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Association between Nonobstructive Aortic Valve Calcification and Left Ventricular Diastolic Dysfunction in Patients with Preserved Ejection Fraction
The 21st Annual Scientific Meeting
O44-4 A Simple Non-invasive Method of Estimating Pulmonary Vascular Resistance by Doppler Echocardiography in Patients without Acute Exacerbated Left Heart Failure Yuichiro Mori, Satoshi Yuda, Shunsuke Sasaki, Masayuki Ohta, Hiroyuki Sato, Kandoh Kawahatsu, Yoshio Kazuno, Masato Kudo, Yasuhiro Ohmoto, Mitsugu Hirokami; Teine Keijinkai Hospital, Hokkaido, Japan Background: Assessment of pulmonary vascular resistance (PVR) plays an important role in managing patients with elevated pulmonary artery pressure. To date, several formulae for estimating PVR with echocardiography have been proposed. The problem is, however, most of them contain values not always measured in routine echocardiographic examination, which makes it difficult to assess one’s PVR retrospectively. The aim of this study is to investigate feasibility of a new simple echocardiographic measurement of PVR (PVRecho), peak tricuspid regurgitation pressure gradient divided by three times of left ventricular cardiac output derived from Doppler echocardiography (TRPG/3LVCO), in patients without acute exacerbated left-sided heart failure. Method: From July 2014 to May 2017, PVR calculated by right heart catheterization (PVRcath), and TRPG and LVCO by echocardiography were available in 57 patients. Patients with cardiac shunt, atrial fibrillation, severe mitral regurgitation, or emergency catheterization were excluded. Among these patients, PVRecho and PVRcath were compared using linear progression and Bland-Altman analysis. Result: Mean PVRcath was 2.2 ± 1.8 WU. PVRecho had a good correlation with PVRcath (r = 0.66, P < .001). On Bland-Altman analysis, the mean difference was 0.1 ± 1.3WU, which is comparable with other formulae previously reported. Patients with lower pulmonary capillary wedge pressure showed better correlation between PVRecho and PVRcath. Conclusion: The new simple formula for estimation of PVR showed comparable correlation with previously reported formulae.
O44-5 Association between Nonobstructive Aortic Valve Calcification and Left Ventricular Diastolic Dysfunction in Patients with Preserved Ejection Fraction Hiroto Utsunomiya, Takayuki Hidaka, Kanako Izumi, Yu Harada, Hitoshi Susawa, Mirai Kinoshita, Toshiro Kitagawa, Satoshi Kurisu, Hideya Yamamoto, Yasuki Kihara; Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan Background: The impact of aortic valve calcification (AVC) itself on cardiac structure and function remains unknown. Methods: We studied 621 patients with nonobstructive AVC (transaortic velocity <2.5 m/s) but normal ejection fraction. Early diastolic myocardial velocities at the mitral annulus (Ea) were obtained. Left ventricular (LV) concentric hypertrophy was defined as LVMI >47 g/m2.7 in women and >49 g/ m2.7 in men and relative wall thickness >0.43. CT scans were also performed to measure the AVCand coronary artery calcification (CAC) scores and the visceral adipose tissue (VAT) area. Results: Patients with AVC had a higher LVMI (42 ± 10 vs. 38 ± 10 g/ m2.7, P < .001) and LV mass/volume ratio (1.73 ± 0.64 vs. 1.51 ± 0.53 g/ml, P < .001), and had a higher prevalence of LV concentric hypertrophy (11.5 vs. 5.4%, P = .008) compared to no AVC group. After adjustment for demographic variables and other confounding factors including CAC score and VAT area, log-transformed AVC score was independently associated with septal and lateral Ea. Interestingly, despite further adjustment for LV mass/volume ratio, AVC score remained as an independent predictor for septal Ea (β-estimate [95%CI] −0.256 [−0.408 to −0.105], P = .001) and lateral Ea (−0.259 [−0.497 to −0.021], P = .033). Conclusion: AVC was independently associated with LV diastolic dysfunction even in patients with nonobstructive AVC. In addition to LV hypertrophy, other mechanism may lie between valve calcification and diastolic dysfunction.
O45-1 Novel Experimental Model Mimics Transition from Compensated Hypertrophy to Decompensated Cardiac Failure Koichi Nishimura1, Masanori Asakura1, Yositaka Okuhara1, Kazumichi Kashiwase1, Yoshiro Naito 1 , Shinichi Hirotani 2 , Masaharu Ishihara 1 , Tohru Masuyama 1 ; 1 Cardiovascular Division, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan; 2Cardiovascular Division, Kawachi General Hospital, Osaka, Japan Background: Transition to decompensated cardiac failure is the major concern in treatment of heart failure. However, no highly reproducible model that mimics this transition exists. Thus, we built a novel mouse model by incorporating β agonist in the compensated hypertrophy period induced by transverse aortic constriction (TAC). Methods and Results: In order to examine suitable durations of TAC before incorporating agonist, 10-week-old male C57BL6/J mice were randomly distributed into three groups: durations of one; two; or three weeks after TAC surgery. Followed by each TAC duration, mice received a low-dose isoproterenol infusion (3 mg/kg/day) for a week by osmotic pump. Proportion of transition to decompensated cardiac failure (FS < 50%) was 44.4% in one-week TAC group, 60.0% in two-week TAC group, and 91.7% in three-week TAC group (TAC3W+I) . We identified TAC3W+I as a new model suitable for mimicking transition to decompensated cardiac failure. HW/TL (10.75 ± 1.12 vs. 6.48 ± 0.53; P < .01) and LW/TL (11.10 ± 3.08 vs. 7.23 ± 0.34; P < .01) ratio was higher in TAC3W+I group compared to four-week sham. In histological examinations, TAC3W+I group
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showed increased myocyte cross-sectional area and fibrosis. Furthermore, Nppa and Col1/3 gene expression were increased in TAC3W+I group. Conclusion: Our new model can induce transition to decompensated cardiac failure with high reproducibility and within a relatively short period of time.
O45-2 PKG1α Oxidation Is Required for PDE5 Inhibition to Be Effective, Whereas sGC Activation Is Beneficial Regardless of PKG1α Redox Taishi Nakamura1, Kenichi Tsujita1, David A. Kass2; 1Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; 2Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, USA Background: Recent clinical heart failure studies have tested the therapeutic potential of enhancing protein kinase G 1α activity by blocking cGMP-selective phosphodiesterase type 5 or stimulating soluble guanylate cyclase (sGC). Their impact has varied, and mechanisms for the disparities remain poorly understood. As PKG1α oxidation alters its regulation of cardiac stress, we hypothesized this may also impact the efficacy of cGMP modulators. Methods and Results: Mice harboring a cysteine redox-insensitive PKG1α (PKG1αC42S) were more protected against pathological hypertrophy/fibrosis induced by trans-aortic constriction (TAC) versus controls. However, addition of a PDE5 inhibitor (sildenafil, SIL) improved heart structure, function, and histology in WT-TAC controls, but had no impact in PKG1αC42S mice. TAC augmented myocardial PKG activity similarly with both genotypes, but SIL increased activity further only in WT-TAC mice. The disparity was related to less PDE5 serine-92 phosphorylation (activation) in PKG1αC42S myocytes. By contrast, augmenting myocardial cGMP using sGC activator (Bay602770) countered cellular and organ-level dysfunction and hypertrophy regardless of the redox-form of PKG1α expressed. Conclusions: PKG1α oxidation reduces its efficacy to counter cardiac pathophysiology but concomitantly facilitates the therapeutic impact from PDE5 inhibition. The efficacy of sGC activation is unaffected by PKG1α redox. These results have implications for targeting different cGMP-enhancement strategies to treat heart disease, with PKG1α redox state being an important variable for predicting drug efficacy.
O45-3 Dpp4 Inhibitor Attenuates Cardiac Systolic Dysfunction in a Murine Dietary Obese Model by Promoting Fibroblast Growth Factor 2-mediated Angiogenesis Masayoshi Suda1, Ippei Shimizu1,2, Yohko Yoshida1,2, Tohru Minamino1; 1Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences; 2Department of Cardiovascular Biology and Medicine, Division of Molecular Aging and Cell Biology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan Dipeptidyl peptidase-4 (Dpp4) inhibitors are used worldwide to combat diabetes, however, their roles in cardiovascular disorders are yet to be defined. Here we show that a DPP4 inhibitor, linagliptin, contributes for the suppression of capillary rarefaction in diabetic heart and systolic dysfunction. The capillary rarefaction in dietary obese mice associated with high DPP4 level in circulation, and the administration of linagliptin suppressed the development of capillary rarefaction and ameliorated cardiac dysfunction. DNA micro array data showed that early growth response protein 1 (EGR1), known as an angiogenic transcription factor, is significantly reduced in the cardiac tissue upon metabolic stress, and this suppression was inhibited by the administration of linagliptin. Fibroblast growth factor 2 (FGF-2) has putative amino acid sequence cleaved by DPP4, and LC-MS/MS studies showed that DPP4 actually cleaves FGF-2. In vitro studies showed that FGF-2 contributes to up-regulation of Egr1 expression, and this was suppressed with DPP4. Furthermore, our studies suggested that vascular endothelial growth factor a (VEGFa) is the critical angiogenic factor mediating FGF-2-EGR-1 signaling. Our studies suggest that DPP4 inhibits FGF-2/EGR-1/VEGFa signaling in cardiac tissues. Suppression of DPP4 is crucial for the suppression of capillary rarefaction and cardiac dysfunction in diabetic heart.
O45-4 Impact of SGLT2 Inhibitor on Diabetic Cardiomyopathy-role of Glucagon-insulin Axis Takahiro Kamihara, Yasuko K. Bando, Kazuyuki Nishiura, Remina Yasheng, Haruya Kawase, Toyoaki Murohara; Department of cardiology, Nagoya University Graduate School of Medicine Background: Clinical trials revealed that the protective impact of SGLT2 inhibitor (SGLT2i) on heart failure via its diuretic effect without hypoglycemia. It remains uncertain whether these effects may be drug-class and whether SGLT2i may affect myocardium. We hypothesized whether SGLT2i may protect heart via glucagon, a counter hormone against insulin that promotes not only glucose-elevating effects but also inotropic effects on heart. Methods: Male 18 week-old C57BL6 mice were randomly allocated in non-diabetic and streptozotocin-induced T1DM group with or without canagliflozin (CAN; 10 mg/kg/day for 4 weeks)(n = 4–6, ea). Results: In nondiabetic mice, CAN had no effects on blood sugar, body weight, systolic left-ventricular (LV) function [FS (%); 44.3 ± 3.7], and chamber size [LVDd/Ds (mm); 2.6/1.4 mm]. However, heart size and circulating Gcg concentration [HW(mg); 119.2 ± 6.8 and HW/BW;
O44-4 A Simple Non-invasive Method of Estimating Pulmonary Vascular Resistance by Doppler Echocardiography in Patients without Acute Exacerbated Left Heart Failure Yuichiro Mori, Satoshi Yuda, Shunsuke Sasaki, Masayuki Ohta, Hiroyuki Sato, Kandoh Kawahatsu, Yoshio Kazuno, Masato Kudo, Yasuhiro Ohmoto, Mitsugu Hirokami; Teine Keijinkai Hospital, Hokkaido, Japan Background: Assessment of pulmonary vascular resistance (PVR) plays an important role in managing patients with elevated pulmonary artery pressure. To date, several formulae for estimating PVR with echocardiography have been proposed. The problem is, however, most of them contain values not always measured in routine echocardiographic examination, which makes it difficult to assess one’s PVR retrospectively. The aim of this study is to investigate feasibility of a new simple echocardiographic measurement of PVR (PVRecho), peak tricuspid regurgitation pressure gradient divided by three times of left ventricular cardiac output derived from Doppler echocardiography (TRPG/3LVCO), in patients without acute exacerbated left-sided heart failure. Method: From July 2014 to May 2017, PVR calculated by right heart catheterization (PVRcath), and TRPG and LVCO by echocardiography were available in 57 patients. Patients with cardiac shunt, atrial fibrillation, severe mitral regurgitation, or emergency catheterization were excluded. Among these patients, PVRecho and PVRcath were compared using linear progression and Bland-Altman analysis. Result: Mean PVRcath was 2.2 ± 1.8 WU. PVRecho had a good correlation with PVRcath (r = 0.66, P < .001). On Bland-Altman analysis, the mean difference was 0.1 ± 1.3WU, which is comparable with other formulae previously reported. Patients with lower pulmonary capillary wedge pressure showed better correlation between PVRecho and PVRcath. Conclusion: The new simple formula for estimation of PVR showed comparable correlation with previously reported formulae.
O44-5 Association between Nonobstructive Aortic Valve Calcification and Left Ventricular Diastolic Dysfunction in Patients with Preserved Ejection Fraction Hiroto Utsunomiya, Takayuki Hidaka, Kanako Izumi, Yu Harada, Hitoshi Susawa, Mirai Kinoshita, Toshiro Kitagawa, Satoshi Kurisu, Hideya Yamamoto, Yasuki Kihara; Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan Background: The impact of aortic valve calcification (AVC) itself on cardiac structure and function remains unknown. Methods: We studied 621 patients with nonobstructive AVC (transaortic velocity <2.5 m/s) but normal ejection fraction. Early diastolic myocardial velocities at the mitral annulus (Ea) were obtained. Left ventricular (LV) concentric hypertrophy was defined as LVMI >47 g/m2.7 in women and >49 g/ m2.7 in men and relative wall thickness >0.43. CT scans were also performed to measure the AVCand coronary artery calcification (CAC) scores and the visceral adipose tissue (VAT) area. Results: Patients with AVC had a higher LVMI (42 ± 10 vs. 38 ± 10 g/ m2.7, P < .001) and LV mass/volume ratio (1.73 ± 0.64 vs. 1.51 ± 0.53 g/ml, P < .001), and had a higher prevalence of LV concentric hypertrophy (11.5 vs. 5.4%, P = .008) compared to no AVC group. After adjustment for demographic variables and other confounding factors including CAC score and VAT area, log-transformed AVC score was independently associated with septal and lateral Ea. Interestingly, despite further adjustment for LV mass/volume ratio, AVC score remained as an independent predictor for septal Ea (β-estimate [95%CI] −0.256 [−0.408 to −0.105], P = .001) and lateral Ea (−0.259 [−0.497 to −0.021], P = .033). Conclusion: AVC was independently associated with LV diastolic dysfunction even in patients with nonobstructive AVC. In addition to LV hypertrophy, other mechanism may lie between valve calcification and diastolic dysfunction.
O45-1 Novel Experimental Model Mimics Transition from Compensated Hypertrophy to Decompensated Cardiac Failure Koichi Nishimura1, Masanori Asakura1, Yositaka Okuhara1, Kazumichi Kashiwase1, Yoshiro Naito 1 , Shinichi Hirotani 2 , Masaharu Ishihara 1 , Tohru Masuyama 1 ; 1 Cardiovascular Division, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan; 2Cardiovascular Division, Kawachi General Hospital, Osaka, Japan Background: Transition to decompensated cardiac failure is the major concern in treatment of heart failure. However, no highly reproducible model that mimics this transition exists. Thus, we built a novel mouse model by incorporating β agonist in the compensated hypertrophy period induced by transverse aortic constriction (TAC). Methods and Results: In order to examine suitable durations of TAC before incorporating agonist, 10-week-old male C57BL6/J mice were randomly distributed into three groups: durations of one; two; or three weeks after TAC surgery. Followed by each TAC duration, mice received a low-dose isoproterenol infusion (3 mg/kg/day) for a week by osmotic pump. Proportion of transition to decompensated cardiac failure (FS < 50%) was 44.4% in one-week TAC group, 60.0% in two-week TAC group, and 91.7% in three-week TAC group (TAC3W+I) . We identified TAC3W+I as a new model suitable for mimicking transition to decompensated cardiac failure. HW/TL (10.75 ± 1.12 vs. 6.48 ± 0.53; P < .01) and LW/TL (11.10 ± 3.08 vs. 7.23 ± 0.34; P < .01) ratio was higher in TAC3W+I group compared to four-week sham. In histological examinations, TAC3W+I group
•
JHFS
S55
showed increased myocyte cross-sectional area and fibrosis. Furthermore, Nppa and Col1/3 gene expression were increased in TAC3W+I group. Conclusion: Our new model can induce transition to decompensated cardiac failure with high reproducibility and within a relatively short period of time.
O45-2 PKG1α Oxidation Is Required for PDE5 Inhibition to Be Effective, Whereas sGC Activation Is Beneficial Regardless of PKG1α Redox Taishi Nakamura1, Kenichi Tsujita1, David A. Kass2; 1Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; 2Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, USA Background: Recent clinical heart failure studies have tested the therapeutic potential of enhancing protein kinase G 1α activity by blocking cGMP-selective phosphodiesterase type 5 or stimulating soluble guanylate cyclase (sGC). Their impact has varied, and mechanisms for the disparities remain poorly understood. As PKG1α oxidation alters its regulation of cardiac stress, we hypothesized this may also impact the efficacy of cGMP modulators. Methods and Results: Mice harboring a cysteine redox-insensitive PKG1α (PKG1αC42S) were more protected against pathological hypertrophy/fibrosis induced by trans-aortic constriction (TAC) versus controls. However, addition of a PDE5 inhibitor (sildenafil, SIL) improved heart structure, function, and histology in WT-TAC controls, but had no impact in PKG1αC42S mice. TAC augmented myocardial PKG activity similarly with both genotypes, but SIL increased activity further only in WT-TAC mice. The disparity was related to less PDE5 serine-92 phosphorylation (activation) in PKG1αC42S myocytes. By contrast, augmenting myocardial cGMP using sGC activator (Bay602770) countered cellular and organ-level dysfunction and hypertrophy regardless of the redox-form of PKG1α expressed. Conclusions: PKG1α oxidation reduces its efficacy to counter cardiac pathophysiology but concomitantly facilitates the therapeutic impact from PDE5 inhibition. The efficacy of sGC activation is unaffected by PKG1α redox. These results have implications for targeting different cGMP-enhancement strategies to treat heart disease, with PKG1α redox state being an important variable for predicting drug efficacy.
O45-3 Dpp4 Inhibitor Attenuates Cardiac Systolic Dysfunction in a Murine Dietary Obese Model by Promoting Fibroblast Growth Factor 2-mediated Angiogenesis Masayoshi Suda1, Ippei Shimizu1,2, Yohko Yoshida1,2, Tohru Minamino1; 1Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences; 2Department of Cardiovascular Biology and Medicine, Division of Molecular Aging and Cell Biology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan Dipeptidyl peptidase-4 (Dpp4) inhibitors are used worldwide to combat diabetes, however, their roles in cardiovascular disorders are yet to be defined. Here we show that a DPP4 inhibitor, linagliptin, contributes for the suppression of capillary rarefaction in diabetic heart and systolic dysfunction. The capillary rarefaction in dietary obese mice associated with high DPP4 level in circulation, and the administration of linagliptin suppressed the development of capillary rarefaction and ameliorated cardiac dysfunction. DNA micro array data showed that early growth response protein 1 (EGR1), known as an angiogenic transcription factor, is significantly reduced in the cardiac tissue upon metabolic stress, and this suppression was inhibited by the administration of linagliptin. Fibroblast growth factor 2 (FGF-2) has putative amino acid sequence cleaved by DPP4, and LC-MS/MS studies showed that DPP4 actually cleaves FGF-2. In vitro studies showed that FGF-2 contributes to up-regulation of Egr1 expression, and this was suppressed with DPP4. Furthermore, our studies suggested that vascular endothelial growth factor a (VEGFa) is the critical angiogenic factor mediating FGF-2-EGR-1 signaling. Our studies suggest that DPP4 inhibits FGF-2/EGR-1/VEGFa signaling in cardiac tissues. Suppression of DPP4 is crucial for the suppression of capillary rarefaction and cardiac dysfunction in diabetic heart.
O45-4 Impact of SGLT2 Inhibitor on Diabetic Cardiomyopathy-role of Glucagon-insulin Axis Takahiro Kamihara, Yasuko K. Bando, Kazuyuki Nishiura, Remina Yasheng, Haruya Kawase, Toyoaki Murohara; Department of cardiology, Nagoya University Graduate School of Medicine Background: Clinical trials revealed that the protective impact of SGLT2 inhibitor (SGLT2i) on heart failure via its diuretic effect without hypoglycemia. It remains uncertain whether these effects may be drug-class and whether SGLT2i may affect myocardium. We hypothesized whether SGLT2i may protect heart via glucagon, a counter hormone against insulin that promotes not only glucose-elevating effects but also inotropic effects on heart. Methods: Male 18 week-old C57BL6 mice were randomly allocated in non-diabetic and streptozotocin-induced T1DM group with or without canagliflozin (CAN; 10 mg/kg/day for 4 weeks)(n = 4–6, ea). Results: In nondiabetic mice, CAN had no effects on blood sugar, body weight, systolic left-ventricular (LV) function [FS (%); 44.3 ± 3.7], and chamber size [LVDd/Ds (mm); 2.6/1.4 mm]. However, heart size and circulating Gcg concentration [HW(mg); 119.2 ± 6.8 and HW/BW;