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Background: Angiotensin II receptor blocker (ARB) as a first-line drug for hypertension in diabetes often fails to control blood pressure adequately. The objective of the study was to evaluate the effect of amlodipine combined therapy on home blood pressure (HBP) useful for management of hypertension., Methods and Results: A total of 263 type 2 diabetes with hypertension refractory to standard dose of ARB were randomized to increased ARB regimen (n=132) or amlodipine combination regimen (n=131). The primary endpoint was change in morning HBP at 1 year. The combination regimen significantly lowered morning HBP than the increased ARB regimen (158.2/82.5 mmHg in the combination regimen, 157.3/84.4 mmHg in the increased ARB regimen, at baseline; 142.7/76.3 vs. 155.0/83.1 mmHg, respectively, P<0.001 for both, at 8 weeks; 139.6/74.6 vs. 149.1/78.1 mmHg, respectively, P<0.001 for systolic and P=0.010 for diastolic, at 1 year). The combination regimen showed significantly higher rates of achieving target morning HBP at 8 weeks (11.3% vs. 2.7%, P=0.015). In the combination regimen, estimated glomerular filtration rate declined slower, and carotid intima-media thickness decreased in contrast to the increased ARB regimen., Conclusions: In type 2 diabetes patients with hypertension refractory to standard dose of ARB, the amlodipine combination regimen provides superior antihypertensive effect on HBP to the increased ARB regimen, and beneficial effects on reducing risks of cardiovascular events.

Background: Beta-blockers are underprescribed for coronary artery disease (CAD) patients in Japan. Considering the vast amount of evidence showing their benefits in this group of patients, the aim of the present study was to investigate the use of beta-blockers in a large cohort of CAD patients., Methods and Results: The 13,812 patients with angiographically confirmed CAD were followed up for 2.7 years. From this group, 4,160 (30.1%) patients were prescribed beta-blockers at the time of discharge. These patients were significantly more likely to have hypertension, hyperlipidemia, obesity, a family history of ischemic diseases and a higher number of diseased arteries. The rate of continuation for beta-blockers was 90.8%. A propensity score matching analysis showed no additional benefits of beta-blockers in reducing all-cause mortality, cardiac events and cerebrovascular events. Lipophilic beta-blockers were significantly more effective than hydrophilic ones in reducing all-cause mortality (hazard ratio 0.467, 95% confidence interval 0.247-0.880, P=0.019)., Conclusions: Despite the low prescription rate of beta-blockers for CAD patients among Japanese physicians, the continuation rate was relatively high. Lipophilic beta-blockers may be a better choice than hydrophilic beta-blockers in terms of mortality risk, although a randomized control study would need to be conducted to verify this assertion.

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.

Background: The benefits of coronary risk modification through medication and other methods have been shown in many clinical studies. Recently, aggressive lowering of low-density lipoprotein-cholesterol (LDL-C) has been shown to confer additive benefits in patients with coronary artery disease (CAD). However, it has not been shown in Japanese patients with CAD if multiple aggressive medical interventions for coronary risk factors are beneficial compared with standard regimens, so a prospective, randomized, open-label, blinded-endpoint (PROBE) multicenter study was designed to evaluate whether aggressive lowering of LDL-C and blood pressure in Japanese hypertensive, hypercholesterolemic CAD patients bestows additional benefits compared with regimens based on current Japanese guidelines., Methods and Results: Seventeen hospitals in Japan are participating in the Japanese Coronary Artery Disease II (JCADII) study. Hypertensive and hypercholesterolemic patients who have >or=75% stenosis in at least one major coronary artery according to American Heart Association guidelines will be allocated randomly to receive either conventional or aggressive therapy. Standard therapy for hypertension and hypercholesterolemia aims to reduce blood pressure to <140/90 mmHg and LDL-C concentration to <100 mg/dl. Aggressive therapy aims for targets of <120/80 mmHg and <80 mg/dl, respectively. We plan to recruit 500 patients and follow them up for 3 years. Antihypertensive agents, when used, include the angiotensin receptor blockers candesartan and/or losartan. Antihypercholesterolemic agents, when used, include at least one of the following statins: pravastatin, simvastatin, and atorvastatin., Conclusion: The JCADII study will provide important information concerning medical treatment of coronary risk factors in Japanese patients with CAD (UMIN-ID: UMIN000000571).

Statins and renin-angiotensin system (RAS) inhibitors are 2 classes of drugs prescribed frequently in clinical practice that may have pleiotropic effects in addition to cholesterol-lowering and blood pressure-lowering effects, respectively. Combined treatment with statins and RAS inhibitors may have additional benefits beyond each monotherapy. We assessed the usefulness of the combined treatment in the Japanese Coronary Artery Disease (JCAD) Study population. In the JCAD Study, 13,812 patients with angiographically shown narrowing in > or =1 of 3 major coronary arteries were followed up for a mean of 2.7 years. The primary end point of the study was all cardiovascular events. In the present study, baseline covariates possibly influencing the event rate were adjusted between the control and treatment groups. Although there were no statistically significant differences in event rates between patients receiving neither statins nor RAS inhibitors and those receiving either drug, Kaplan-Meier analysis showed a 22% decrease (p = 0.0286) in the event rate with combined treatment. In conclusion, statins combined with RAS inhibitors may decrease cardiovascular events in patients with coronary artery disease.

Background: Actual data regarding coronary artery disease (CAD) patients in Japan is scarce, so in the present study a large database of Japanese patients with significant CAD was constructed for analysis of the relationship between medical treatments and outcomes in this cohort., Methods and Results: The present study enrolled 15,628 patients who underwent coronary angiography and were diagnosed as having significant stenosis in at least 1 coronary artery. Of these, 13,812 patients were followed up and included in the analysis: 10,626 (77%) men and 3,186 (23%) women. Diagnosis at the time of registration was acute myocardial infarction (AMI) for 2,955 patients, old myocardial infarction for 3,913 patients and unstable angina pectoris for 2,049 patients. Patients were followed up for an average of 2.7 years. At the start of the follow-up, 37.4% of the patients were prescribed statins, 50.2% calcium-channel blockers (CCB), 31.6% angiotensin-converting enzyme inhibitors (ACEI), 13.5% angiotensin II receptor blockers (ARB) and 60.2% nitrates. Univariate Cox regression model analysis showed that the hazard ratio (HR) of statins was 0.780 (95% confidence intervals (CI), 0.710-0.856; p<0.001); fibrates, 0.580 (95%CI, 0.425-0.790; p=0.001); CCB, 1.067 (95%CI, 0.976-1.166; p=0.153); ACEI, 1.062 (95%CI, 0.968-1.166; p=0.202); ARB, 1.036 (95%CI, 0.914-1.174; p=0.581); nitrates, 1.147 (95%CI, 1.043-1.260; p=0.005). When the data were adjusted for background data and all cardiovascular medications, the HR of statins was 0.809 (95%CI, 0.726-0.901; p<0.001), CCB 1.031 (95%CI, 0.937-1.135; p=0.535), ACEI 1.023 (95%CI, 0.924-1.132; p=0.663), ARB 0.991 (95%CI, 0.867-1.132; p=0.890), nitrates 1.074 (95%CI, 0.973-1.186; p=0.155). For patients presenting with AMI at the time of registration, the HR of CCB was 1.340 (95%CI, 1.084-1.655; p=0.007) and that of nitrates was 0.862 (95%CI, 0.703-1.059; p=0.157)., Conclusion: In a cohort of CAD patients in Japan, the prescription pattern differed from that of Western studies. Statins and fibrates were shown to be significantly beneficial in the whole cohort. In the AMI subgroup, CCB showed a deleterious effect and nitrates showed a non-significant tendency for beneficial effect, which should be investigated in future randomized control trials.

Purpose: During the storage of red blood cell concentrates (CRCs), red blood cells are progressively destroyed and free hemoglobin and potassium concentrations increase. In this study, we focused on an electrostatic field that maintains food freshness without freezing, even at less than the freezing point. We hypothesized that the storage of CRCs under an electrostatic field could keep red blood cells in better condition than conventional storage., Methods: Each of 15 packs of 2-day-old CRCs, preserved in MAP (mannitol, adenine, glucose, phosphate, and citrate) solution (MAP-CRC) was divided into 4 smaller equal-size packs and stored at 4 degrees C in a newly developed refrigerator that can generate an electrostatic field. Each group was exposed to a 0-, 500-, 1500-, or 3000-volt (V) electric field for 30 days. Concentrations of free hemoglobin, total haptoglobin, sodium (Na), and potassium (K), and the pH, were measured in the supernatant., Results: Haptoglobin was not detected. The Na concentration decreased with time but was significantly lower in the 0-V than in the 500-, 1500-, and 3000-V groups. K and free hemoglobin concentrations increased with time, with significantly higher values in the 0-V than in the 500-, 1500-, and 3000-V groups. The pH decreased in the 500-, 1500-, and 3000-V groups, while it did not change in the 0-V group. The pH decrease was smaller in the 500-V than in the 1500- and 3000-V groups., Conclusion: Storing MAP-CRC in an electrostatic field of 500 to 3000 V could decrease hemolysis in the preparation. Considering the lower pH decrease, 500 V might be the field of choice.

Background: The coexistence of type 2 diabetes mellitus and hypertension increases the risk of cardiovascular diseases. The U.K. Prospective Diabetes Study has shown that blood pressure control as well as blood glucose control is efficient for prevention of complications in hypertensive patients with diabetes mellitus. However, some reports have shown that it is difficult to control the blood pressure and the concomitant use of a plurality of drugs is needed in hypertensive patients with diabetes mellitus. In recent years renin-angiotensin system depressants are increasingly used for the blood pressure control in diabetic patients. Particularly in Japan, angiotensin II (A II) antagonists are increasingly used. However, there is no definite evidence of the point of which is efficient for the control, the increase in dose of A II antagonist or the concomitant use of another drug, in hypertensive patients whose blood pressure levels are inadequately controlled with A II antagonist., Methods/design: Hypertensive patients of age 20 years or over with type 2 diabetes mellitus who have been treated by the single use of AII antagonist at usual doses for at least 8 weeks or patients who have been treated by the concomitant use of AII antagonist and an antihypertensive drug other than calcium channel blockers and ACE inhibitors at usual doses for at least 8 weeks are included., Discussion: We designed a multi-center, prospective, randomized, open label, blinded-endpoint trial, ADVANCED-J, to compare the increases in dose of A II antagonist and the concomitant use of a Ca-channel blocker (amlodipine) and A II antagonist in hypertensive patients with diabetes mellitus, whose blood pressure levels were inadequately controlled with A II antagonist. This study is different from the usual previous studies in that home blood pressures are assessed as indicators of evaluation of blood pressure. The ADVANCED-J study may have much influence on selection of antihypertensive drugs for treatment in hypertensive patients with diabetes mellitus. It is expected to give an important hint for considering the validity of selection of antihypertensive drugs from the aspects not only of the antihypertensive effect but medical cost-effectiveness.

A 60 year-old male was referred for treatment of a cardiac myxoma in the right atrium. He had a past history of left atrial cardiac myxoma at age 49 and pituitary microadenoma related to acromegaly at age 55. He did not have a family history of cardiac neoplasm or endocrinopathy. The intracardiac tumor was resected and its pathology was compatible with myxoma. A diagnosis of Carney complex (CNC) was made because the diagnostic criteria of this neoplastic syndrome were satisfied by the presence of recurrent cardiac myxoma, endocrine tumor and spotty skin pigmentation. In genetic analysis novel frame shift mutation was detected in exon 2 in a heterozygous fashion in the causative gene of CNC, protein kinase A regulatory subunit 1 alpha (PRKAR1A). This genetic mutation is thought to cause haplo-insufficiency of PRKAR1A resulting in tumorigenesis. Although it is the most common, usually benign, cardiac tumor, myxoma can cause a critical clinical situation and thus detecting the PRKAR1A mutation can assist with prognosis.

Changes in the expression levels of several genes have been described in aortic aneurysm specimens, however, the spectrum of diverse molecular alterations remains to be elucidated. We attempted to identify key molecules that modulate the pathogenesis of aortic aneurysm, using a complimentary DNA microarray carrying approximately 13,000 human genes. Segments of thoracic aortic aneurysms (TAA) and adjacent normal thoracic aortic tissues without aneurysmal changes (NTA) were obtained from 20 patients undergoing graft surgery. RNA obtained from five pairs of TAA and NTA samples was compared to determine aneurysm-specific alterations using microarray. Further, the expression levels of several genes of interest were verified in the remaining specimens by real-time reverse transcription-polymerase chain reaction (RT-PCR). In microarray assays, several types of the matrix metalloproteinases were upregulated as reported previously. Also, 220 genes suggested to be involved in protein degradation, inflammation, apoptosis, stress response, intracellular signaling, and other processes were significantly upregulated. Many of these genes have not been previously implicated in cardiovascular disease. The real time RT-PCR independently confirmed that the expression levels of MMP-2, MMP-9, ADAMTS-1, and caspase 4 were consistently increased in TAA. The results indicate that many genes are involved in a complicated manner in the pathogenesis of TAA. Investigation of these genes will help clarify the pathogenesis of this disease, and may lead to the discovery of novel therapeutic targets.