Shigefumi Fukui

SLCO4C1 Transporter Eliminates Uremic Toxins and Attenuates Hypertension and Renal Inflammation

Hypertension in patients with chronic kidney disease (CKD) strongly associates with cardiovascular events. Among patients with CKD, reducing the accumulation of uremic toxins may protect against the development of hypertension and progression of renal damage, but there are no established therapies to accomplish this. Here, overexpression of human kidney-specific organic anion transporter SLCO4C1 in rat kidney reduced hypertension, cardiomegaly, and inflammation in the setting of renal failure. In addition, SLCO4C1 overexpression decreased plasma levels of the uremic toxins guanidino succinate, asymmetric dimethylarginine, and the newly identified trans-aconitate. We found that xenobiotic responsive element core motifs regulate SLCO4C1 transcription, and various statins, which act as inducers of nuclear aryl hydrocarbon receptors, upregulate SLCO4C1 transcription. Pravastatin, which is cardioprotective, increased the clearance of asymmetric dimethylarginine and trans-aconitate in renal failure. These data suggest that drugs that upregulate SLCO4C1 may have therapeutic potential for patients with CKD.

Right ventricular reverse remodelling after balloon pulmonary angioplasty

Balloon pulmonary angioplasty (BPA) has been reported to improve haemodynamics and functional capacity, with an acceptable risk, in patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are not candidates for pulmonary endarterectomy. However, right ventricular (RV) function, an important predictor in CTEPH, remains to be elucidated. We aimed to examine the impact of BPA on RV remodelling and dysfunction relative to haemodynamic improvements in patients with inoperable CTEPH. 20 consecutive patients with inoperable CTEPH who underwent BPA with cardiovascular magnetic resonance before and after BPA were retrospectively studied. BPA led to significant amelioration of the mean pulmonary arterial pressure, cardiac index and pulmonary vascular resistance (PVR), without death or major complications. Furthermore, BPA significantly ameliorated right-sided heart failure symptoms and signs, and exercise capacity. Cardiovascular magnetic resonance revealed a marked improvement in RV end-diastolic and end-systolic volume index, with concomitant improvements in RV ejection fraction, mass and interventricular septal bowing after BPA. Changes in RV volumes strongly correlated with changes in cardiac index and PVR. BPA induced RV reverse remodelling and improved systolic dysfunction safely by ameliorating haemodynamics in patients with inoperable CTEPH. Evaluating RV function with cardiovascular magnetic resonance may be effective for noninvasively monitoring BPA efficacy. BPA safely ameliorates haemodynamics, leading to right ventricular reverse remodelling in inoperable CTEPH http://ow.ly/tQX2R

Long-term inhibition of Rho-kinase ameliorates diastolic heart failure in hypertensive rats.

Diastolic heart failure (DHF) is a major cardiovascular disorder with poor prognosis; however, its molecular mechanism still remains to be fully elucidated. We have previously demonstrated the important roles of Rho-kinase pathway in the molecular mechanisms of cardiovascular fibrosis/hypertrophy and oxidative stress, but not examined in the development of heart failure. Therefore, we examined in this study whether Rho-kinase pathway is also involved in the pathogenesis of DHF in Dahl salt-sensitive rats, an established animal model of DHF. They were maintained with or without fasudil, a Rho-kinase inhibitor (30 or 100 mg/kg/day, PO) for 10 weeks. Untreated DHF group exhibited overt heart failure associated with diastolic dysfunction but with preserved systolic function, characterized by increased myocardial stiffness, cardiomyocyte hypertrophy, and enhanced cardiac fibrosis and superoxide production. Fasudil treatment significantly ameliorated those DHF-related myocardial changes. Western blot analysis showed that cardiac Rho-kinase activity was significantly increased in the untreated DHF group and was dose-dependently inhibited by fasudil. Importantly, there was a significant correlation between the extent of myocardial stiffness and that of cardiac Rho-kinase activity. These results indicate that Rho-kinase pathway plays an important role in the pathogenesis of DHF and thus could be an important therapeutic target for the disorder.

Diabetes mellitus accelerates left ventricular diastolic dysfunction through activation of the renin–angiotensin system in hypertensive rats

Diabetes mellitus (DM) is a major risk factor for heart failure, independent of coronary artery disease or hypertension (HT). Therefore, our study was designed to examine the mechanisms of DM-induced left ventricular (LV) diastolic dysfunction. In this study, we made five different 10-week treatment groups of Dahl salt-sensitive rats as follows: Control; a low-salt (0.5% NaCl) diet, HT; a high-salt (5% NaCl) diet, DM; a low-salt diet with streptozotocin (STZ) injection (30 mg kg−1 i.p.), HT+DM; a high-salt diet with STZ injection, and the Olmesartan group; a high-salt diet with STZ treated with an angiotensin receptor blocker, olmesartan (1 mg kg−1 day−1). Cardiac diastolic dysfunction with a preserved systolic function was noted in the HT group, and was most prominently noted in the HT+DM group, characterized by enhanced cardiac fibrosis, whereas the extent of HT and myocardial hypertrophy was comparable between the two groups. Myocardial expressions of collagen III, transforming growth factor-β2, angiotensin-converting enzyme (ACE), angiotensin II type-1 receptor and myocardial oxidative stress (evaluated by 4-hydroxy-2-nonenal-modified protein) were mostly enhanced in the HT+DM group. Importantly, there was a positive correlation between the extent of diastolic dysfunction and that of myocardial ACE expression. All these cardiac abnormalities induced by DM and HT were ameliorated in the olmesartan group. These results indicate that DM accelerates diastolic dysfunction in hypertensive heart disease through activation of the renin–angiotensin system, with subsequent inflammatory and oxidative stresses and myocardial fibrosis, suggesting that an inhibition of the system is effective for the treatment of diastolic dysfunction in this combined disorder.

Characteristics of heart failure associated with the Great East Japan Earthquake

BACKGROUND On March 11, 2011, the Tohoku district was struck by the most powerful known earthquake to hit Japan. Although stress-induced heart diseases rise after strong psychosocial stress, little is known about the characteristics of heart failure (HF) caused by psychosocial stress related to earthquakes. METHODS We examined patients admitted to our hospital for HF during a three-week period between March 11 and March 31, 2011 (Disaster group) and compared them to patients during the corresponding period of 2010 (Non-Disaster group). RESULTS The number of patients was larger in the Disaster group (n=30, 18 men, 12 women; mean age 77.3±9.8 years) than in the Non-Disaster group (n=16, 8 men, 8 women; mean age 77.3±11.6 years). A total of 14 of 30 patients (46.7%) in the Disaster group did not have past history of admission for HF, compared to 2 patients (12.5%) in the Non-Disaster group (p=0.02). The number of patients with hypertension was larger in the Disaster group than in the Non-Disaster group (53.3% vs. 37.5%, p=0.04). The number of patients with atrial fibrillation was also larger in the Disaster group than in the Non-Disaster group (56.7% vs. 25.0%, p=0.03). Left ventricular systolic ejection fraction (EF) did not differ between the Disaster and Non-Disaster groups (45.2±17.8% vs. 45.6±14.0%, p=0.46), however, the proportion of patients whose EF was more than 45% were significantly higher in the Disaster group more than in the Non-Disaster group (56.7% vs. 43.8%, p=0.04). The in-hospital mortality rate for patients in the Disaster group was higher than in the Non-Disaster group (20.0% vs. 6.3%, p=0.04). CONCLUSION The incidence and in-hospital mortality rate of HF increased after the Great East Japan Earthquake, suggesting that psychosocial stress brought on by such a disaster could lead to the development of HF with preserved EF more than that with reduced EF.

Efficacy and safety of balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension guided by cone-beam computed tomography and electrocardiogram-gated area detector computed tomography

BACKGROUND Chronic thromboembolic pulmonary hypertension (CTEPH) is a disease characterized by chronic obstructive thrombus and pulmonary hypertension. Balloon pulmonary angioplasty (BPA), an emerging alternative catheter-based treatment for inoperable patients with CTEPH, has not yet been standardised, especially for lesion assessment in distal pulmonary arteries. Recent advancement in computed tomography enables distal CTEPH lesions to be visualized. METHODS We retrospectively studied 80 consecutive patients with inoperable CTEPH who received BPA guided by cone-beam computed tomography (CT) (CBCT) or electrocardiogram (ECG)-gated area detector CT (ADCT) for target lesion assessment. We collected clinical and hemodynamic data, including procedural complications, before BPA and at 3 months and 1year after BPA. RESULTS Three hundred eight-five BPA sessions (4.8 sessions/patient) were performed for the lesions of subsegmental arteries (1155 lesions), segmental arteries (738 lesions), and lobar arteries (4 lesions) identified by CBCT or ECG-gated ADCT. Significant improvements in the symptoms, 6-min walk distance, brain natriuretic peptide level, exercise capacity, and haemodynamics were observed 3 months and 1year after BPA. No cases of death or cardiogenic shock with a low rate of severe wire perforation (0.3%) and severe reperfusion oedema (0.3%) were observed. CONCLUSIONS BPA guided by CBCT or ECG-gated ADCT is effective and remarkably safe in patients with CTEPH . These new advanced CT techniques may be useful in pre-BPA target lesion assessment.

Efficacy of cardiac rehabilitation after balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension

Objective To determine safety and efficacy of cardiac rehabilitation (CR) initiated immediately following balloon pulmonary angioplasty (BPA) in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) who presented with continuing exercise intolerance and symptoms on effort even after a course of BPA; 2–8 sessions/patient. Methods Forty-one consecutive patients with inoperable CTEPH who underwent their final BPA with improved resting mean pulmonary arterial pressure of 24.7±5.5 mm Hg and who suffered remaining exercise intolerance were prospectively studied. Participants were divided into two groups just after the final BPA (6.8±2.3 days): patients with (CR group, n=17) or without (non-CR group, n=24) participation in a 12-week CR of 1-week inhospital training followed by an 11-week outpatient programme. Cardiopulmonary exercise testing, haemodynamics, and quality of life (QOL) were assessed before and after CR. Results No significant between-group differences were found for any baseline characteristics. At week 12, peak oxygen uptake (VO2), per cent predicted peak VO2 (70.7±9.4% to 78.2±12.8%, p<0.01), peak workload, and oxygen pulse significantly improved in the CR group compared with the non-CR group, with a tendency towards improvement in mental health-related QOL. Quadriceps strength and heart failure (HF) symptoms (WHO functional class, 2.2–1.8, p=0.01) significantly improved within the CR group. During the CR, no patient experienced adverse events or deterioration of right-sided HF or haemodynamics as confirmed via catheterisation. Conclusions The combination of BPA and subsequent CR is a new treatment strategy for inoperable CTEPH to improve exercise capacity to near-normal levels and HF symptoms, with a good safety profile.

Successful balloon pulmonary angioplasty with gadolinium contrast media for a patient with chronic thromboembolic pulmonary hypertension and iodine allergy

A 28-year-old male was referred to our hospital with dyspnea. He was diagnosed as having chronic thromboembolic pulmonary hypertension, and a pulmonary endarterectomy (PEA) was performed. However, exertional dyspnea remained because of residual pulmonary hypertension; therefore, the patient was re-admitted to our hospital 1 year after PEA. We performed computed tomography and pulmonary angiography and found web and band lesions in the distal pulmonary artery with a high pulmonary artery pressure. Although further management was complicated because the patient had an anaphylactic shock to iodine-based contrast media, we eventually completed five sessions of balloon pulmonary angioplasty (BPA) using gadolinium contrast medium. His symptoms and hemodynamics dramatically improved after a series of BPA. After 15 months, mean pulmonary arterial pressure reduced from 67 mmHg to 20 mmHg, and subjective symptoms improved from stage Ⅳ to I as per the WHO classification system. BPA is a potential procedure for residual pulmonary hypertension after PEA and could be safely performed using gadolinium contrast medium for patients with iodine allergy.

Congenitally Corrected Transposition of the Great Arteries and Situs Inversus in an Octogenarian With Systemic Right Ventricular Failure

Systemic right ventricular (RV) failure in patients with congenitally corrected transposition of the great arteries (ccTGA), a major cause of mortality in the long-term follow-up, is usually induced by concomitant severe morphologically tricuspid regurgitation (TR) with/without Ebsteins anomaly or progressive conduction tissue disturbances. However, whether or not myocardial fibrosis is a common cause of systemic RV failure in patients with ccTGA remains unclear. Here, we describe an 82-year-old man who had been diagnosed previously as having uncomplicated ccTGA and situs inversus and recently developed systemic RV failure, which was neither associated with severe TR nor advanced conduction tissue abnormalities. Cardiovascular magnetic resonance (CMR) with delayed-enhancement imaging clearly detected extensive myocardial scars (presumably fibrosis) in the RV wall as well as prominent dilatation, hypertrophy, and systolic dysfunction of the systemic RV. These findings suggest that myocardial fibrosis can cause systemic RV failure in elderly patients with uncomplicated ccTGA despite the absence of severe TR or advanced conduction tissue abnormalities and that CMR may be a useful examination to accurately detect systemic RV failure associated with myocardial fibrosis and to subsequently clarify the prognosis in these patients.

Thalidomide for Hereditary Hemorrhagic Telangiectasia With Pulmonary Arterial Hypertension

initiate thalidomide, which increases platelet-derived growth factor-B expression and downregulates vascular endothelial growth factor in endothelial cells, stimulating mural cell coverage and leading to normal vascular maturation.1,2 After the initiation of thalidomide (50 mg daily), the anemia was dramatically improved without blood transfusion (Figure H) and telangiectatic lesions in the tongue were no longer notable (Figure A-2). Although intensive therapy with pulmonary vasodilators might induce bleeding, we were able to add tadalafil 10 mg daily and increase ambrisentan to 7.5 mg daily without any bleeding side-effects. Twelve months after thalidomide treatment, right heart failure developed with deteriorating pulmonary hemodynamics (mean PAP, 90 mmHg; cardiac index, 1.88 L/min/m2; Table, January 2014). Wedged distal pulmonary angiography showed markedly decreased peripheral vessels (Figure I-2) as compared with that before thalidomide therapy (Figure I-1). After the discontinuation of thalidomide, the bleeding recurred and PAH did not improve, as reflected by serial changes in B-type natriuretic peptide and tricuspid regurgitation pressure gradient (Figure G,H). Finally, the patient died due to right heart failure. Thalidomide was beneficial against mucocutaneous bleeding,1–7 but careful consideration is required with regard to its initiation in HHT patients with PAH.