Calcium channel blockers (CCB) and statins are frequently prescribed for patients with coronary artery disease (CAD) complicated by hypertension and/or hypercholesterolemia. CCB have pleiotropic actions beyond their blood pressure-lowering effect, while statins have pleiotropic actions beyond their cholesterol-lowering effect. We assessed the hypothesis that combined treatment with CCB and statins has additional prognostic benefits resulting from potential additive or synergistic pleiotropic actions of both classes of drugs in the Japanese CAD (JCAD) study population. The JCAD study consisted of 13,812 patients with angiographically demonstrable significant coronary narrowing in at least 1 of 3 major coronary arteries who were followed-up for a mean of 2.7 years (follow-up rate, 88.4%). The primary endpoint of the present study was all cardiovascular events. We compared the event rate between patients receiving neither CCB nor statins and those receiving each drug alone or as a combination treatment using propensity score matching analysis. The rate of all events was 62.8 per 1,000 patient-years in the JCAD study. Kaplan-Meier analysis with the log-rank test showed no statistically significant difference in the event rate in each comparison. In conclusion, there may be no additional prognostic benefit beyond the blood-pressure-lowering and cholesterol-lowering effects in the combined treatment with CCB and statins for angiographically documented CAD patients.

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Despite wide interindividual variability in response to clopidogrel, platelet P2Y₁₂ ADP receptor inhibition in Japanese patients has not been fully studied using specific methodology. This study compared platelet P2Y₁₂ ADP receptor inhibition during treatment with clopidogrel versus clopidogrel plus cilostazol in patients undergoing coronary stenting.
Forty-two patients in whom platelet function was measured within 2 months after coronary stenting were enrolled. All patients were treated with aspirin 100 or 200 mg/day, and were divided into a dual therapy group (aspirin plus clopidogrel 75 mg/day; n = 34) and a triple therapy group (aspirin plus clopidogrel 75 mg/day plus cilostazol 200 mg/day; n = 8). Vasodilator-stimulated phosphoprotein (VASP) phosphorylation analysis and 5 and 20 μmol/L-induced maximal platelet aggregation were assessed.
No differences were found in baseline characteristics except for a higher incidence of diabetes mellitus (DM) in the triple therapy group. Although there were no differences in platelet aggregation between the 2 groups, VASP index was significantly lower in the triple therapy group than in the dual therapy group (23.1 ± 15.3% versus 51.2 ± 19.9%; P = 0.001). The rate of low responsiveness to clopidogrel, defined by VASP index > 50%, was lower in the triple therapy group than in the dual therapy group (12.5% versus 55.9%; P = 0.047). Similarly, in DM patients the triple therapy group had a lower VASP index compared with the dual therapy group (23.1 ± 15.3% versus 47.0 ± 23.5%; P = 0.015).
Clopidogrel plus cilostazol is more effective in inhibiting the platelet P2Y₁₂ ADP receptor pathway than clopidogrel alone. This may be useful for reducing clopidogrel resistance in Japanese patients.

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This study was carried out to image subendocardial myocardial blood flow (SMBF) by dye-staining cardioscopy (DSC) in patients with coronary artery disease.
In patients with epicardial coronary artery disease, SMBF plays a direct and critical role in determining the extent and severity of cardiac function and symptoms. If SMBF could be clinically imaged instantaneously, the effects of medical and interventional treatment on it can be directly evaluated. However, there are no clinically available methods for direct and real-time imaging of SMBF.
Twenty-three patients [6 with chest pain syndrome (CPS); 3 with vasospastic angina pectoris (VSA); 9 with angina pectoris due to organic coronary stenosis (AP); 5 with old myocardial infarction OMI)] underwent DSC of the left ventricle by selective intracoronary injection of 1 mL of 2.5% Evans blue dye solution (EB). Five patients with acute myocardial infarction (AMI) underwent DSC before and after coronary stent deployment.
The endocardial surface was stained diffusely blue with EB indicating normal blood flow in patients with CPS; stained in a patchy fashion indicating patchy blood flow in patients with VSA; and stained in a patchy fashion or not stained indicating patchy or no blood flow in those with AP and OMI. Myocardial staining with EB was observed after coronary stent deployment in all patients with AMI, indicating restoration of the SMBF.
It is evident that SMBF could be imaged by DSC. This imaging modality is useful for the evaluation of therapies and accurate guidance of transendocardial therapies of the ischemic myocardium.

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A recent study showed that statins reduce cardiovascular events in stable coronary artery disease patients with chronic kidney disease (CKD). However, it remains unclear whether acute coronary syndrome (ACS) patients with CKD benefit from statins. A total of 501 patients with ACS who underwent successful percutaneous coronary intervention were investigated and CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/minute/1.73 m² at discharge. Three hundred and twenty-four of 501 patients (64.7%) had CKD and 173 patients (34.5%) received statins. The patients with CKD were older and had higher blood pressure than those without CKD. With a mean follow-up of 5.2 years, irrespective of treatment assignment, 74 patients with CKD experienced cardiac events (22.8%) in comparison to 25 without CKD (14.1%, HR 1.81; 95% CI 1.15-2.84, P = 0.0095). Cardiac events occurred in only 18 of the patients with CKD treated with statins (16.2%) and in 56 of those treated with CKD without statins (26.3%, HR 0.58; 95% CI 0.34-0.98, P = 0.039), whereas, no significant reduction of the events was observed in the patients without CKD treated with statins versus without having statins (P = 0.130). These data indicate that statin therapy reduces cardiac events in ACS patients with CKD.

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This study compared the prognosis of ST-elevation myocardial infarction (STEMI) in patients with multivessel disease (MVD) with that of single vessel disease (SVD) and investigated the revascularization benefit of noninfarct-related artery (IRA) in MVD patients undergoing primary percutaneous coronary intervention (PCI). Between 2002 and 2009, 1278 patients with STEMI underwent primary PCI. Of these patients, 717 (56.1%) with SVD (only IRA obstruction) were placed in group A, while 561 (43.9%) with MVD (Group B) were further categorized into group 1 (PCI for IRA) and group 2 (staged PCI for IRA+non-IRA). The results demonstrated a lower degree of successful reperfusion in IRA and higher 30-day and 1-year cumulative mortality rates in group B (P < 0.001). While there was no difference in successful reperfusion in IRA between group 1 and group 2, the 30-day and one-year cumulative mortality rates were higher in group 1. Multivariate analysis identified MVD as an independent predictor of 1-year mortality (P < 0.001). In conclusion, patients with subsequent PCI for MVD had better 30-day and 1-year outcomes than those with conservative treatment.

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The prognostic value of integrated R-wave voltages of precordial leads (V₁-V₆) in patients with acute anterior wall ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) was investigated.
Between July 2006 and October 2009, 292 patients with anterior wall STEMI with presentation < 12 hours underwent primary PCI. Thirty-four patients with electrocardiographic presentation of either complete right bundle branch block (BBB) or complete left BBB were categorized into group A, while the remaining 258 patients without BBB served as group B that was further subdivided into those with lower R-wave voltage (summation of V₁-V₆ ≤ 1.7 mV) (group 1) and higher voltage (> 1.7 mV) (group 2) according to the ROC curve (sensitivity = 66.3%, specificity = 66%, P < 0.0001).
While the procedural success rate was similar between groups A and B and groups 1 and 2, 30-day mortality was higher in group A than B (P ≤ 0.0001). Additionally, left ventricular ejection fraction (LVEF) was lower, whereas peak level of creatine phosphopkinase (CPK), incidence of advanced congestive heart failure, and 30-day mortality were higher in group 1 than 2 (P < 0.01). Multivariate analysis revealed that lower R-wave voltage, multivessel disease, leukocyte count, peak CPK, and creatinine level were predictive of 30-day unfavorable clinical outcomes (all P < 0.01). R-wave voltage in precordial leads was a significant independent predictor of 30-day prognostic outcome in patients with anterior wall STEMI undergoing primary PCI.

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We examined the relationship between the efficacy of combined treatment with antiarrhythmic drugs (AAD) plus enalapril for maintaining sinus rhythm and circadian variation in the onset of paroxysmal AF.
Three hundred and forty-four patients with paroxysmal AF (239 men, mean age, 69 ± 11 years) who could be followed up ≥ 12 months were divided into 3 groups on the basis of circadian variation in the onset of AF: a diurnal group (7:00 AM-5:00 PM, n = 57), a nocturnal group (5:00 PM-7:00 AM, n = 108), and a mixed group (onset during both periods, n = 169). The maintenance rate of sinus rhythm during the follow-up period was compared between combined therapy (AAD plus enalapril) and AAD alone.
In the diurnal group, the maintenance rates of sinus rhythm at 12, 36, 60, and 90 months were 100%, 100%, 100%, and 100%, respectively, for patients treated with AAD plus enalapril (n = 22) versus 97%, 91%, 89%, and 80% for patients treated with AAD alone (n = 35, P < 0.05). In the nocturnal group, the maintenance rates of sinus rhythm at 12, 36, 60, and 90 months were 96%, 96%, 96%, and 92%, respectively, in patients treated with AAD plus enalapril (n = 24) versus 100%, 100%, 100%, and 100% in patients treated with AAD alone (n = 84, P = NS). In the mixed group, maintenance rates of sinus rhythm at 12, 36, 60, and 90 months were 90%, 71%, 61%, and 57%, respectively, in patients treated with AAD plus enalapril (n = 49) versus 88%, 78%, 68%, and 61% in patients treated with AAD alone (n = 120, P = NS).
Our findings suggest that the preventive efficacy of combined therapy with AAD plus enalapril is dependent on the timing of onset of paroxysmal AF, and this regimen seems to be most beneficial for the diurnal type of paroxysmal AF.

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Antiplatelet therapy is widely performed for arteriosclerosis obliterans (ASO) to relieve ischemic symptoms and prevent cardiovascular events. However, the overall rate of cardiovascular events in patients with ASO under treatment with antiplatelet agents has not been fully investigated in Japan. The SEASON registry is a nationwide observational prospective cohort study designed to compile data from over 2,000 institutions across Japan, whose aims are to (1) understand the current status for the management of ASO and clarify the incidence of cardiovascular events in patients with ASO undergoing antiplatelet therapy, and (2) compare the effectiveness of sarpogrelate, a 5-HT_2A receptor antagonist, in decreasing the event rate with those of other antiplatelet agents [UMIN ID: UMIN000003385]. The registry will recruit approximately 10,000 patients receiving antiplatelet therapy (8,000 patients for sarpogrelate and 2,000 for other antiplatelet agents), and the patients will be followed every 6 months during a two-year follow-up period. The investigators plan to report all cardiovascular events and exacerbations of ASO. Analysis focusing on the sarpogrelate-treated subgroup will also be performed. Exploratory analysis will be performed to determine the clinical characteristics of the patients and to elucidate the relationships between risk factors and cardiovascular events. The SEASON registry is the first attempt to create a nationwide database regarding the incidence of cardiovascular events in 10,000 ASO patients in Japan. In addition, it ultimately may enable us to conclude that sarpogrelate prevents cardiovascular events. Information on the severity and risk factors in ASO patients in the clinical settings will be applicable to epidemiological analysis.

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Recent advances in the treatment of pulmonary arterial hypertension provide a rational basis for earlier, noninvasive diagnosis of pulmonary arterial hypertension. However, the reliability of transthoracic echocardiography, plasma BNP levels, and other parameters for the diagnosis of pulmonary arterial hypertension remains unclear. Thus, the purpose of this study was to determine the utility of these modes of investigation for the prediction of pulmonary arterial pressure as compared with the current gold standard, Swan-Ganz catheterization.
Among 46 PAH patients, 37 had connective tissue diseases, while the remainder had primary pulmonary arterial hypertension, chronic pulmonary thromboembolism, and interstitial pneumonitis. Systolic pulmonary arterial pressure calculated by transthoracic echocardiography was significantly correlated with systolic pulmonary arterial pressure measured using a Swan-Ganz catheter (r = 0.51, P < 0.01). Plasma BNP concentration did not correlate with systolic pulmonary arterial pressure (r = 0.10, NS) in the overall patient population. However, when we excluded left ventricular heart failure and left ventricular hypertrophy, BNP concentration was correlated with systolic pulmonary arterial pressure (r = 0.508, P < 0.05). Among other variables tested, ECG electrical axis was correlated with pulmonary arterial pressure (r = 0.46, P < 0.05) but uric acid, lactate dehydrogenase, %DLCO, enhanced IIp sound, and pulmonary artery enlargement on chest x-ray did not correlate with pulmonary arterial pressure.
These data suggest that echocardiography is the noninvasive modality of choice for the assessment of pulmonary arterial hypertension. Plasma BNP level also predicts pulmonary arterial pressure, when left ventricular heart failure and cardiac hypertrophy are excluded.

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Despite development of therapeutic modalities, myocardial ischemia-reperfusion (I/R) injury remains an important cause of cardiac dysfunction. Multiple strategies exist experimentally, but few are clinically available. Nuclear factor kappa-B (NF-κB) is a key transcription factor in the inflammatory response and is implicated in I/R injury. We hypothesized that the NFκB inhibitor BAY 11-7082 (BAY) would decrease the extent of injury after myocardial I/R. Hypoxia-reoxygenation (H/R) was induced in rat neonatal cardiomyocytes with or without BAY pretreatment. NF-κB activation, vascular cell adhesion molecule (VCAM)-1, and monocyte chemoattractant protein (MCP)-1 were assayed by immunocytochemistry, Western blot or reverse transcriptase-polymerase chain reaction (RT-PCR). Sprague-Dawley rats (n = 7) were administered BAY (130 μg/kg) and I/R was induced by ligation of the left anterior descending artery (LAD) for 30 minutes followed by reperfusion. Infarct size was analyzed after 24 hours. At 2 weeks, echocardiography was performed to evaluate ventricular function and hearts were analyzed for fibrosis and apoptosis. BAY treatment inhibited NF-κB p65 activation, as well as VCAM-1 and MCP-1 expression induced by H/R in cardiomyocytes. Compared with control rats, BAY pretreated rats showed reduced infarct size. Echocardiograms demonstrated preserved systolic function as a fractional shortening in the BAY+I/R group (P < 0.05). Fibrosis was reduced in the BAY+I/R group (P < 0.05) and apoptosis was also reduced in the BAY+I/R group (P < 0.05).
In the rat myocardial I/R injury model, BAY significantly reduced the infarct size, and preserved myocardial function. These data demonstrate that a currently available and well-tolerated inhibitor of NF-κB can decrease the risk of myocardial injury associated with I/R.

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Sustained atrial fibrillation (AF) was induced by atrial burst pacing, and monophasic action potentials (MAPs) were recorded. MAP alternans was observed at a cycle length (CL) of 167.5 ± 28.2 msec before burst pacing and 201.3 ± 40.2 msec after burst pacing. AF > 5 minutes duration was induced in 1 dog in the control condition but in all 8 dogs after burst pacing. The difference in RA MAPD₈₀ of the first spontaneous beat and steady-state sinus rhythm was significantly larger after atrial burst pacing than before atrial burst pacing (31.5 ± 15.9 msec versus 8.2 ± 9.0 msec) In 4 dogs, late phase 3 early afterdepolarization was observed after rapid atrial pacing. Rapid atrial pacing-induced electrical remodeling includes APD alternans during rapid atrial pacing and also causes an increase in the MAPD of the initial several beats and the development of late phase 3 early afterdepolarizations after a sudden increase in CL.

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Most previous studies have examined the effects of antihypertensive drugs in hypertensive animals for only a few months, and little information has been provided as to the protective effects of lifetime antihypertensive medication against cardiovascular organ injury. In this study, spontaneously hypertensive rats (SHR) were treated for 1 year with an angiotensin-II receptor antagonist (ARB) and the development of hypertensive organ injury was evaluated. Male 15-week-old SHR (n = 9) were given 25 mg/L candesartan (CS) in their drinking water for 1 year. Twelve SHR and 9 normotensive Wistar-Kyoto rats (WKY) were given normal tap water. Tail-cuff blood pressure was almost normalized by CS throughout 1 year (at 12-months: WKY 132 ± 3, SHR 229 ± 3, CS 137 ± 4 mmHg). After 1 year, cardiac ventricular weight (SHR +33%, CS -2% versus WKY) and aortic thickness (SHR +34%, CS +4% versus WKY) in the CS-treated SHR rats were not different than those of WKY. Echocardiographic midwall fractional shortening (SHR -18%, CS -1% versus WKY) and left ventricular hydroxyproline content (SHR +47%, CS +11% versus WKY) were also improved by CS to the WKY level. With respect to kidney function, GFR (SHR -24%, CS +9% versus WKY) was preserved, proteinuria (SHR +312%, CS +12% versus WKY) was reduced, and the histological glomerular injury rate (SHR +186%, CS +6% versus WKY) was reduced by CS. These results suggest that long-term antihypertensive therapy with CS can completely prevent hypertensive cardiovascular and renal injuries in SHR.

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We report the case of a 70-year-old man presenting with the development of torsade de pointes (TDP) during infusion of propofol in the setting of severe hypoalbuminemia. TDP developed 15 hours after the beginning of a standard infusion of propofol, following the development of a prominent U wave and prolongation of the QTc interval. While the serum concentrations of electrolytes were within normal ranges, serum albumin as low as 1.4 mg/dL was observed. TDP disappeared during the infusion of isoproterenol, and QTc normalized after the discontinuation of propofol. We hypothesize that hypoalbuminemia increased the free fraction of propofol, causing marked QTc prolongation and TDP.

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We report a case who had confirmed tumor cells in the biopsy specimens by transvenous endomyocardial biopsy with intra-procedural consultation and fast smear cytology. A 57-year-old female was admitted to our hospital because of shortness of breath and left back pain. Transthoracic echocardiography (TTE) and contrast-enhanced computed tomography (CT) scans demonstrated a large mass in the right atrium and multiple liver tumors thought to be due to spread of the disease. Coronary angiography showed the right coronary artery was involved in the mass. In order to confirm the histological diagnosis, we attempted transvenous endomyocardial tumor biopsy under fluoroscopic guidance. However, we failed to obtain adequate tissue material. Due to several risks associated with a surgical procedure such as an open surgical biopsy, transvenous endomyocardial tumor biopsy was again attempted with the aid of transesophageal echocardiography (TEE). Intra-procedural consultation and fast smear cytology enabled us to finish the procedure. Hematoxylin-eosin stained sections demonstrated spindle-shaped cells. Immunohistochemical stains of these cells were positive for anti-factor VIII antigen, CD31, and CD34. These findings indicated a definite diagnosis of angiosarcoma. Since there was no surgical indication for this tumor, the patient underwent chemotherapy with docetaxel and radiotherapy. Three months later, CT scans showed a reduction in the size of the cardiac tumor.

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