Takaaki Senbonmatsu

The (pro)renin receptor is cleaved by ADAM19 in the Golgi leading to its secretion into extracellular space

The (pro)renin receptor ((P)RR), which is a recently discovered molecule of the renin–angiotensin system, plays an important role in the development of cardiovascular diseases. However, the molecular properties and the subcellular distribution of (P)RR remain controversial. In this study, (P)RR-Venus in Chinese hamster ovary (CHO) cells ((P)RR-Venus-CHO) or endogenous (P)RR in human vascular smooth muscle cells (VSMC) were constitutively cleaved without any stimulation, and secretion of the amino-terminal fragment (NTF-(P)RR) into the media was determined using western blot analysis. Immunofluorescent analysis showed robust expression of (P)RR in the endoplasmic reticulum (ER) or the Golgi but not in the plasma membrane. Moreover, we identified ADAM19, which is expressed in the Golgi, as one of cleaving proteases of (P)RR. Transfected ADAM19 evoked the shedding of (P)RR, whereas transfected dominant negative ADAM19 suppressed it. Although (P)RR contains a furin cleavage site, neither the furin-deficient LoVo cells nor furin inhibitor-treated VSMC lost NTF-(P)RR in the media. The secreted NTF-(P)RR induced the renin activity of prorenin in the extracellular space. We describe that (P)RR is mainly localized in the subcellular organelles, such as the ER and Golgi, and (P)RR is cleaved by ADAM19 in the Golgi resulting in two fragments, NTF-(P)RR and CTF-(P)RR. These results may suggest that (P)RR is predominantly secreted into the extracellular space.

Impact of hypoalbuminemia, frailty, and body mass index on early prognosis in older patients (≥85 years) with ST-elevation myocardial infarction

BACKGROUND The optimal treatment strategies for acute ST-elevation myocardial infarction (STEMI) in older patients are unclear because of the high risk of mortality in this population. Hypoalbuminemia, frailty, and body mass index (BMI) have been reported to worsen the prognosis of some older patients with cardiovascular disease, but the specific impact of these factors on the prognosis after STEMI is poorly understood. The aim of this study was to investigate the impact of these factors on early outcomes in patients aged ≥85 years with acute STEMI. METHODS Sixty-two consecutive eligible patients aged ≥85 years (mean age, 88.1±2.5 years; age range, 85-94 years; female, 41.9%; primary percutaneous coronary intervention, 67.7%) who were admitted to our hospital with STEMI were retrospectively reviewed. Baseline patient characteristics, echocardiographic, electrocardiographic, and laboratory findings, and the Canadian Study of Health and Aging Clinical Frailty Scale (CSHA-CFS) score were assessed. The primary endpoint was in-hospital mortality and the secondary endpoint was failure of discharge to home. Independent baseline variables with a p-value of <0.15 in the univariate analyses were included in the multivariate analyses. RESULTS Multivariate analysis identified a higher baseline serum troponin I level [p=0.046; odds ratio (OR): 1.02], lower baseline albumin level (p=0.035, OR: 0.16), and CSHA-CFS score ≥6 (p=0.028, OR: 6.38) as independent predictors of in-hospital mortality. Lower BMI (p<0.001, OR: 0.49) and CSHA-CFS frailty score ≥6 (p=0.002, OR: 16.69) were identified as independent predictors of failure of discharge to home. CONCLUSIONS These findings indicate that the serum albumin level, CSHA-CFS score, and BMI, in addition to serum troponin I level, have an impact on the early prognosis of older patients with STEMI.

Beneficial Effects of Canagliflozin in Combination with Pioglitazone on Insulin Sensitivity in Rodent Models of Obese Type 2 Diabetes

Background Despite its insulin sensitizing effects, pioglitazone may induce weight gain leading to an increased risk of development of insulin resistance. A novel sodium glucose co-transporter 2 (SGLT2) inhibitor, canagliflozin, provides not only glycemic control but also body weight reduction through an insulin-independent mechanism. The aim of this study was to investigate the combined effects of these agents on body weight control and insulin sensitivity. Methods Effects of combination therapy with canagliflozin and pioglitazone were evaluated in established diabetic KK-Ay mice and prediabetic Zucker diabetic fatty (ZDF) rats. Results In the KK-Ay mice, the combination therapy further improved glycemic control compared with canagliflozin or pioglitazone monotherapy. Furthermore, the combination significantly attenuated body weight and fat gain induced by pioglitazone and improved hyperinsulinemia. In the ZDF rats, early intervention with pioglitazone monotherapy almost completely prevented the progressive development of hyperglycemia, and no further improvement was observed by add-on treatment with canagliflozin. However, the combination significantly reduced pioglitazone-induced weight gain and adiposity and improved the Matsuda index, suggesting improved whole-body insulin sensitivity. Conclusions Our study indicates that combination therapy with canagliflozin and pioglitazone improves insulin sensitivity partly by preventing glucotoxicity and, at least partly, by attenuating pioglitazone-induced body weight gain in two different obese diabetic animal models. This combination therapy may prove to be a valuable option for the treatment and prevention of obese type 2 diabetes.

Cardiac magnetic resonance imaging-based myocardial strain study for evaluation of cardiotoxicity in breast cancer patients treated with trastuzumab: A pilot study to evaluate the feasibility of the method.

BACKGROUND Trastuzumab, used to treat breast cancer overexpressing human epidermal growth factor receptor 2, may be cardiotoxic. Cardiac magnetic resonance (CMR) imaging with myocardial strain studies has been used to evaluate subclinical biventricular myocardial changes, however, its clinical utility during chemotherapy has not been evaluated. METHODS The clinical outcomes, CMR and cardiac biomarkers of 9 women aged 62.3 ± 12.6 years with early or locally advanced breast cancer were evaluated at baseline, and at 3, 6 and 12 months after the initiation of trastuzumab. RESULTS None of the patients developed heart failure or elevated serum cardiac biomarkers. Global left ventricular (LV) peak systolic longitudinal and circumferential strains were significantly decreased at 6 months (longitudinal strains, -21.1 ± 1.7% [baseline] vs. -19.5 ± 1.0% [6 months], p = 0.039, and circumferential strains, -23.4 ± 1.8% [baseline] vs. -21.6 ± 2.5% [6 months], p = 0.036). These changes were analogous to those observed in the LV ejection fraction. Right ventricular (RV) free wall peak systolic circumferential strains were decreased at 6 months (-20.9% ± 2.4% [baseline] vs. -19.1% ± 2.3% [6 months], p = 0.049), whereas RV longitudinal strains and ejection fraction remained unchanged. The LV longitudinal strain was the most reproducible of the 4 peak strain parameters. CONCLUSIONS The LV longitudinal and circumferential strains measured by CMR decreased during trastuzumab therapy, although their predictive value for later heart failure or association with RV parameters was not determined. These techniques may be a useful means of diagnosing and monitoring trastuzumab-related cardiotoxicity.

The effect of adaptive servo-ventilation on dyspnoea, haemodynamic parameters and plasma catecholamine concentrations in acute cardiogenic pulmonary oedema

Background: Adaptive servo-ventilation has a potential sympathoinhibitory effect in acute cardiogenic pulmonary oedema (ACPO). Aims: To evaluate the acute effects of adaptive servo-ventilation in patients with ACPO. Methods: Fifty-eight consecutive patients with ACPO were divided into those who underwent adaptive servo-ventilation and those who received oxygen therapy alone as part of their immediate care. Visual analogue scale, vital signs, blood gas data and plasma catecholamine concentrations at baseline and 1 h during emergency care, and subsequent clinical events (death within 30 days, intubation within seven days or between seven and 30 days, and length of hospital stay) were assessed. Pre-matched and post-propensity score (PS)-matched datasets were analysed. Results: During the first hour of adaptive servo-ventilation, plasma catecholamine concentrations fell significantly (baseline versus 1 h: epinephrine p = 0.003, norepinephrine p <0.001, dopamine p <0.001), with falls in blood pressure, heart rate, respiratory rate and pCO2, and rise in HCO3 and pH. In the PS-matched model, visual analogue scale (p = 0.036), systolic blood pressure (from 153.8 ± 30.7 to 133.1 ± 16.3 mmHg; p = 0.025) and plasma dopamine concentration (p = 0.034) fell significantly in the adaptive servo-ventilation group compared with the oxygen therapy alone group. The clinical outcomes between the groups were comparable. Conclusion: In patients with ACPO, emergency care using adaptive servo-ventilation attenuated plasma catecholamine concentrations and led to the improvement of dyspnoea, vital signs and acid-base balance, without adversely influencing clinical outcomes. Using adaptive servo-ventilation, rather than standard oxygen alone, may relieve dyspnoea and improve haemodynamic status, possibly by modulating sympathetic nerve activity.

Cardiac Magnetic Resonance Imaging in Giant Cell Myocarditis Intriguing Associations With Clinical and Pathological Features

Giant cell myocarditis (GCM) is rare and often fatal. Proper diagnosis is crucial, because immunosuppressive therapy has been reported to increase the median transplant-free survival time from 3.0 to 12.3 months.1 Although endomyocardial biopsy plays an essential role in early diagnosis, it may yield false-negative results. Imaging examinations including cardiac magnetic resonance (CMR) may facilitate the diagnosis, but the associations between specific CMR findings and the clinical features and pathological findings remain unclear. We present a patient with characteristic CMR findings, with intriguing associations with the clinical features and pathological findings of the biopsy and autopsy. A 73-year-old woman presented with acute chest pain and dyspnea that had continued for 7 hours. Her medical history was unremarkable, with the exception of uveitis and dyslipidemia. Initial examination showed resting blood pressure 132/83 mm Hg, heart rate 103 bpm, and respiratory rate 17 breaths/min. She required 5 L/min of oxygen via facemask to maintain Spo2>98%. Coarse crackles were heard over both lung fields. X-ray demonstrated mild cardiomegaly with bilateral pulmonary congestion (Figure 1). Electrocardiography, which had been within normal limits 2 years previously, showed changes resembling acute myocardial infarction (Figure I in the online-only Data Supplement). Echocardiography showed global hypokinesis in the left ventricular (LV) wall, and regional akinesis in the septum and inferoseptal wall. Coronary artery angiography revealed no significant stenosis or intracoronary plaque rupture. Her serum creatinine kinase level was high at 2558 IU/L. CMR was performed on day 7. Cine-CMR showed global hypokinesis in …

Improved Myocardial Strain Measured by Strain-Encoded Magnetic Resonance Imaging in a Patient With Cardiac Sarcoidosis

A woman aged 64 years with cardiac sarcoidosis responded favourably to corticosteroid therapy in terms of recovered longitudinal myocardial strain, as evaluated by strain-encoded magnetic resonance imaging (SENC-MRI). In contrast, circumferential myocardial strain and late gadolinium enhancement demonstrated minimal improvement, suggesting relatively advanced pathology of the myocardial middle layer. We propose SENC-MRI as a marker of disease at an early stage of cardiac sarcoidosis.

Left atrial appendage wall-motion velocity associates with recurrence of nonparoxysmal atrial fibrillation after catheter ablation.

Catheter ablation (CA) for nonparoxysmal atrial fibrillation (AF) is controversial due to its high recurrence rate. The aim of this study was to assess retrospectively the diagnostic value of preprocedural left atrial appendage (LAA) wall‐motion velocity in predicting recurrence of AF within 1 year after CA. We hypothesized that tissue Doppler‐derived measurement of LAA wall‐motion velocity associate with recurrence of AF within 1 year after CA. We retrospectively reviewed 47 consecutive patients with nonparoxysmal AF (defined as AF lasting for 1 week or longer) who underwent both transthoracic and transesophageal echocardiography before their first treatment by CA in a single center. Forty‐one patients aged 58 ± 10 years were included, and variables predicting the recurrence of AF within 1 year after CA were evaluated. Seventeen patients (41%) developed recurrence of AF within 1 year after CA. Univariate analyses showed that preprocedural LAA upward wall‐motion velocity at the apex assessed by transesophageal echocardiography was significantly lower in patients with recurrence of AF than those without recurrence (OR = 1.45, 95% CI: 1.13–2.01, P = 0.009). Multivariate logistic analyses including other potential predictors (duration of AF, left ventricular ejection fraction, E‐wave deceleration time, and left atrial wall‐motion velocity) identified LAA upward wall‐motion velocity at the apex as an independent predictor of outcome. These data suggest in patients with nonparoxysmal AF, preprocedural LAA upward wall‐motion velocity at the apex, as determined by tissue Doppler imaging during transesophageal echocardiography, may be a useful indicator for predicting recurrence of AF within 1 year after CA.

Clinical implications of pleural effusion in patients with acute type B aortic dissection.

Background: Pleural effusion may complicate acute Stanford type B aortic dissection (ABAD). Aims: To identify the relationships between the quantity and side of the pleural effusion, biomarkers and outcomes in patients with ABAD. Methods: We undertook a retrospective review of 105 patients with ABAD. Their demographics, the data on admission and during hospital stay, the volume of pleural effusion calculated from the area on computed tomography images and clinical outcomes were analysed. Results: The median estimated peak volume (median 6.7 days after onset) was 129 ml (63–192, range 26–514 ml) on the left and 11 ml (6–43, range 2–300 ml) on the right. On univariate analysis, the volume of bilateral effusions was associated with anaemia, hypoalbuminaemia and inflammatory markers, whereas the volume of left-sided effusions was associated with older age, low diastolic blood pressure and maximum aortic diameter. Multivariate analysis revealed that hypoalbuminaemia was independently associated with bilateral effusion volume (P<0.001), while maximum aortic diameter was associated with left-sided effusion volume (P=0.019). A greater volume of bilateral plural effusion was associated with longer intensive care unit stay. Conclusions: Larger bilateral pleural effusions in patients with ABAD were associated with hypoalbuminaemia and potentially with anaemia and inflammation, and may increase the length of intensive care unit stay. Left-sided effusion volume appears to be influenced by the nature of the aortic dilatation. Multiple mechanisms may underpin the development of pleural effusion in ABAD, and are likely to influence clinical outcomes.

Percutaneous Coronary Intervention for Septic Emboli in the Left Main Trunk as a Complication of Infective Endocarditis

Infective endocarditis (IE) complicated by acute myocardial infarction (AMI) is frequently fatal and may require emergent interventions. However, the optimal treatment of this rare condition remains controversial as it lacks established guidelines. We successfully treated a patient with IE complicated by AMI during the acute phase using percutaneous coronary intervention (PCI) followed by surgery. A 73-year-old man was diagnosed with IE of the mitral and aortic valves caused by Streptococcus oralis. Four weeks after the initiation of antibiotics sensitive to the causative bacteria, he suddenly developed AMI manifested by chest pain and dyspnoea with cardiovascular collapse. Emergent coronary angiography revealed that the myocardial infarction was secondary to septic emboli in the left main trunk. Emergent PCI comprising aspiration and stent deployment, was successfully performed, and his vital signs were immediately stabilised. He subsequently underwent mitral and aortic valve replacement and debridement without major post-operative complications. Although the optimal treatment strategy for haemodynamically unstable AMI secondary to IE requires further discussion, the present case indicates the importance of early diagnosis and the potential effectiveness of aggressive PCI as a bridge to the following surgery.