Prostaglandin E2 (PGE₂) is produced in inflammatory responses and regulates a variety of immunological reactions through 4 different receptor subtypes; EP1, 2, 3 and 4. However, the precise role of each receptor in cardiovascular disease has not yet been elucidated. Enhanced expression of some EPs has been observed in clinical and experimental cardiovascular diseases. EP agonists have been developed to clarify the role of each receptor. Recently, we developed a novel selective agonist to examine the effects of EP4 on cardiac transplantation, myocardial ischemia, and myocarditis. Of note, a selective EP4 agonist attenuated inflammatory cytokines and chemokines via attenuation of macrophage activation in inflammatory heart diseases. In this review article, we discuss the effects of PGE₂ receptor agonists on the development of cardiovascular diseases.

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Percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) increases forward blood flow, possibly resulting in an increase in lumen diameter. We investigated the determinants of luminal gain at the distal reference segment following PCI for CTO. Forty-eight consecutive patients who underwent PCI for CTO were included in this study. Clinical and angiographic data were obtained at baseline and follow-up (mean follow-up period: 251 ± 73.6 days). Overall, the reference lumen diameter was 2.53 ± 0.38 mm at post-procedure and 2.38 ± 0.84 mm at follow-up. The distal reference lumen diameter (segment 5 mm distal to the stent) was larger at follow-up than at post-procedure (1.64 ± 0.64 and 1.38 ± 0.51 mm, respectively, P < 0.05). Luminal gain (LG), in the distal reference segment, defined as an increase in lumen diameter from post-procedure to follow-up, was observed in 33 of 48 patients (69%). Univariate and multivariate logistic regression analyses were performed to identify the clinical and angiographic predictors of LG. Minimum lumen diameter and left ventricular ejection fraction at baseline were both significant predictors of LG in univariate and multivariate logistic regression analyses. Luminal gain was observed at the distal reference segment following PCI for CTO. Left ventricular ejection fraction may have an impact on the lumen diameter distal to lesions responsible for CTO.

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Coronary microvessels play a direct and critical role in determining the extent and severity of myocardial ischemia and cardiac function. However, because direct observation has never been performed in vivo, the functional properties of the individual microvesssels in patients with coronary artery disease remain unknown.
Subendocardial coronary microvessels were observed by cardioscopy in 149 successive patients with coronary artery disease (81 with stable angina and 68 with old myocardial infarction).
Twenty-four arterial microvessels (AMs) and 27 venous microvessels (VMs) were observed in the left ventricular subendocardium. All 12 AMs and 13 of 14 VMs that were located in normokinetic-to-hypokinetic left ventricular wall segments were filled with blood during diastole and were collapsed during systole. In contrast, 8 of 12 AMs and 9 of 13 VMs that were located in akinetic-to-dyskinetic wall segments were filled with blood during systole and were collapsed during diastole. There were no significant correlations between the timing of blood filling and the severity of coronary stenosis and collateral development.
In patients with coronary artery disease, the timing of blood filling of AMs and VMs was dependent on the regional left ventricular contractile state; during diastole when contraction was preserved and during systole when it was not. It remains to be elucidated whether and how blood filling is disturbed in other categories of heart disease.

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This study tested whether the plasma level of total homocysteine (tHcy) was predictive of obstructive coronary artery disease (CAD) and clinical outcome in patients undergoing coronary angiographic (CAG) study. From September 2002 to October 2004, 1,305 consecutive patients with angina pectoris undergoing CAG study were consecutively enrolled. Blood samples were prospectively collected to assess the plasma level of tHcy from each patient before catheterization. Of these 1305 patients, 676 (51.8%) had multivessel disease (group 1), 367 (28.1%) had single-vessel disease (group 2), and 262 (20.1%) had normal coronary artery or insignificant coronary artery disease (group 3). The plasma level of tHcy was notably higher in group 1 than in groups 2 and 3 (11.6 ± 4.4 versus 10.9 ± 4.0 versus 10.4 ± 3.8, P < 0.001). Univariate binary logistic regression analysis demonstrated that the plasma tHcy level was strongly associated with multiple-vessel disease (MVD) (defined as ≥ 2 vessel disease) (P < 0.001). Multivariate binary logistic regression analysis showed that tHcy level, fasting blood sugar, diabetes mellitus, and age were significantly and independently predictive of MVD (all P < 0.03). Univariate Cox regression analysis demonstrated that tHcy level was predictive of long-term mortality (P = 0.042). However, the tHcy level was not an independent predictor of long-term mortality on multivariate Cox regression analysis (P > 0.05). The results of our study support the hypothesis that tHcy level is an independent predictor of MVD in patients with chest pain undergoing CAG study. Conversely, our study did not support the tHcy level as an independent predictor of long-term mortality in this clinical setting.

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Ventricular tachycardia (VT) and ventricular fibrillation (VF) leading to sudden cardiac death remains responsible for significant mortality in patients with prior myocardial infarction (MI). The study population consisted of 50 normal controls and 50 patients with prior MI. The MI subjects were divided into 3 groups: VT/VF (-) group; 25 patients without ventricular tachyarrhythmia, VT group; 13 patients with sustained VT, and VF group; 12 patients with resuscitated VF. The parameters on the signal-averaged ECG and the frequency components recorded from the wavelet-transformed ECG were compared. The high-frequency components (HFC; 80-150 Hz) were developed in the MI group to a greater extent than those in the control group. Among the MI patients, the HFC were more developed in the VT and VF groups than in the VT/VF (-) group. In the VF group, the positive rate of LP was 50%. Meanwhile, when the peak power value at 150 Hz > 300 was defined as abnormal, the HFC was detected in 13 (100%) patients in the VT group and 12 (91.7%) in the VF group. The sensitivity of the abnormal HFC in identifying patients with VT/VF was higher than that of SAECG (96% versus 72%), although the specificity remained similar (68.5% versus 64.3%). Abnormal HFC recorded from the wavelet-transformed ECG may be a novel factor in detecting patients who are prone to VT/VF.

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The right ventricular outflow tract (RVOT) is considered the arrhythmogenic region that gives rise to Brugada syndrome. To obtain a better understanding of this substrate, we performed electroanatomic mapping of the right ventricle (RV) in patients with Brugada syndrome.
The RV was mapped electroanatomically with the CARTO system in 11 patients with asymptomatic Brugada syndrome but in whom ventricular fibrillation was induced by programmed ventricular stimulation, and in 5 control patients. The low voltage zone area (< 1.5 mV) was larger (16.1% versus 7.8%, P < 0.01) and the bipolar electrogram duration was greater (81.6 ± 7.8 ms versus 53.4 ± 5.6 ms, P < 0.01) in the patients with Brugada syndrome versus the control patients; the bipolar electrogram duration was greater in the septal portion and free wall of the RVOT.
Our data suggest that regional endocardial conduction slowing based on structural abnormalities exists at the RVOT in Brugada syndrome.

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Many genes change their transcription in atrial fibrillation (AF) patients, which indicates the functional relationship of these genes with AF. Thus, identifying the over-represented motifs in the upstream region of these genes would shed light on the mechanism of this disease. We analyzed a set of microarray experiments, selected from genes whose expression was changed, and extracted their regulatory sequences from genome databases. In addition, we used a motif discovery algorithm to obtain frequent DNA motifs in these sequences. Representative motifs were selected and matched to known transcription factor binding sites by clustering analysis, and 3 putative motifs related to AF were finally identified.

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Proinflammatory cytokine responses might occur in elderly individuals with cardiovascular (CV) disease, cerebro-vascular (CVA) disease, and/or pulmonary disease (PD). Spiritual activation is an important coping mechanism, since psychiatric depression is an important risk factor for these individuals.
Thirty-three very elderly individuals (87 ± 8 years) with previous CVD, CVA and/or PD participated in weekly 30 minute sermons by chaplains for over 20 months of chaplain liturgy (CL group). All underwent Holter ECG during the procedures and cardiac autonomic activities were assessed by maximum entropy analysis. Plasma IL-10 and IL-6 levels were compared with 26 age-matched (85 ± 10 years) individuals who did not participate in these activities (non-CL group). Both high frequency (HF) and pNN50 of heart rate variability (HRV) were higher in the CL group than in the non-CL group (HF, 190 ± 55 versus 92 ± 43 nu, P < 0.05; pNN50, 10.5 ± 16% versus 3.6 ± 3.8%, P < 0.05), whereas LF/HF was lower (1.4 ± 1.5 versus 2.2 ± 2.8, P < 0.05). Levels of IL-10/IL-6 were higher in the CL group (3.96 ± 5.0 versus 1.79 ± 1.6, P < 0.05). Hospitalization rates due to CVD and/or PD were lower in the CL group than in the non-CL group (4/33 versus 11/26, P < 0.05).
We conclude that spiritual activation can modify proinflammatory cytokines and suppress CVD, CVA and/or PD via vagal modifications. Spiritual activation might be helpful for health in these very elderly individuals.

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In order to begin searching for new markers for safe exercise training in patients with cardiac diseases, we tested the sensitivity and reliability of the short-term variability of repolarization (STV_QT) in comparison with QT interval, QTc, and T_peak-T_end interval (T_p-e) in patients with cardiac diseases.
Nine patients (8 men, 1 woman; 58 ± 10 years) were enrolled. The cardiac rehabilitation (CR) program consisted of walking, bicycling on an ergometer, and calisthenics for 30-50 minutes/session and 3-5 sessions/week for 3 months. ECGs of 31 consecutive sinus beats were obtained before and after the CR program. RR and QT intervals were measured in the aVL lead. The mean orthogonal distance from the diagonal to the points of the Poincaré plots was determined using the following equation; STV_QT [= Σ |QT_n+1-QT_n/(30 × 2^1/2)], as a marker of temporal dispersion of repolarization. Also, T_p-e of 5 consecutive beats was measured as a marker of spatial dispersion.
No fatal arrhythmias were observed in the CR. No significant difference was observed in the RR or QT interval between at baseline and at the end of the CR program. Meanwhile, QTc, STV_QT and T_p-e decreased significantly from 429 ± 27 to 400 ± 17 (P < 0.01), from 6.8 ± 1.3 to 4.7 ± 1.4 msec (P < 0.001), and from 74.8 (61.2/79.1) to 64.8 (51.4/70.7) msec (median (25th/75th percentile), P < 0.01), respectively.
STV_QT together with T_p-e and QTc may reflect the time-courses of safe exercise training.

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Fabry disease is an X-linked lysosomal storage disorder caused by mutations of the α-galactosidase A gene (GLA), and the disease is a relatively prevalent cause of left ventricular hypertrophy mimicking idiopathic hypertrophic cardiomyopathy. We assessed clinically 5 patients of a three-generation family and also searched for GLA mutations in 10 family members. The proband had left ventricular hypertrophy with localized thinning in the basal posterior wall and late gadolinium enhancement (LGE) in the near-circumferential wall in cardiovascular magnetic resonance images and her sister had vasospastic angina pectoris without organic stenosis of the coronary arteries. LGE notably appeared in parallel with decreased α-galactosidase A activity and increased NT-pro BNP in our patients. We detected a new GLA missense mutation (G195V) in exon 4, resulting in a glycine-to-valine substitution. Of the 10 family members, 5 family members each were positive and negative for this mutation. These new data extend our clinical and molecular knowledge of GLA gene mutations and confirm that a novel missense mutation in the GLA gene is important not only for a precise diagnosis of heterozygous status, but also for confirming relatives who are negative for this mutation.

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Inappropriate myocardial protection is considered one of the main causes of mortality and morbidity in the correction of tetralogy of Fallot (TOF). Results of previous reports about the effects of ischemic postconditioning on myocardial protection in animals and humans are very encouraging. This randomized and controlled trial aimed to assess the effect of ischemic postconditioning on protection against myocardial ischemia reperfusion injury in TOF patients receiving cardioplegia.
From January 2008 to June 2010, 80 consecutive children undergoing correction of TOF were enrolled and randomly assigned to either a postconditioning group (three cycles of 30 seconds of ischemia and 30 seconds of reperfusion using re-clamping and de-clamping starting 30 seconds after the initial de-clamping of the aorta, n = 41) or a control group (n = 39). Cardiac troponin I (cTnI) was assayed preoperatively, and then 4 hours, 8 hours, 12 hours, 20 hours, and 48 hours after persistent reperfusion. The pre-, intra- and postoperative relevant data of all selected patients were analyzed. As a result, ischemic postconditioning reduced postoperative peak release by 45% for cTnI compared with the control group (0.43 ± 0.18 ng/mL versus 0.78 ± 0.15 ng/mL, P < 0.0001). Ischemic postconditioned patients had a lower peak inotropic score during the first postoperative 24 hours (5.6 ± 2.2 μg/kg/minute versus 8.6 ± 3.6 μg/kg/minute, P < 0.0001), extubation time (21.5 ± 7.3 hours versus 30.2 ± 12.4 hours, P = 0.0002) and length of ICU stay (43.4 ± 12.6 hours versus 56.3 ± 17.8 hours, P = 0.0003), while they had a higher cardiac output on the first postoperative day (1.41 ± 0.26 L/minute versus 1.28 ± 0.25 L/minute, P = 0.0255) as compared to the control group.
In conclusion, ischemic postconditioning may to some extent provide myocardial protection in children undergoing correction of tetralogy of Fallot.

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Increased action potential duration (APD) induces early afterdepolarization (EAD) in vitro and torsade de pointes in vivo, and ATP-sensitive K⁺ channel openers decrease APD in cardiac tissue. We tested whether the ATP-sensitive K⁺ channel opener nicorandil has antiarrhythmic effects on class III antiarrhythmic drug-induced ventricular arrhythmia. In 10 anesthetized dogs with chronic atrioventricular block, we recorded monophasic action potentials (MAPs) from the left and right ventricular (LV and RV) endocardium. The class III antiarrhythmic drug nifekalant (1 mg/kg, IV) was administered at 5 minute intervals (total doses; 2-6 mg/kg) until the appearance of EADs, premature ventricular contractions (PVCs), or polymorphic ventricular tachycardias (PVTs). Five minutes after the end of nifekalant administration, nicorandil (1.0 mg/kg) was administered over 5 minutes. Nifekalant decreased the ventricular escape rate from 75 ± 5 beats/minute to 45 ± 10 beats/minute and increased RV-MAP duration (MAPD) from 217 ± 32 msec to 308 ± 2 msec (P < 0.01) and LV-MAPD from 232 ± 32 msec to 353 ± 82 msec (P < 0.01). EADs were recorded in 9 dogs, frequent premature ventricular contractions (PVCs) developed in 10 dogs, incessant PVTs developed in 3 dogs, and monomorphic ventricular tachycardia developed in 3 dogs after nifekalant administration. Nicorandil decreased RV-MAPD to 267 ± 57 msec and LV-MAPD to 279 ± 44 msec. It suppressed EADs, decreased the incidence of PVCs, and abolished PVT. Nicorandil may be clinically useful for treatment of PVCs and PVTs accompanying acquired long QT syndrome.

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A 49-year-old woman suffering from rapidly progressing right-sided heart failure assessed as World Health Organization functional class (WHO-FC) IV is described. After treatment with oxygen and diuretics, she was in WHO-FC III on admission to our hospital, as confirmed by her poor exercise tolerance in cardiopulmonary exercise testing. Upon detailed examination, she was diagnosed as having idiopathic pulmonary arterial hypertension (IPAH). Right heart catheterization (RHC) revealed severe pulmonary hypertension (mPAP = 65 mmHg) with a markedly decreased cardiac index (CI = 1.0 L/minute/m²), and an acute vasoreactivity test with nitric oxide inhalation did not show any response. Due to her severe condition, we decided to attempt oral combination therapy consisting of bosentan, tadalafil, and beraprost, prescribed in the same order and titrated up to their maximum respective doses, instead of intravenous (IV) epoprostenol therapy. Her clinical symptoms improved day by day, and the hemodynamic parameters recovered to nearly normal ranges about 6 months after initiation of the combination therapy. Initial/programmed oral combination therapy for severe IPAH patients is not yet fully established, and there is less evidence concerning its efficacy than IV epoprostenol therapy. However, it has tremendous advantages for PAH patients when they respond well. It is very important to further identify what types of PAH patients will respond to this oral combination therapy and should be treated with it as the first-line therapy.

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Interrupted inferior vena cava (IVC) with azygos continuation is a rare congenital anomaly, and is frequently associated with other cardiovascular malformations and situs anomalies, such as left isomerism. These patients usually develop deep vein thrombosis (DVT), and asymptomatic patients above 60 years of age are very rare. Here we report a case of interrupted IVC which we diagnosed in a 72-year-old woman. She was admitted to our hospital suffering from heart failure and supraventricular tachycardia. Echocardiography detected secundum atrial septal defect (ASD). An abnormal paravertebral pleural line on the chest X-rays indicated the existence of venous anomaly. Anatomical images obtained by Multidetector Computed Tomography (MDCT) helped us to successfully perform right heart catheterization procedures through azygos continuation including blood sampling from pulmonary veins. Even in elderly patients, a careful examination of chest X-rays can indicate undiagnosed venous anomalies; thus, it is critically important before planning surgical or interventional procedures.

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