Toshiaki Mano

Activation of Matrix Metalloproteinases Precedes Left Ventricular Remodeling in Hypertensive Heart Failure Rats: Its Inhibition as a Primary Effect of Angiotensin-Converting Enzyme Inhibitor

Background—Matrix metalloproteinases (MMPs) are activated in dilated failing hearts, and angiotensin-converting enzyme (ACE) inhibition prevents left ventricular (LV) dilatation. However, it remains unclear whether activation of MMPs precedes or is secondary to LV remodeling, and an effect of ACE inhibition on MMPs is unknown. Methods and Results—Dahl salt-sensitive rats fed a high-salt diet from 8 weeks served as the hypertensive heart failure (HF) model. LV echo, histological study, measurement of mRNA levels, and gelatin zymography were performed before (at 23 weeks) and after (at 26 weeks) the development of LV dilatation and pulmonary edema. The same procedures were conducted in the HF model rats treated with a subdepressor dose of ACE inhibitor (enalapril 5 mg · kg−1 · d−1) from 9 weeks. Rats fed on normal chow served as age-matched controls. In the untreated HF model rats, gene expression of MMP-2 and MMP-9 and tissue gelatinase activity were elevated at 23 weeks without LV dilatation. LV dilatation, LV systolic dysfunction, and pulmonary edema occurred at 26 weeks, with further enhancement of the expression and activity of MMPs. ACE inhibition prevented such geometrical and functional deterioration. The gene expression and activity of MMPs were suppressed by ACE inhibition at 23 weeks without a decrease in blood pressure, and the suppressive effects continued at 26 weeks. Conclusions—MMPs are likely to trigger and promote LV remodeling, and ACE inhibition directly exerts inhibitory effect on MMPs, leading to the prevention of LV remodeling and dysfunction.

AT1 Receptor Blocker Added to ACE Inhibitor Provides Benefits at Advanced Stage of Hypertensive Diastolic Heart Failure

Abstract—Diastolic heart failure (DHF) has become a social burden; however, evidences leading to its therapeutic strategy are lacking. This study investigated effects of addition of angiotensin II type 1 receptor blocker (ARB) to angiotensin-converting enzyme inhibitor (ACEI) at advanced stage of DHF in hypertensive rats. Dahl salt-sensitive rats fed 8% NaCl diet from age 7 weeks served as DHF model, and those fed a normal chow served as control. The DHF model rats were arbitrarily assigned to 3 treatment regimens at age 17 weeks: ACEI (temocapril 0.4 mg/kg per day), combination of ACEI (temocapril 0.2 mg/kg per day) with ARB (olmesartan 0.3 mg/kg per day), or placebo. At age 17 weeks, this model represents progressive ventricular hypertrophy and fibrosis, relaxation abnormality, and myocardial stiffening. Data were collected at age 20 weeks. As compared with the monotherapy with ACEI, the addition of ARB induced more prominent suppression of ventricular hypertrophy and fibrosis, leading to suppression of myocardial stiffening, improvement of relaxation, and inhibition of hemodynamic deterioration. Such benefits were associated with greater decreases in reactive oxygen species (ROS) generation, macrophage infiltration, and gene expression of transforming growth factor (TGF)-&bgr;1 and interleukin (IL)-1&bgr;, but not with changes in gene expression of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-&agr;. Thus, ARB added to ACEI provides more benefits as compared with ACEI alone in DHF when initiated at an advanced stage. The additive effects are likely provided through more prominent suppression of ROS generation and inflammatory changes without effects on expression of MCP-1 and TNF-&agr;.

Interleukin-18 gene deletion protects against sepsis-induced cardiac dysfunction by inhibiting PP2A activity

BACKGROUND Interleukin-18 (IL-18) neutralization protects against lipopolysaccharide (LPS)-induced injuries, including myocardial dysfunction. However, the mechanism is yet to be fully elucidated. The aim of the present study was to determine whether IL-18 gene deletion prevents sepsis-induced cardiac dysfunction and to elucidate the potential mechanisms underlying IL-18-mediated cardiotoxicity by LPS. METHODS AND RESULTS Ten-week-old male wild-type (WT) and IL-18 knockout (IL-18 KO) mice were intraperitoneally administered LPS. Serial echocardiography showed better systolic pump function and less left ventricular (LV) dilatation in LPS-treated IL-18 KO mice compared with those in LPS-treated WT mice. LPS treatment significantly decreased the levels of phospholamban (PLN) and Akt phosphorylation in WT mice compared with those in saline-treated WT mice, while the LPS-induced decrease in the phosphorylation levels was attenuated in IL-18 KO mice compared with that in WT mice. IL-18 gene deletion also attenuated an LPS-induced increase of type 2 protein phosphatase 2A (PP2A) activity, a molecule that dephosphorylates PLN and Akt. There was no difference in type 1 protein phosphatase (PP1) activity. To address whether IL-18 affects PLN and Akt phosphorylation via PP2A activation in cardiomyocytes, rat neonatal cardiac myocytes were cultured and stimulated using 100ng/ml of recombinant rat IL-18. Exogenous IL-18 decreased the level of PLN and Akt phosphorylation in cardiomyocytes. PP2A activity but not PP1 activity was increased by IL-18 stimulation in cardiomyocytes. CONCLUSIONS IL-18 plays a pivotal role in advancing sepsis-induced cardiac dysfunction, and the mechanisms underlying IL-18-mediated cardiotoxicity potentially involve the regulation of PLN and Akt phosphorylation through PP2A activity.

Transferrin Receptor 1 in Chronic Hypoxia-Induced Pulmonary Vascular Remodeling

BACKGROUND Iron is associated with the pathophysiology of several cardiovascular diseases, including pulmonary hypertension (PH). In addition, disrupted pulmonary iron homeostasis has been reported in several chronic lung diseases. Transferrin receptor 1 (TfR1) plays a key role in cellular iron transport. However, the role of TfR1 in the pathophysiology of PH has not been well characterized. In this study, we investigate the role of TfR1 in the development of hypoxia-induced pulmonary vascular remodeling. METHODS PH was induced by exposing wild-type (WT) mice and TfR1 hetero knockout mice to hypoxia for 4 weeks and evaluated via assessment of pulmonary vascular remodeling, right ventricular (RV) systolic pressure, and RV hypertrophy. In addition, we assessed the functional role of TfR1 in pulmonary artery smooth muscle cells in vitro. RESULTS The morphology of pulmonary arteries did not differ between WT mice and TfR1 hetero knockout mice under normoxic conditions. In contrast, TfR1 hetero knockout mice exposed to 4 weeks hypoxia showed attenuated pulmonary vascular remodeling, RV systolic pressure, and RV hypertrophy compared with WT mice. In addition, the depletion of TfR1 by RNA interference attenuated human pulmonary artery smooth muscle cells proliferation induced by platelet-derived growth factor-BB (PDGF-BB) in vitro. CONCLUSIONS These results suggest that TfR1 plays an important role in the development of hypoxia-induced pulmonary vascular remodeling.

Interleukin-18 disruption suppresses hypoxia-induced pulmonary artery hypertension in mice

Article history: Received 31 July 2015 Received in revised form 24 September 2015 Accepted 28 September 2015 Available online 03 October 2015 atria, RV free wall was removed from left ventricle (LV). Each ventricle was weighed and the ratio of RV weight to LV plus septum weight (RV/LV + Sp) was calculated. Lungs were fixed with 4% buffered paraformaldehyde for 24 h, embedded in paraffin, and cut into 4-μm-thick sections. Hematoxylineosin (HE) and Elastica van Gieson (EVG) stainings were performed using standard protocols. Immunofluorescence staining was performed using a primary anti-α-smooth muscle actin (α-SMA) mouse antibody

Report of the American College of Cardiology (ACC) Scientific Sessions 2016, Chicago

The 65(th)Annual Scientific Sessions of the American College of Cardiology (ACC) were held at McCormick Place, Chicago, from April 2-4, 2016. The ACC Scientific Sessions are one of the 2 major scientific cardiology meetings in the USA and one of the major scientific meetings of cardiology in the world. It had an attendance of 18,769 and over 2,000 oral and poster abstracts, including 8 late-breaking clinical trials. This report presents the key presentations and the highlights from the ACC Scientific Sessions 2016 in Chicago. (Circ J 2016; 80: 1308-1313).

Temporary dietary iron restriction affects the process of thrombus resolution in a rat model of deep vein thrombosis.

Background Deep vein thrombosis (DVT) is a major cause of pulmonary thromboembolism and sudden death. Thus, it is important to consider the pathophysiology of DVT. Recently, iron has been reported to be associated with thrombotic diseases. Hence, in this study, we investigate the effects of dietary iron restriction on the process of thrombus resolution in a rat model of DVT. Methods We induced DVT in 8-week-old male Sprague-Dawley rats by performing ligations of their inferior venae cavae. The rats were then given either a normal diet (DVT group) or an iron-restricted diet (DVT+IR group). Thrombosed inferior venae cavae were harvested at 5 days after ligation. Results The iron-restricted diet reduced venous thrombus size compared to the normal diet. Intrathrombotic collagen content was diminished in the DVT+IR group compared to the DVT group. In addition, intrathrombotic gene expression and the activity of matrix metalloproteinase-9 were increased in the DVT+IR group compared to the DVT group. Furthermore, the DVT+IR group had greater intrathrombotic neovascularization as well as higher gene expression levels of urokinase-type plasminogen activator and tissue-type plasminogen activator than the DVT group. The iron-restricted diet decreased intrathrombotic superoxide production compared to the normal diet. Conclusions These results suggest that dietary iron restriction affects the process of thrombus resolution in DVT.

Adaptive Servo-Ventilation Treatment Increases Stroke Volume in Stable Systolic Heart Failure Patients With Low Tricuspid Annular Plane Systolic Excursion

We hypothesized that the effects of adaptive servo-ventilation (ASV) therapy were influenced by right-sided heart performance. This study aimed to clarify the interaction between the effects of ASV and right-sided heart performance in patients with stable heart failure (HF) with reduced ejection fraction (HFrEF).Twenty-six stable HF inpatients (left ventricular ejection fraction < 0.45, without moderate to severe mitral regurgitation (MR) were analyzed. Echocardiography was performed before and after 30 minutes of ASV. ASV increased stroke volume index (SVI) in 14 patients (30.0 ± 11.9 to 41.1 ± 16.1 mL/m2) and reduced SVI in 12 patients (36.0 ± 10.1 to 31.9 ± 12.2 mL/m2). Multivariate linear regression analysis revealed that tricuspid annular plane systolic excursion (TAPSE) before ASV was an independent association factor for (SV during ASV - SV before ASV)/LVEDV × 100 (%) (%ΔSV/LVEDV). ROC analysis of TAPSE for %ΔSV/LVEDV > 0 showed that the cut-off point was 16.5 mm. All patients were divided into 2 groups according to the TAPSE value. Although no significant differences were found in the baseline characteristics and blood tests, there were significant differences in tricuspid lateral annular systolic velocity, TAPSE, right atrial area, and right ventricular (RV) area before ASV between patients with TAPSE ≤ 16.5 mm and those with TAPSE > 16.5 mm. Interestingly, ASV reduced RV area and increased TAPSE in patients with TAPSE ≤ 16.5 mm, while it reduced TAPSE in those > 16.5 mm.ASV therapy has the potential to increase SVI in stable HFrEF patients with low TAPSE.

Long-term administration of tolvaptan increases myocardial remodeling and mortality via exacerbation of congestion in mice heart failure model after myocardial infarction.

BACKGROUND In contrast to loop diuretics, tolvaptan does not cause neurohormonal activation in several animal heart failure models. However, it remains unknown whether chronic vasopressin type 2 receptor blockade exerts beneficial effects on mortality in murine heart failure after myocardial infarction (MI). In an experimental heart failure model, we tested the hypothesis that tolvaptan reduces myocardial remodeling and mortality. METHODS AND RESULTS MI was induced in 9-week-old male C57Bl6/J by the left coronary artery ligation. In study 1, animals were randomly assigned to treatment with placebo or tolvaptan starting 14days post-MI. In study 2, animals were randomized to tolvaptan or furosemide+tolvaptan starting 14days post-MI. Interestingly, results showed lower survival rate in tolvaptan group compared to placebo. Tolvaptan group had higher serum osmolality, heavier body weight, more severe myocardial remodeling, and lung congestion at day 28 of drug administration compared to placebo. In study 2, addition of furosemide significantly reduced mortality rate seen with tolvaptan, and presented with decreased osmolality, myocardial remodeling, and lung congestion compared to tolvaptan-treated mice. Increase in proximal tubular expression of aquaporin 1, Angiotensin II, and vasopressin seen with tolvaptan treatments were normalized to basal levels, similar to levels in placebo-treated mice. CONCLUSIONS Contrary to our hypothesis, tolvaptan was associated with increased mortality in murine heart failure after MI. This increase in lung congestion, myocardial remodeling, could be prevented by co-administration of furosemide, which resulted in normalized serum osmolality, neurohormonal activation, and renal aquaporin 1 expression, and hence decreased mortality post-MI.

Correlates and Prognostic Values of Appearance of L Wave in Heart Failure Patients With Preserved vs. Reduced Ejection Fraction

BACKGROUND Mid-diastolic mitral forward flow (L wave) is occasionally detected in heart failure (HF), but its correlates and prognostic value are still unknown, particularly in light of the type of HF, that is, HF with preserved or with reduced ejection fraction (HFpEF, HFrEF). Methods and Results: Of 151 patients with HF, L wave was observed in 23 of 82 HFrEF patients and in 25 of 69 HFpEF patients. Mitral early diastolic velocity (E), the ratio of E to mitral annulus velocity, and left atrial volume index were greater in the patients with L wave than in those without L wave in both subsets. Left ventricular (LV) mass index and relative wall thickness were greater in the patients with L wave than in those without L wave in the HFpEF group, but there was no difference in either parameter in the HFrEF group. Prognosis was poorer in those with L wave than in those without L wave both in the HFrEF and HFpEF groups. CONCLUSIONS Appearance of L wave is associated with the degree of LV diastolic dysfunction, but there was a difference in LV geometrical correlates of the appearance of L wave between the HFpEF and HFrEF groups. Detection of L wave is suggestive of poor prognosis independent of LVEF in HF.