or more risk factors (ie, systolic BP 130–179mmHg, non-fasting blood glucose 110–139mg/dl, and low-density lipoprotein cholesterol 120–219mg/dl) participated in a 6-month exercise intervention. The exercise program consisted of moderate-intensity bicycle exercise for ∼40min, performed on average 2.5 times per week. Systolic and diastolic BP reductions were found to be greater in women than in men (SBP, −10.6 vs. −5.5mmHg; DBP, −6.2 vs. −3.3mmHg; both P<0.05). Decreases in body mass index were larger in women than in men (P<0.05). There was no significant gender difference in the changes in blood glucose and lipid profiles and hsCRP levels. After adjustment for confounders (exercise frequency, weight loss, age, and baseline values), there were still significant gender differences in the SBP and DBP reductions. hsCRP reduction were similar in both genders even after adjusting for weight loss. Conclusions: There could be gender differences in the beneficial effects of exercise training on the potent CV risk factors of BP and body weight, but not on hsCRP.  (Circ J 2013; 77: 646–651)

View full abstract

Background: We hypothesized that the tissue components of in-stent restenosis (ISR) might differ between drug-eluting stents (DES) and bare-metal stents (BMS) and that these differences could be distinguished by qualitative and quantitative optical coherence tomography (OCT) analyses. Methods and Results: One-hundred and twenty-two initial ISR lesions (sirolimus-eluting stents: n=28; paclitaxel-eluting stents: n=51; BMS: n=43) were evaluated with OCT. Based on their OCT appearance, the lesions were classified as homogeneous, layered or heterogeneous. The optical properties of backscatter, attenuation and signal intensity of the neointimal tissue (NIT) were quantified. To evaluate the vascular response after balloon angioplasty (BA), the rate of reduction of the NIT area (NITA) was calculated (NITA before – after BA/NITA before BA at the minimum lumen cross-sectional area). Among the morphologic OCT patterns, the layered type was predominant with DES, whereas lesions were homogeneous with BMS (P<0.001). Backscatter and signal intensity were significantly higher with BMS (P<0.05 and P<0.001 respectively). The NITA reduction rate was significantly greater in the layered and heterogeneous groups than in the homogeneous group (P<0.01). Conclusions: The morphologic OCT patterns of the NIT in ISR differed significantly between DES and BMS, probably reflecting pathologic differences. Layered and heterogeneous tissues might respond better than homogeneous tissue to simple balloon dilatation, suggesting a possible direction for OCT-based ISR treatment strategies.  (Circ J 2013; 77: 652–660)

View full abstract

Background: Oscillatory breathing, alternating between hyperpnea and hypopnea, has been recognized in cardiac patients, especially in those with heart failure. We evaluated whether the cycle length and amplitude of oscillatory breathing correlate with impaired cardiopulmonary function during exercise. Methods and Results: We analyzed respiratory gas data during cardiopulmonary exercise testing (CPX) in 17 cardiac patients (68±12 years) who showed clear oscillatory ventilation during CPX. The cycle length (time from peak to peak) and the amplitude (difference between peak and nadir) for both oscillating ventilation (VE) and oscillating O₂ uptake (VO₂) were calculated from several consecutive oscillations noted at rest, and compared with indices of CPX. Oscillating VO₂ preceded oscillating VE in 16 of the 17 patients. Peak VO₂ (10.3±3.1mlmin^–1kg^–1) correlated significantly negatively with the cycle length of the VE oscillation (r=–0.60, P=0.010), and of the VO₂ oscillation (r=–0.61, P=0.008), and the difference in time between the peak of oscillating VE and the corresponding peak of VO₂ (r=–0.58, P=0.012). Similarly, the slope of the increase in VE to the increase in CO₂ output (45.6±11.5) correlated significantly positively with the cycle length of the VE and VO₂ oscillations (r=0.68, P=0.002; r=0.67, P=0.003, respectively). Conclusions: The cycle length of oscillatory breathing is closely related to impaired cardiac reserve during exercise in cardiac patients.  (Circ J 2013; 77: 661–666)

View full abstract

Background: The characteristics of the renal marker cystatin C (Cys-C) in association with the postoperative management of children with congenital heart disease (CHD) remain unclear. Methods and Results: Serum Cys-C and creatinine (Cr) levels were measured preoperatively and on the third postoperative day in 53 consecutive CHD patients (age, 1 day–11 years). On the third postoperative day, the patients were divided into 2 groups: the clinically severe group, requiring continuous infusion of diuretic drugs or peritoneal dialysis; and the non-severe group, composed of those without such needs. Preoperative Cys-C level decreased with age (by month) during the first year of life and remained almost constant thereafter, while Cr level increased with age. The Cys-C ratio (Cys-C level on the third postoperative day/preoperative level) was positively correlated with Cr ratio (R=0.57, P<0.001). Both Cys-C and Cr levels increased in correlation with the clinical severity of renal impairment. Receiver operating characteristic curve analysis failed to demonstrate an advantage of Cys-C over Cr in detecting severity. Conclusions: Cys-C may be a useful marker of renal function in terms of hemodynamic status in the postoperative management of CHD, although its superiority over Cr could not be confirmed. Future studies should clarify the role of Cys-C in clinical decision-making and evaluate the relationship of Cys-C with factors that may affect its levels.  (Circ J 2013; 77: 667–672)

View full abstract

Background: Although coronary vasospasm (CVS) would be one of the major causes of out-of-hospital cardiac arrest (OHCA), the characteristics of patients with cardiac arrest caused by CVS have not been clarified. Methods and Results: In study 1, 1,000 consecutive patients with OHCA were retrospectively categorized based on the cause of OHCA, and the prevalence of CVS OHCA was elucidated. In study 2, 138 consecutive CVS patients were divided into 2 groups: CVS with cardiac arrest (arrest-CVS, n=12) and CVS without cardiac arrest (non-arrest-CVS, n=126). In study 1, 589 patients had OHCA caused by cardiovascular disease and 121 patients were successfully resuscitated. Among the 121 resuscitated patients, 9 had CVS OHCA. In study 2, the incidence of cardiac events (ie, cardiac arrest or chest pain) occurring on vigorous exertion, in the daytime and without prodromal chest symptoms was higher in the arrest-CVS group than in the non-arrest-CVS group. Conclusions: CVS is an important cause of OHCA. Because significantly different characteristics are observed between CVS patients with cardiac arrest and those without, care should be taken to diagnose CVS as the cause of cardiac arrest.  (Circ J 2013; 77: 673–678)

View full abstract

Background: It is unclear whether weight change since young adulthood affects the risk of mortality due to cardiovascular disease (CVD). The aim of this study was to investigate weight change since age 20 in relation to the risk of CVD mortality. Methods and Results: A total of 41,364 eligible Japanese men and women aged 40–79 years participated in the Ohsaki Cohort Study baseline survey in 1994. Hazard ratios (HRs) and 95% confidence intervals (CIs) for CVD mortality were calculated according to weight change since age 20 (loss ≥10.0kg; loss 5.0−9.9kg; stable [±4.9 kg]; gain 5.0−9.9kg; gain ≥10.0kg). During 13.3 years of follow-up, 1,756 participants died of CVD. The association between weight change and CVD mortality was L-shaped in men and U-shaped in women; the multivariate HR (95% CI) for men with weight loss ≥10.0kg was 1.52 (1.25–1.85), and that for women with weight loss ≥10.0kg and weight gain ≥10.0kg was 1.62 (1.25–2.11) and 1.36 (1.09–1.69), respectively. Cross-classification analysis based on body mass index (BMI) at age 20 and weight change tended to be U-shaped, except for men whose BMI had been <25kg/m² at age 20, in which case it was L-shaped. Conclusions: Weight loss since young adulthood is associated with excess risk of mortality due to CVD in men, while a U-shaped relationship was observed for women.  (Circ J 2013; 77: 679–686)

View full abstract

Background: The relationship between acute kidney injury (AKI) in the acute phase of acute decompensated heart failure (ADHF) and patient outcome has not yet been reported. Methods and Results: Data for 625 patients with ADHF admitted to the intensive care unit were analyzed. No AKI occurred in 281 patients (no AKI) during the first 5 days. The AKI patients were assigned to 3 groups based on the timing: AKI present on admission and stable risk, injury, failure, loss, and endstage (RIFLE) class (stable early AKI; n=125), stepped-up RIFLE class (worsening early AKI; n=49), or AKI that occurred after admission (late AKI; n=170). The AKI patients were grouped into another 3 groups based on severity: class R (risk; n=214), class I (injury; n=73), or class F (failure; n=57). A multivariate logistic regression model found class I, class F, late AKI and worsening early AKI to be independently associated with in-hospital mortality. Kaplan-Meier survival curves showed that the survival rate in any-cause death during 2 years was significantly lower in class I, class F and the worsening early-AKI group, and there were significantly more HF events in class F and the worsening early-AKI group. There were significantly more class I and class F patients in the worsening early-AKI group. Conclusions: The presence of AKI on admission, worsening of AKI, and severe AKI (class I or class F) are associated with a poorer prognosis for ADHF patients.  (Circ J 2013; 77: 687–696)

View full abstract

Background: Left ventricular (LV) diastolic dysfunction may be a mechanism of left atrial (LA) electroanatomical remodeling in atrial fibrillation (AF). We evaluated the association between LV diastolic function and LA mechanical function in non-valvular paroxysmal AF (PAF). Methods and Results: In 286 patients with PAF (males 73%, 57±11 years), LA size, indexed LA volume, LV diastolic function, and LA appendage flow velocity (LAA-FV) in sinus rhythm were measured using transthoracic echocardiography, transesophageal echocardiography and cardiac computed tomography. The LA voltage map was obtained using NavX contact mapping. Patients with impaired LA mechanical function (LAA-FV <58cm/s, n=142) showed a higher E/Em ratio (10.3 vs. 9.2, P=0.034) and lower Em velocity (6.8 vs. 7.7cm/s, P=0.004) than those with preserved function (LAA-FV ≥58cm/s, n=144). The patient population displayed weak correlations of E/Em with LAA-FV (r=-0.19, P=0.003) and LA voltage (r=-0.23, P=0.004), but more significant association of E/Em and LAA-FV (r=-0.39, P<0.001) for age ≥55 years and LA diameter ≥40mm. E/Em was an independent predictor of LAA mechanical function (β=-0.20, P=0.013) even after age, sex, LA size and comorbidities were controlled for. Conclusions: In patients with non-valvular PAF, LA mechanical function is closely related to the degree of LA remodeling and LV diastolic function. Impaired LV diastolic function significantly contributes to LA electoanatomical remodeling in older patients with a larger LA.  (Circ J 2013; 77: 697–704)

View full abstract

Background: The clinical significance of nutritional risk assessment in patients with heart failure with preserved ejection fraction (HFpEF) remains undefined. Geriatric nutritional risk index (GNRI) is a simple nutritional assessment tool for elderly subjects. Its predictive value was evaluated in patients with HFpEF, a common HF phenotype in the elderly population. Methods and Results: The present study enrolled 152 consecutive patients (mean age, 77±11 years; male, 53.9%) who were hospitalized with HFpEF at the authors’ institution. GNRI on admission was calculated as follows: 14.89×serum albumin (g/dl)+41.7×body mass index/22. Characteristics and mortality (median follow-up of 2.1 years) were compared between 2 groups: low GNRI (<92) with moderate or severe nutritional risk; and high GNRI (≥92) with no or low nutritional risk. Patients in the low-GNRI group were more often female, and had lower serum hemoglobin and sodium, but higher serum blood urea nitrogen (BUN), C-reactive protein, and B-type natriuretic peptide (BNP) compared to those in the high-GNRI group (P<0.05, respectively). Physical activity at discharge measured by Barthel index was significantly lower in the low-GNRI group than the high-GNRI group (P<0.05). On Cox hazard analysis, lower GNRI predicted increased mortality independent of age, gender, prior HF hospitalization, and higher BUN and BNP (P<0.01). Conclusions: GNRI may be useful for predicting functional dependency and mortality in patients with HFpEF.  (Circ J 2013; 77: 705–711)

View full abstract

Background: Numerous reports have shown that both carotid artery ultrasound (carotid US) findings and ankle-brachial index (ABI) are associated with the prevalence of coronary artery disease. The relationship between carotid US findings and ABI and the complexity of coronary artery disease (as measured by SYNTAX [SX] score), was evaluated. Methods and Results: The subjects included 496 consecutive patients who underwent carotid US, ABI analysis and initial coronary angiography. The mean common carotid artery intima-media thickness (mean IMT) was evaluated on carotid US. Patients with mean IMT ≥0.9mm had significantly higher SX scores than patients without thickening (mean IMT <0.9mm; P<0.0001). Similarly, patients with low ABI (<0.9) had significantly higher SX scores than patients with ABI ≥0.9 (P<0.0001). When the patients were divided into 4 groups on the basis of mean IMT and ABI (group A, mean IMT <0.9mm, ABI ≥0.9; group B, mean IMT <0.9mm, low ABI; group C, mean IMT ≥0.9mm, ABI ≥0.9; group D, mean IMT ≥0.9mm, low ABI), the SX scores were significantly different. Among the patients in group D, 75% had coronary artery disease. Conclusions: Carotid US and ABI are associated with SX score. The combination of carotid US and ABI provides useful information for predicting the complexity and presence of coronary artery disease.  (Circ J 2013; 77: 712–716)

View full abstract

Background: In cardiovascular disease, numerous evidence-based prognostic models have been created, usually based on regression analyses of isolated patient datasets. They tend to focus on one outcome event, based on just one baseline evaluation of the patient, and fail to take the disease process in its dynamic nature into account. We present so-called microsimulation as an attractive alternative for clinical decision-making in individual patients. We aim to further familiarize clinicians with the concept of microsimulation and to inform them about the modeling process. Methods and Results: We describe the modeling process, advantages and disadvantages of microsimulation. We illustrate the concept using a hypothetical 60-year-old patient, with several cardiac risk factors, who is hospitalized for myocardial infarction. By using microsimulation, we calculate this patient’s probability of death. In our example, this particular patient’s estimated life expectancy turns out to be 8.9 years. While calculating this life expectancy, we were able to account for multiple outcome events and changing patient characteristics. Conclusions: Microsimulation takes into account the dynamic nature of coronary artery disease by estimating most likely outcomes regarding a broad range of clinical events. Moreover, microsimulation can be used to evaluate treatment effects by estimating the event-free life expectancy with and without treatment. Hence, microsimulation has several advantages compared to modeling techniques such as regression.  (Circ J 2013; 77: 717–724)

View full abstract

Background: Pregnancy-related acute myocardial infarction (AMI) is uncommon, but can result in maternal and/or fetal death. This study retrospectively reviews pregnancy-related AMI reported from medical institutions in Japan. Methods and Results: We electronically or manually searched the literature for reports of pregnancy-related AMI between 1981 and 2011. In total, 62 patients were described and the numbers increased in accordance with the rising average age of the mothers. AMI occurred frequently in women aged 30–34 years (mean age, 33), in the third trimester and postpartum (n=11 and n=28, respectively). The prevalence of conventional risk factors was relatively low (n=21). On the other hand, 29 patients had obstetric and/or non-obstetric complications, and 24 received medication. Only 8 AMI were caused by atherosclerosis, while coronary dissection, thrombus and spasm were the cause in 14, 9 and 12 cases, respectively. All patients with atherosclerosis had conventional risk factors, and some patients with spasm had a history of smoking. Medication with ergot derivatives was associated mostly with spasm, whereas ritodrine was potentially related to dissection. Conclusions: The prevalence of pregnancy-related AMI in Japan seems lower than in Western countries, and the etiology differs considerably. However, as the trend of later childbearing continues, more pregnant women have more risk factors, complications, and require medication. Cardiologists and obstetricians must consider the increased risk of AMI.  (Circ J 2013; 77: 725–733)

View full abstract

Background: We investigated the sex-dependent associations of testosterone and sex hormone-binding globulin (SHBG) levels with metabolic syndrome (MetS). Methods and Results: We conducted a cross-sectional study of 9,424 community-dwelling adults aged 45–74 years (median age, 63.7 years). MetS was defined according to the updated version of the National Cholesterol Education Program Adult Treatment Panel III criteria. Serum total testosterone (TT) and SHBG levels were determined using a chemiluminescent microparticle immunoassay, and free testosterone (FT) concentrations were calculated. In a multivariate analysis, TT levels were inversely associated with MetS in men (odds ratio [OR] of each standard deviation increase in the logarithmic value, 0.70; 95% confidence interval [CI], 0.65–0.76), whereas they were positively associated in women (OR, 1.17; 95% CI, 1.10–1.24). FT levels were positively associated with MetS in women only (OR, 1.39; 95% CI, 1.30–1.49). However, SHBG levels were negatively associated with MetS in both men (OR, 0.57; 95% CI, 0.52–0.61) and women (OR, 0.61; 95% CI, 0.57–0.66). Conclusions: Our data showed that higher TT levels were associated with a reduced prevalence of MetS in men and an elevated prevalence of MetS in women. Higher SHBG levels were associated with decreased prevalence of MetS in both sexes. These results suggest sex differences in the associations of endogenous testosterone and SHBG with MetS.  (Circ J 2013; 77: 734–740)

View full abstract

Background: Left ventricular (LV) hypertrophy is often present in patients with diastolic heart failure. However, stiffness of hypertrophied cardiomyocytes in the transverse direction has not been fully elucidated. The aim of this study was to assess passive cardiomyocyte stiffness of hypertrophied hearts in the transverse direction and the influence of actin-myosin cross-bridge formation on the stiffness. Methods and Results: Wistar rats received a vehicle (control) or isoproterenol (ISO) subcutaneously. After 7 days, compared with the controls, ISO administration had significantly increased heart weight and LV wall thickness and had decreased peak early annular relaxation velocity (e’) assessed by echocardiography. Elastic modulus of living cardiomyocytes in the transverse direction assessed by an atomic force microscope was significantly higher in the ISO group than in controls. We added butanedione monoxime (BDM), an inhibitor of actin-myosin interaction, and blebbistatin, a specific myosin II inhibitor, to the medium. BDM and blebbistatin significantly reduced the elastic modulus of cardiomyocytes in the ISO group. X-ray diffraction analysis showed that the reflection intensity ratio (I_(1,0)/I_(1,1)) at diastole was not different before and after treatment with BDM, which induces complete relaxation, in control hearts, but that I_(1,0)/I_(1,1) was significantly increased after BDM treatment in the ISO group, indicating residual cross-bridge formation in hypertrophied hearts. Conclusions: Passive cardiomyocyte stiffness in the transverse direction is increased in hearts with ISO-induced hypertrophy and this is caused by residual actin-myosin cross-bridge formation.  (Circ J 2013; 77: 741–748)

View full abstract

Background: Although adult congenital heart disease (ACHD) patients encounter unique challenges related to social adaptation and mental health, only minimal research has been conducted on this functioning in Japanese ACHD patients. The aims of this study were to describe aspects of the psychosocial functioning of ACHD patients and to determine the psychosocial factors influencing their mental health. Methods and Results: Seventy-two ACHD patients (aged 18–39 years) and 86 control participants (aged 18–39 years) completed the 36-item Short Form Health Survey, a measure of mental health, and 4 self-report questionnaires measuring aspects of psychosocial functioning: Independent-Consciousness, Problem-solving, Locus of Control, and Self-esteem. Compared to the control group, ACHD patients had significantly lower scores for Independence, Problem-solving, and Self-esteem; whereas they had higher scores for Dependence on Parents. To examine the psychosocial factors influencing mental health, a structural equation model was used. The psychosocial factor Problem-solving was found to have the most direct influence on mental health. This factor was associated with Independence and Self-esteem. Conclusions: ACHD patients in Japan have psychosocial difficulties, and the psychosocial factors influencing patients’ mental health are social problem-solving, independence, and self-esteem. The patients have poorer abilities than the control group in all of these areas and hence, they run the risk of developing poor mental health.  (Circ J 2013; 77: 749–755)

View full abstract

Background: The development of right ventricular (RV) dysfunction in pulmonary hypertension (PH) patients is associated with adverse outcome, so that the assessment of RV function has become increasingly important in the management of such patients. The present objective was to test the hypothesis that RV free-wall longitudinal speckle-tracking strain (RV-free), an independent echocardiographic predictor of hemodynamic RV performance, can predict long-term outcome. Methods and Results: Forty-two PH patients were studied. RV-free was calculated by averaging the 3 regional peak systolic strains for the RV free wall. For comparison, tricuspid annular plane systolic excursion (TAPSE), RV fractional area change, RV index of myocardial performance, and tissue Doppler-derived tricuspid lateral annular systolic velocity were also studied. Long-term follow-up was performed for 4 years after adding PH-specific drugs. Receiver operating characteristic curve analysis identified RV-free ≤19.4% as the best predictor of cardiovascular events with 90% sensitivity, 69% specificity, and area under the curve of 0.819 (P=0.0001). Furthermore, the Kaplan-Meier curve indicated that patients with RV-free >19.4% experienced fewer cardiovascular events than those with RV-free ≤19.4% (log-rank P=0.0008). Importantly, the co-occurrence of RV-free ≤19.4% and TAPSE <16mm was associated with the highest frequency of cardiovascular events. Conclusions: RV-free may serve as a non-invasive predictor of cardiovascular events for PH patients. Combining RV-free with TAPSE may be more effective for predicting long-term cardiovascular events.  (Circ J 2013; 77: 756–763)

View full abstract

Background: Endothelial progenitor cells (EPCs) have a role in the repair of endothelial surfaces after injury. Reduced numbers of EPCs are related to endothelial dysfunction and adverse clinical events, suggesting that endothelial injury in the absence of sufficient repair by circulating EPCs promotes the progression of vascular disease or valvular disorder. The aim of the present study was to assess the number and role of EPCs in patients with aortic valve regurgitation (AR). Methods and Results: We assessed the number of EPCs and apoptotic EPCs in 31 patients with significant AR and compared them with 30 patients who had similar risk factors and no valvular disease. The numbers of EPCs and apoptotic EPCs were assessed by flow cytometry. The 2 groups had similar clinical characteristics. Patients with AR had fewer circulating EPCs and late apoptotic EPCs as compared with the control group (0.054±0.03% vs. 0.079±0.06%, P=0.039 and 0% (0–3.4%) vs. 5% (0–14%), P=0.03, respectively). In patients with AR, circulating EPCs correlated negatively with septal thickness (r=-0.47, P=0.01), whereas late apoptotic EPCs had a negative correlation with left ventricular end-systolic diameter (r=–0.57, P=0.01). Conclusions: Patients with AR have fewer EPCs and late apoptotic EPCs. These data suggest an impaired valvular endothelial cell regenerative process in patients with AR.  (Circ J 2013; 77: 764–771)

View full abstract

Background: The proliferation and migration of vascular endothelial cells (VECs) plays a vital role in angiogenesis, a process that influences plaque vulnerability in human atherosclerosis. Luteolin is a type of flavonoid that has shown a positive effect on the morbidity and mortality of cardiovascular diseases. However, it remains unclear whether this compound has a protective effect against the proliferation and migration of human umbilical vein endothelial cells (HUVECs) induced by angiotensin II (AngII). Methods and Results: HUVECs were treated with different concentrations of luteolin for varying lengths of time. Analysis using methyl thiazolyl tetrazolium and 5-ethynyl-2’-deoxyuridine revealed that 25μmol/L luteolin had a particularly inhibitory effect on the AngII-induced proliferation of HUVECs. A Transwell chamber was then used to assay the migration of HUVECs in the presence of 12.5μmol/L luteolin. The results showed that the migration of AngII-induced HUVECs was also inhibited by luteolin. Further investigations showed that the phosphorylation levels of Src, p-Akt (308), and p-Akt (473) in the group treated with both luteolin and AngII were significantly lower than those of the group treated with only AngII. Conclusions: The inhibitory effects of luteolin on the proliferation and migration of VECs stimulated by AngII are mediated through the downregulation of the PI3K/Akt signaling pathway.  (Circ J 2013; 77: 772–779)

View full abstract

Background: Vascular dysfunction is a surrogate marker of early-stage atherosclerosis. Serum leukocyte count is a non-traditional risk factor of cardiovascular (CV) disease and has predictive value for CV outcome. The aim of this study was to investigate the relationship between leukocyte count and peripheral vascular dysfunction. Methods and Results: In this cross-sectional study, 357 individuals without known CV disease and with low Framingham risk (10-year hard coronary heart disease risk <10%) were identified. Vascular function was measured by assessing reactive hyperemia-induced vasodilation (reactive hyperemia index, RHI). In 105 individuals with vascular dysfunction (29.4%), the median leukocyte count was significantly higher than in those with normal RHI (6.4×10⁹/L vs. 6.0×10⁹/L; P=0.04). The neutrophil count was the strongest predictor of impaired vascular function among leukocyte subtypes (odds ratio [OR], 2.70; 95% confidence interval [CI]: 1.58–4.60, P<0.001). In a multivariate logistic regression model, the highest quintile of neutrophil count (OR, 2.36; 95% CI: 1.35–4.12; P=0.003), body mass index (OR, 1.05; 95% CI: 1.01–1.09; P=0.009) and systolic blood pressure (OR, 0.97; 95% CI: 0.97–0.99; P<0.001) were independently predictive for vascular dysfunction. Conclusions: The highest quintile of leukocyte count is independently associated with vascular dysfunction in individuals with low CV risk. This suggests that subclinical inflammation affects vascular function. Leukocyte count may be useful for personalized risk stratification.  (Circ J 2013; 77: 780–785)

View full abstract