Pathophysiology and Treatment of Chronic Thromboembolic Pulmonary Hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a condition in which an organic thrombus remains in the pulmonary artery (PA) even after receiving anticoagulation therapy for more than 3 months and is complicated by pulmonary hypertension (PH), leading to right-sided heart failure and death. CTEPH is a progressive pulmonary vascular disease with a poor prognosis if left untreated. The standard treatment for CTEPH is pulmonary endarterectomy (PEA), which is usually performed only in specialized centers. In recent years, balloon pulmonary angioplasty (BPA) and drug therapy for CTEPH have also shown good results. This review discusses the complex pathogenesis of CTEPH and presents the standard of care, PEA, as well as a new device called BPA, which is showing remarkable progress in efficacy and safety. Additionally, several drugs are now demonstrating established evidence of efficacy in treating CTEPH.

Recent Advances in the Treatment of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a disease in which stenosis or obstruction of the pulmonary arteries (PAs) causes an increase in PA pressure, leading to right-sided heart failure and death. Basic research has revealed a decrease in the levels of endogenous vasodilators, such as prostacyclin, and an increase in the levels of endogenous vasoconstrictors, such as endothelin, in patients with PAH, leading to the development of therapeutic agents. Currently, therapeutic agents for PAH target three pathways that are selective for PAs: the prostacyclin, endothelin, and nitric oxide pathways. These treatments improve the prognosis of PAH patients. In this review, we introduce new drug therapies and provide an overview of the current therapeutic agents.

Clinically feasible method for assessing leukocyte rheology in whole blood.

This study reports a novel method for assessment of leukocyte rheological activation with a new designed microchannel array chip to mimic the human microvascular network for microchannel array flow analysis (MCFAN). Study subjects were 79 healthy volunteers and 42 patients with type 2 diabetes mellitus (DM) and 36 patients with acute coronary syndrome (ACS). Using the anticoagulants heparin and ethylene-diamine-tetraacetic acid (EDTA)-2Na which inhibits platelets and leukocytes by chelating Ca2+, we were able to quantify leukocyte rheological activation by the subtraction of passage time of blood treated with both heparin and EDTA-2Na from that of blood treated with heparin only. We confirmed that passage times of whole blood with heparin + EDTA-2Na were always shorter than those of whole blood with only heparin in healthy subjects and patients with DM or ACS under suction pressures of - 30 cmH2O. There was a significant correlation between delta whole blood passage time {(heparin tube) - (EDTA-2Na + heparin)} and serum levels of myeloperoxidase and adhesive leukocyte number, respectively, even in blood from patients with DM or ACS, who suffered from inflammation. In conclusion we have developed a clinically feasible method for assessing leukocyte rheological activation in whole blood in ex vivo.

Sleep-Disordered Breathing-a Real Therapeutic Target for Hypertension, Pulmonary Hypertension, Ischemic Heart Disease, and Chronic Heart Failure?

Sleep-disordered breathing (SDB) is a risk factor for cardiovascular disease including acute coronary syndrome and acute myocardial infarction, and treating SDB prevents their development and recurrence and improves a patient's prognosis. Therefore, SDB is considered a therapeutic target for cardiovascular disease. In 2010, the Japanese Circulation Society published guidelines for the diagnosis and treatment of SDB in patients with cardiovascular disease. However, therapeutic intervention for patients with SDB was recently reported not to suppress the development or deterioration of cardiovascular disease in three middle- to large-sized randomized clinical trials: the SERVE-HF trial, which examined the effects of adaptive servo-ventilation (ASV) on patients with chronic heart failure (CHF) and central sleep apnea; the CAT-HF trial, which examined the effects of ASV therapy on patients with CHF after acute deterioration; and the SAVE study, which examined the secondary preventive effect of continuous positive airway pressure (CPAP) on patients with ischemic heart disease who had mild to moderate obstructive sleep apnea. These studies caused hesitation among clinicians to proactively treat SDB by ASV or CPAP therapy. The present review is focused on hypertension, pulmonary hypertension, ischemic heart disease, and CHF to newly summarize the studies available to date from the viewpoints of epidemiology, pathogenesis, and treatment. I expect this review be informative and useful for physicians who treat patients with SDB by CPAP or ASV therapy in the clinical setting.

Improvement of glycemic control by re-education in insulin injection technique in patients with diabetes mellitus.

INTRODUCTION: The aim of this study was to evaluate the effectiveness of re-education in the insulin injection technique for glycemic control. METHODS: A preliminary experimental study was performed with 87 insulin-treated diabetic outpatients (11 with type 1 diabetes, 76 with type 2 diabetes; 43 men, 44 women). All patients had been treated with insulin for more than 3 years. After answering questions about the insulin injection technique, the patients' knowledge levels were scored. Correct answers and explanation sheets were subsequently given to all patients. The physicians in charge gave a short lecture and provided 10 min of individual advice. Two, three, and four months after re-education the HbA1c and glycoalbumin levels were measured. RESULTS: The mean HbA1c levels of almost all patients significantly improved from 7.46 ± 0.09% to 6.73 ± 0.10% (P < 0.01), and the mean glycoalbumin levels significantly improved from 22.76 ± 0.50% to 20.26 ± 0.68% (P < 0.01). Twenty-five patients demonstrated a poor understanding (score of ≤6 points) and showed a significant decrease in the HbA1c level from 7.62 ± 0.20% to 6.71 ± 0.21% (P = 0.02). Forty-three patients demonstrated a moderate understanding (score of 7 or 8 points) and showed a decrease in the HbA1c level from 7.40 ± 0.13% to 6.68 ± 0.07% (P = 0.07). Finally, 19 patients demonstrated a good understanding (score of ≥9 points) and showed a slight decrease in the HbA1c level from 7.38 ± 0.15% to 6.93 ± 0.12% (P = 0.09). Patients with a poor understanding showed the largest decrease in the mean level of HbA1c. CONCLUSION: Re-education in the insulin injection technique led to an improvement in glycemic control in insulin-treated diabetic patients, especially in those with a poor understanding of the insulin injection technique. More attention should be paid to these strategies for outpatients.

Clinical significance of plasma apolipoprotein F in Japanese healthy and hypertriglyceridemic subjects.

AIM: Apolipoprotein F (apo F), also known as lipid transfer inhibitory protein (LTIP), is a protein component of plasma lipoprotein classes including HDL and functions to inhibit lipid transfer between lipoproteins in vitro. To study the role of plasma apo F, a reliable and sensitive tool for the quantification would be needed. METHODS: We have developed a sandwich ELISA using two monoclonal antibodies for human plasma apo F, and analyzed apo F concentration in 397 Japanese healthy and 221 hypertriglyceridemic subjects. RESULTS: Our ELISA enables apo F to be assayed in the range of 0.6-25 µg/mL with intra- and inter-assay coefficients of variation less than 3.8% and 7.8%, respectively. In healthy subjects, plasma apo F concentration was 12.5±2.9 µg/mL (mean±SD), and was significantly higher in females than in males (p<0.05). By linear regression analysis in healthy subjects, plasma apo F concentration correlated positively with HDL cholesterol and apo A-I levels, and in males but not in females, negatively with apo B and triglyceride levels. It also correlated negatively with intrinsic CETP activity measured using intrinsic apo B-containing lipoprotein as an acceptor, and positively with PLTP mass and apo J levels. Apo F concentration in hypertriglyceridemic patients (10.3±3.1 µg/mL) was lower than in healthy controls (p<0.0001) and correlated positively with PLTP mass. CONCLUSIONS: Our ELISA is reliable and sensitive for the quantification of plasma apo F concentration. This system can be applicable for clinical significance in lipoprotein metabolism and reverse cholesterol transport.

Severe hypoglycemia accompanied with thyroid crisis.

We report a 32-year-old Japanese women with severe hypoglycemia accompanied with thyroid crisis. She complained of dyspnea, general fatigue, and leg edema. She was diagnosed with hyperthyroidism with congestive heart failure and liver dysfunction. Soon after admission, sudden cardiopulmonary arrest occurred. She was then transferred to the intensive care unit. Her serum glucose level was 7 mg/dl. Intravenous glucose, hydrocortisone, diuretics, and continuous hemodiafiltration (CHDF) saved her. We considered that hypoglycemia occurred due to heart failure and liver dysfunction due to thyroid crisis.

Alternative medicine safety: Agaricus blazei and propolis.

All medicines pose a potential health risk, be they Eastern or Western medicines. Newly developed Western drugs must undergo rigorous testing to ensure their efficacy and safety, while with Eastern drugs, safety has generally been established because of their long histories of safe usage as traditional medicines. The regulation of Western medicines is much stronger than that of Eastern medicines, partly as pure chemicals are used and their effects and side effects are more likely to be acute. Eastern medicines consist of multiple components, generally extracted from a single or several plants or other natural sources, and their effects are not so acute, with delayed onset of side effects. However, the chronic usage of many Eastern medicines may result in the gradual accumulation of toxic compounds in the body. For example, Agaricus blazei extracts have been used as alternative medicines for cancer, but contain the known carcinogen agaritine (this carcinogen is also present in Agaricus bisporus). To ensure the safety of this alternative medicine, agaritine should be removed or its content reduced if the extract is to be taken chronically. Clearly, the safety of not only pure medicines, but also alternative medicines and daily foods, should be carefully controlled.

Clinical efficacy and cost-benefit analysis of nocturnal home oxygen therapy in patients with central sleep apnea caused by chronic heart failure.

BACKGROUND: There is increasing evidence that both obstructive and central sleep apnea contribute to the progression and prognosis in patients with chronic heart failure (CHF). In the main study of nocturnal home oxygen therapy (HOT) in patients with central sleep apnea because of CHF (CHF-HOT), significant improvements in oxygen desaturation index, apnea - hypopnea index, left ventricular ejection fraction, and specific activity scale were reported following 12 weeks of nocturnal HOT in these patients. METHODS AND RESULTS: The present study is designed to further evaluate the clinical efficacy and cost - benefit of nocturnal HOT according to the results of a follow-up survey on changes in frequencies of hospitalization, emergency visits, and regular outpatient visits by 53 patients undergoing nocturnal HOT for more than 6 month periods. Medical costs were estimated from the DPC-MDC5 charge for hospitalization because of worsening heart failure (HF), and from the standard model case estimation for emergency and regular outpatient visits for HF. To reveal the time-saving benefit following nocturnal HOT, the influence on estimated days spent for hospital-care was also analyzed. The present study revealed significant reduction in frequencies and length of hospitalization (2.1 to 0.5 times/year, 38.7 to 34.6 days, medical cost: -2,686,267 yen), emergency visit (2.5 to 0.7 times/year, -15,984 yen), and regular outpatient visit (17.7 to 12.6 times/year, -6,324 yen) as compared with those before the induction of nocturnal HOT, which resulted in a total medical cost-reduction of 1,854,175 yen/patient/year, even with the additional charge for nocturnal HOT (854,400 yen/patient/year). Furthermore, nocturnal HOT produced a remarkable decline in estimated days spent for hospital-care (88.2 to 21.2 days/patient/year). CONCLUSION: The present analysis calculated a remarkable cost-benefit (1,854,175 yen/patient/year) from the reduction in hospitalization and emergency visits, and also time-saving benefits from an increase in expected days free from hospital-care (67 days/patient/year).

Effects of olmesartan medoxomil as an angiotensin II-receptor blocker in chronic hypoxic rats.

We established a rat chronic alveolar hypoxia in vivo model to evaluate the efficacy against hypoxic pulmonary hypertension of a new angiotensin II-receptor I blocker, olmesartan medoxomil. Three groups of rats were established: rats exposed for 2-6 weeks to 10% oxygen atmosphere in a normobaric chamber; hypoxic rats treated with olmesartan medoxomil oral administration (5 mg/day) every day; and control rats fed in a normoxic condition. After hypoxia treatment, the presence, etiology and severity of pulmonary hypertension, was echocardiographically evaluated, and expressions of brain natriuretic peptide (BNP), transforming growth factor (TGF-beta) and endothelin-1 genes measured by both immunohistochemical assay and real-time polymerase chain reaction. Olmesartan medoxomil significantly reduced the induction of hypoxic cor pulmonale not only on echocardiographical observations but also in BNP, TGF-beta and endothelin gene expressions in molecular studies. However, systolic blood pressure was independent of olmesartan medoxomil. The present study clearly indicates that the angiotensin II-type I-receptor blocker olmesartan medoxomil has significant efficacy for hypoxic cor pulmonale.

Chronic pulmonary thromboembolism. Air trapping on computed tomography and correlation with pulmonary function tests.

OBJECTIVE: We evaluated lung attenuation on inspiratory/expiratory computed tomography (CT) and spiral CT angiography (CTA) from patients with chronic pulmonary embolism and correlated the CT findings with pulmonary function test (PFT) results. METHODS: We retrospectively reviewed 9 patients with chronic embolism (mean age, 62.3 years; 5 women and 4 men). Paired inspiratory, expiratory CT and matching CTA images were reviewed, and lung attenuation was evaluated in each segment. Lower attenuation on inspiratory images and air trapping on expiratory images were subjectively assessed and correlated with PFT results. The relationship between the presence of clot and lung attenuation was evaluated. Nine age-matched normal subjects served as controls. RESULTS: Lower attenuation with mosaic perfusion and air trapping were identified in 6 and 9 patients, respectively (mean scores, 8.1 and 11.3, respectively). Air trapping was identified in 19 (42.2%) of 45 segments with lower attenuation on inspiratory images, but was also noted in 31 segments with normal inspiratory attenuation. Air trapping was associated with the presence of proximal arterial stenosis (P<0.01), and the area showed less contrast enhancement than the adjacent lung (P<0.05). Extent of air trapping correlated inversely with PFT parameters of peripheral airway obstruction such as maximum mid-expiratory flow rate (r=-0.86, P=0.003). On the other hand, extent of mosaic perfusion did not correlate with PFT. CONCLUSIONS: Air trapping is commonly seen in chronic embolism and is found in areas of relative hypoperfusion. The extent of air trapping correlates with parameters of peripheral airway obstruction.

Genetic detection for hematogenous micrometastasis in patients with various types of malignant tumors using Uroplakin II derived primers in polymerase chain reaction.

The presence of circulatory metastasis is one of the most significant factors for poor-prognosis in patients with several types of cancer. To establish a sensitive reverse transcription PCR assay to detect micrometastasis in blood containing several cancer types, we first investigated Uroplakin II (UP II), a novel molecular marker for human transitional cell carcinoma of the bladder, in 25 types of normal organs. In our study, UP II mRNA was detected in 10 types of organs, including bladder, kidney, lung and pancreas, but was not detected in normal lymph nodes or leukocytes. The data indicated evidence of UP II expression in various types of normal tissues by RT-nested PCR analysis. UP II mRNA was detected in 2 of 11 (18.2%) peripheral blood samples from lung cancer patients with no metastasis, and in 5 of 12 (41.7%) peripheral blood samples of lung cancer patients with metastasis. UP II was also detected in 6 of 16 (37.5%) peripheral blood samples of patients with pancreatic cancer. The data are particularly important in that the molecular detection of micrometastasis in the blood by means of UP II mRNA identification is feasible for UP II-positive neoplasms, including lung and pancreatic cancers.

Detection of circulating prostate tumor cells: alternative spliced variant of PSM induced false-positive result.

RT-nested PCR has been introduced as a highly specific and sensitive assay method to detect the prostate-specific membrane antigen (PSM) mRNA in peripheral blood. However, appreciable percentages of false-positive cases have been reported. Additionally, primer sets reported previously could not discriminate between PSM and PSM', an alternatively spliced variant, mRNA. These isoforms can be produced from a single gene. Switches in alternative splicing patterns are often controlled with strict cell-type or developmental-stage specificity. Therefore, it is most important to discriminate between PSM mRNA and PSM' mRNA. Using our highly specific primer sets, PSM mRNA was detected in 3 of 24 peripheral blood samples of normal male volunteers (12.5%) and was not detected in peripheral blood of 11 normal female volunteers. PSM' mRNA was detected in 5 of 24 peripheral blood samples of normal male volunteers (20.8%) and in 4 of 11 of normal female volunteers (36.4%). PSM' mRNA induced false-positive results, it is important for genetic diagnosis of prostate cancer to discriminate between PSM and PSM' using our primer sets with high specificity. The advances in the uniquely designed primer sets may allow researchers to detect a real PSM mRNA without PSM' mRNA.

Evaluation of panipenem/betamipron (PAPM/BP) in pneumonia in elderly patients.

The present multicenter study evaluated the clinical and bacteriological efficacy and safety of panipenem/betamipron (PAPM/BP) for treating pneumonia in elderly patients. Forty-three episodes of pneumonia in 43 patients were treated with PAPM/BP as the sole antibiotic agent. All patients were 65 years of age or older, and were given PAPM/BP at a total daily dosage range of 0.5-2.0 g. The clinical efficacy rate, expressed as a percentage of the total number of excellent and good responses, was 56.4%. Of the 43 patients, 13 were evaluated bacteriologically. In these 13 patients, the eradication rate, expressed as a percentage of the total number of "eradicated" and "replaced" efficacies, was 30.8%. Adverse effects and abnormal laboratory findings occurred in 2 patients, which was 4.6% of the total number of patients evaluated. No serious adverse effects were observed. We concluded that PAPM/BP was well tolerated overall, and was effective and safe for most of the elderly patients.

[A case of successful pulmonary embolectomy for massive acute pulmonary thromboembolism].

A 54-year-old man was admitted to our hospital complaining of sudden-onset dyspnea in shock. Chest computed tomography(CT) showed thrombi in the right main and left intermediate pulmonary arteries. The case was diagnosed as a massive acute pulmonary thromboembolism. Although his hemodynamic status was stable after catecholamine infusion, his dyspnea was still in progress. Emergency pulmonary embolectomy was performed and the life of patient was saved. It is thought that progressive dyspnea is an important sign of a deteriorating hemodynamic status and the predictive symptom indicating a surgical procedure in patients with massive acute pulmonary thromboembolism.