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S1-4 Effectiveness of Aldosterone Blockade in Patients with Hypertension and CKD
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Abstracts of the 17th Asian Pacific Congress of Cardiology
Symposia Symposium 1. Heart Failure 1: Aldosterone and Heart Failure S1-1 The Role and Regulation of Mineralocorticoid Receptor Activation in Heart Failure Morag J. Young. Prince Henry’s Institute of Medical Research, Clayton, Australia Mineralocorticoid receptor (MR) activation by either administration of exogenous mineralocorticoids, or by endogenous glucocorticoids, promotes oxidative stress, vascular inflammation and cardiac fibrosis in experimental animals. These studies suggest potential mechanisms for the benefits observed in recent large scale clinical trials investigating the cardioprotective effects of MR antagonists given in conjunction with current best practice. Given that few patients showed elevated plasma aldosterone, novel mechanisms involved in activating the MR in the failing heart are now being investigated. We have investigated the contribution of specific cell types to MR-mediated cardiac pathology using Cre-Lox technology to create tissue specific MR knockouts mice. Our data suggests that MR signalling in macrophages contributes to the regulation of proinflammatory and profibrotic genes associated with the onset of cardiac fibrosis. Importantly, macrophage MR null mice given DOC/salt for 8 weeks show no increase in cardiac fibrosis and systolic blood pressure, in contrast to wild type littermates. Given that macrophage recruitment is equivalent in MR macrophage knockout mice and wild type mice these data suggest that macrophage MR may play a distinct role in tissue remodelling but that MR activation elsewhere in the cardiovascular system is also important. Selective modulators of the MR that are specifically directed towards non-epithelial cardiovascular tissue would increase tissue protection without the side effects associated with renal MR blockade. Moreover, activation of the MR by other ligands would argue for the use of MR antagonists in renal and cardiovascular protection even when plasma aldosterone is normal. S1-2 Physiological and Pathophysiological Actions of Aldosterone to Cardiomyocytes Michihiro Yoshimura. The Jikei University School of Medicine, Japan It is recognized that aldosterone is potentially cardiotoxic, though its local effects in the heart are not well understood. We therefore examined the effects of aldosterone on cultured rat cardiomyocytes in the presence of normal and elevated extracellular Na+ . We evaluated the intracellular fluid volume of cardiomyocytes by measuring cell size. Intracellular Na+ was measured using the fluorescent sodium indicator SBFI, and cardiac hypertrophy was assessed using BNP transcription and 3 H-leucine incorporation as indices. Acutely, cardiomyocytes shrank in the presence of 146 mEq/L Na+ due to the increased extracellular osmolarity. Aldosterone (10 7 mol/L) mitigated the shrinkage by stimulating Na+ uptake by the cells. This acute effect of aldosterone was blocked by SM20220, a Na+ /H+ exchanger 1 (NHE1) inhibitor, but not by eplerenone, a mineralocorticoid receptor (MR) blocker. Chronic exposure to aldosterone in the presence of 146 mEq/L Na+ led to marked increases in cardiomyocyte size, 3 H-leucine incorporation, and BNP and NHE1 transcription that were significantly greater than were seen in the presence of 141 mEq/L Na+ . All but
the last were blocked by either eplerenone or SM20220; the increase in NHE1 transcription was blocked only by eplerenone. In conclusion, aldosterone acutely exerts a beneficial effect via NHE1 to block cardiomyocyte shrinkage in the presence of elevated extracellular Na+ , but chronic exposure to aldosterone in the presence of elevated extracellular Na+ leads to cardiomyocyte hypertrophy via genomic effects mediated by the MR. We are now examining the effect of aldosterone on cultured rat cardiomyocytes under high glucose condition; and this research will be useful for the understanding about possible physiological and pathophysiological actions of aldosterone in diabetes. S1-3 Effects of Aldosterone Blockade on Cardiac Renin Angiotensin-Aldosterone System in Salt-Sensitive Hypertension Yoshiyu Takeda, Aoshuang Zhu, Takashi Yoneda. Department of Internal Medicine, Graduate School of Medical Science, Kanazawa University, Japan Background: The activation of local renin angiotensinaldosterone system (RAAS) plays a pivotal role in the overall pathophysiology of the cardiac diseases. A highsalt diet reduces the activity of the circulating RAAS, but augments local RAAS, leading to hypertension and tissue injuries. Aldosterone can activate local renin and angiotensin converting enzyme (ACE). However, the effects of blockade of aldosterone on tissue RAAS including (pro)renin receptor and ACE2 in salt-sensitive hypertension were unknown. Therefore, we examined the effect of high-salt diet and that of RAAS blockade on salt-sensitive hypertensive rats. Methods and results: DS rats fed a high-salt diet increased blood pressure (BP), heart weight, cardiac fibrosis, and cardiac collagen III. Under these conditions, the rats exhibited decreased PRA and plasma aldosterone concentration and concomitant with increased expression of cardiac (pro)renin receptor protein and mRNA levels of angiotensinogen and decreased cardiac ACE2. Treatment with eplerenone, a selective aldosterone blocker, was associated with significant improvements in heart weight, cardiac collagen III and cardiac fibrosis and decreased cardiac (pro)renin receptor protein expression and angiotensinogen and increased cardiac ACE2 mRNA levels. Conclusion: These results suggest that a high-salt diet increased cardiac RAAS, while blockade of aldosterone attenuated cardiac injuries by decreasing the activity of tissue RAAS in salt-sensitive hypertension. S1-4 Effectiveness of Aldosterone Blockade in Patients with Hypertension and CKD Atsuhisa Sato. Department of Internal Medicine, International University of Health and Welfare Mita Hospital, Tokyo, Japan There is increasing evidence that aldosterone exerts major adverse cardiovascular effects through classical mineralocorticoid receptors (MR) in nonepithelial tissues such as the brain and heart. This nonepithelial role of aldosterone has been underscored by the recent RALES and EPHESUS trials. These studies may have given the impression that only aldosterone blockade was beneficial, but in fact combination therapy with an ACE inhibitors or ARB works best. When using MR antagonist as an cardiac-protecting drug, further organ protection could be derived by the addition of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II type 1 receptor blocker (ARB). The longterm effect of aldosterone on the heart was not inhibited in some subjects, so the possibility of organ damage due to so-
Symposia called breakthroughed aldosterone can not be ignored. These effects can be inhibited by MR anagonist at a small dose, not lower blood pressure. In this symposium, we will focus on the effectiveness of MR antagonist (aldosterone blocker) in patients with essential hypertension, with or without chronic kidney disease (CKD) in our outpatients. In patients without CKD, aldosterone blocker in addition to an ACE inhibitor or ARB, significantly lowered blood pressure and reduced urinary albumin excretion without any adverse effects. We had almost similar results in patients with CKD, however, the adverse effect of greatest concern is hyperkalemia which can occur when aldosterone blocker is combined with an inhibitor of the renin angiotensin system. If subjects are selected and followed closely, the adverse effects, especially hyperkalemia, will rarely become problematic. Symposium 2. Heart Failure 2: Assessment of Left Ventricular Function in Heart Failure S2-1 Assessment of Left Ventricular Systolic Function in Diastolic Heart Failure Using Cardiac Time Intervals Akira Kisanuki, Mihoko Kono, Chuwa Tei. Kagoshima University, Kagoshima, Japan Background and objectives: Systolic function in diastolic heart failure is defined as preserved left ventricular (LV) ejection fraction (EF). However, EF may not reflect the systolic function in DHF fully, especially the abnormalities during isovolumetric contraction time (ICT). Cardiac time interval analysis may add another information on LV systolic function which LV EF cannot provide. Methods: We examined LV systolic and diastolic function in 80 consecutive patients with DHF, 30 patients with asymptomatic diastolic dysfunction (ADD) and 30 normal subjects (Control). LV and left atrial volumes, LV EF, LV ICT and isovolumetric relaxation time (IRT), early diastolic mitral flow velocity, systolic mitral annular velocity (S ) and early diastolic mitral annular velocity were obtained using tissue and Doppler echocardiography. Results: LV ICT in DHF was significantly increased compared to those in ADD and Control. ICT in ADD were equal to that in Control. LV end - diastolic volume index in DHF was significantly increased compared to those in ADD and Control. S in DHF and ADD were significantly decreased compared to that in Control. Conclusion: LV systolic function in DHF appears to be abnormal despite preserved LV EF. S2-2 Assessment of Left Ventricular Diastolic Function by Novel Ultrasound Techniques Satoshi Nakatani. Osaka University Graduate School of Medicine, Japan Strain/strain rate imaging is the most remarkable advancement among recently developed ultrasound technologies. Strain and strain rate have been obtained based on tissue Doppler echocardiography with excellent temporal resolution but with a limitation of Doppler angle dependency. However, they can now be obtained independent of Doppler angle using speckle tracking technique. Strain and strain rate are thus obtained in longitudinal and transverse directions in the apical views and in radial and circumferential directions in the short-axis views. Longitudinal strain and strain rate well reflect global left ventricular function because most of subendocardial fibers are oriented longitudinally. Diastolic strain rate is an index of regional relaxation and has been related to global left ventricular relaxation. Further,
S13 strain rate during isovolumic relaxation time showed a good correlation with time constant of left ventricular relaxation. Speckle tracking technique can provide not only strain and strain rate but also rotational degrees and velocity at a certain short-axis image. By subtracting apical rotation from basal rotation, we can assess left ventricular twisting in systole and untwisting in diastole. The peak untwisting rate has been reported to correlate with left ventricular diastolic suction and relaxation. These new parameters are promising to assess left ventricular diastolic function independently of conventional echocardiographic parameters. S2-3 Assessment of LV Function by 3D Echo Tsui-Lieh Hsu. Taipei Veterans General Hospital, Taipei, Taiwan The advance of 3-dimensional (3D) echocardiography allows to acquiring a full volumetric dataset of the left ventricle (LV) which are using for off-line quantitative analysis of LV function. Studies have been demonstrated the accuracy of 3D method in comparison with MRI for the calculation of LV volume, ejection fraction and mass. New algorithm provides regional volume data over one cardiac cycle, which further calculation of LV dyssyncnhrony index for the selection of patients who may benefit from the cardiac resynchronization therapy. The pitfalls of current 3D technology include difficult in atrial fibrillation rhythm, loss of clear endocardium boundary in the dilated heart. The 3 layer of myocardial fiber orientation appear as a spiral, circular and longitudinal fashion. Two-dimensional speckle tracking imaging and data analysis of LV twist motion has been elucidated the importance of cardiac mechanics in normal and disease state. New modality of 3D speckle tracking technology further explores the potential clinical application of 3D volume dataset for assessing the LV function and determination of the torsion. It would have profound clinical impact for quantitative assessment of global and regional LV function. In conclusion, 3D echo could add additional diagnostic value for assessing of LV function in the diagnosis and management of failing heart. S2-4 Echo, Small Coronary Artery Stenosis in HCM Woo-Shik Kim. Kyung Hee University, Seoul, Korea The pathogenesis of myocardial ischemia in patients with hypertrophic cardiomyopathy (HCM) in the absence of epicardial coronary artery stenosis remains uncertain. Although there is growing evidence that abnormalities of the coronary microvasculature can result in myocardial ischemia in patient with HCM with normal epicardial coronary artery, clinical evaluation of the coronary microcirculation has not been fully investigated due to technical difficulties. Recent advances in transthoracic Doppler echocardiography (TTDE) allow evaluation of flow velocity not only in the left anterior descending coronary artery (LAD) but also in the intramyocardial coronary artery (IMCA, 500 1000 mm). We have observed some clinical cases of acceleration flow signal within the IMCA in patients with HCM by TTDE. Since the acceleration flow signal on color Doppler echocardiography is generally observed at the site of a segmentally narrowed portion, we hypothesized the acceleration signal observed in the IMCA might be an abnormal flow velocity which suggests a narrowed lumen in the small coronary artery. To determine whether TTDE could detect abnormal flow for a stenosis, we evaluated acceleration flow signal in IMCA. We also evaluated the
Abstracts of the 17th Asian Pacific Congress of Cardiology
Symposia Symposium 1. Heart Failure 1: Aldosterone and Heart Failure S1-1 The Role and Regulation of Mineralocorticoid Receptor Activation in Heart Failure Morag J. Young. Prince Henry’s Institute of Medical Research, Clayton, Australia Mineralocorticoid receptor (MR) activation by either administration of exogenous mineralocorticoids, or by endogenous glucocorticoids, promotes oxidative stress, vascular inflammation and cardiac fibrosis in experimental animals. These studies suggest potential mechanisms for the benefits observed in recent large scale clinical trials investigating the cardioprotective effects of MR antagonists given in conjunction with current best practice. Given that few patients showed elevated plasma aldosterone, novel mechanisms involved in activating the MR in the failing heart are now being investigated. We have investigated the contribution of specific cell types to MR-mediated cardiac pathology using Cre-Lox technology to create tissue specific MR knockouts mice. Our data suggests that MR signalling in macrophages contributes to the regulation of proinflammatory and profibrotic genes associated with the onset of cardiac fibrosis. Importantly, macrophage MR null mice given DOC/salt for 8 weeks show no increase in cardiac fibrosis and systolic blood pressure, in contrast to wild type littermates. Given that macrophage recruitment is equivalent in MR macrophage knockout mice and wild type mice these data suggest that macrophage MR may play a distinct role in tissue remodelling but that MR activation elsewhere in the cardiovascular system is also important. Selective modulators of the MR that are specifically directed towards non-epithelial cardiovascular tissue would increase tissue protection without the side effects associated with renal MR blockade. Moreover, activation of the MR by other ligands would argue for the use of MR antagonists in renal and cardiovascular protection even when plasma aldosterone is normal. S1-2 Physiological and Pathophysiological Actions of Aldosterone to Cardiomyocytes Michihiro Yoshimura. The Jikei University School of Medicine, Japan It is recognized that aldosterone is potentially cardiotoxic, though its local effects in the heart are not well understood. We therefore examined the effects of aldosterone on cultured rat cardiomyocytes in the presence of normal and elevated extracellular Na+ . We evaluated the intracellular fluid volume of cardiomyocytes by measuring cell size. Intracellular Na+ was measured using the fluorescent sodium indicator SBFI, and cardiac hypertrophy was assessed using BNP transcription and 3 H-leucine incorporation as indices. Acutely, cardiomyocytes shrank in the presence of 146 mEq/L Na+ due to the increased extracellular osmolarity. Aldosterone (10 7 mol/L) mitigated the shrinkage by stimulating Na+ uptake by the cells. This acute effect of aldosterone was blocked by SM20220, a Na+ /H+ exchanger 1 (NHE1) inhibitor, but not by eplerenone, a mineralocorticoid receptor (MR) blocker. Chronic exposure to aldosterone in the presence of 146 mEq/L Na+ led to marked increases in cardiomyocyte size, 3 H-leucine incorporation, and BNP and NHE1 transcription that were significantly greater than were seen in the presence of 141 mEq/L Na+ . All but
the last were blocked by either eplerenone or SM20220; the increase in NHE1 transcription was blocked only by eplerenone. In conclusion, aldosterone acutely exerts a beneficial effect via NHE1 to block cardiomyocyte shrinkage in the presence of elevated extracellular Na+ , but chronic exposure to aldosterone in the presence of elevated extracellular Na+ leads to cardiomyocyte hypertrophy via genomic effects mediated by the MR. We are now examining the effect of aldosterone on cultured rat cardiomyocytes under high glucose condition; and this research will be useful for the understanding about possible physiological and pathophysiological actions of aldosterone in diabetes. S1-3 Effects of Aldosterone Blockade on Cardiac Renin Angiotensin-Aldosterone System in Salt-Sensitive Hypertension Yoshiyu Takeda, Aoshuang Zhu, Takashi Yoneda. Department of Internal Medicine, Graduate School of Medical Science, Kanazawa University, Japan Background: The activation of local renin angiotensinaldosterone system (RAAS) plays a pivotal role in the overall pathophysiology of the cardiac diseases. A highsalt diet reduces the activity of the circulating RAAS, but augments local RAAS, leading to hypertension and tissue injuries. Aldosterone can activate local renin and angiotensin converting enzyme (ACE). However, the effects of blockade of aldosterone on tissue RAAS including (pro)renin receptor and ACE2 in salt-sensitive hypertension were unknown. Therefore, we examined the effect of high-salt diet and that of RAAS blockade on salt-sensitive hypertensive rats. Methods and results: DS rats fed a high-salt diet increased blood pressure (BP), heart weight, cardiac fibrosis, and cardiac collagen III. Under these conditions, the rats exhibited decreased PRA and plasma aldosterone concentration and concomitant with increased expression of cardiac (pro)renin receptor protein and mRNA levels of angiotensinogen and decreased cardiac ACE2. Treatment with eplerenone, a selective aldosterone blocker, was associated with significant improvements in heart weight, cardiac collagen III and cardiac fibrosis and decreased cardiac (pro)renin receptor protein expression and angiotensinogen and increased cardiac ACE2 mRNA levels. Conclusion: These results suggest that a high-salt diet increased cardiac RAAS, while blockade of aldosterone attenuated cardiac injuries by decreasing the activity of tissue RAAS in salt-sensitive hypertension. S1-4 Effectiveness of Aldosterone Blockade in Patients with Hypertension and CKD Atsuhisa Sato. Department of Internal Medicine, International University of Health and Welfare Mita Hospital, Tokyo, Japan There is increasing evidence that aldosterone exerts major adverse cardiovascular effects through classical mineralocorticoid receptors (MR) in nonepithelial tissues such as the brain and heart. This nonepithelial role of aldosterone has been underscored by the recent RALES and EPHESUS trials. These studies may have given the impression that only aldosterone blockade was beneficial, but in fact combination therapy with an ACE inhibitors or ARB works best. When using MR antagonist as an cardiac-protecting drug, further organ protection could be derived by the addition of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II type 1 receptor blocker (ARB). The longterm effect of aldosterone on the heart was not inhibited in some subjects, so the possibility of organ damage due to so-
Symposia called breakthroughed aldosterone can not be ignored. These effects can be inhibited by MR anagonist at a small dose, not lower blood pressure. In this symposium, we will focus on the effectiveness of MR antagonist (aldosterone blocker) in patients with essential hypertension, with or without chronic kidney disease (CKD) in our outpatients. In patients without CKD, aldosterone blocker in addition to an ACE inhibitor or ARB, significantly lowered blood pressure and reduced urinary albumin excretion without any adverse effects. We had almost similar results in patients with CKD, however, the adverse effect of greatest concern is hyperkalemia which can occur when aldosterone blocker is combined with an inhibitor of the renin angiotensin system. If subjects are selected and followed closely, the adverse effects, especially hyperkalemia, will rarely become problematic. Symposium 2. Heart Failure 2: Assessment of Left Ventricular Function in Heart Failure S2-1 Assessment of Left Ventricular Systolic Function in Diastolic Heart Failure Using Cardiac Time Intervals Akira Kisanuki, Mihoko Kono, Chuwa Tei. Kagoshima University, Kagoshima, Japan Background and objectives: Systolic function in diastolic heart failure is defined as preserved left ventricular (LV) ejection fraction (EF). However, EF may not reflect the systolic function in DHF fully, especially the abnormalities during isovolumetric contraction time (ICT). Cardiac time interval analysis may add another information on LV systolic function which LV EF cannot provide. Methods: We examined LV systolic and diastolic function in 80 consecutive patients with DHF, 30 patients with asymptomatic diastolic dysfunction (ADD) and 30 normal subjects (Control). LV and left atrial volumes, LV EF, LV ICT and isovolumetric relaxation time (IRT), early diastolic mitral flow velocity, systolic mitral annular velocity (S ) and early diastolic mitral annular velocity were obtained using tissue and Doppler echocardiography. Results: LV ICT in DHF was significantly increased compared to those in ADD and Control. ICT in ADD were equal to that in Control. LV end - diastolic volume index in DHF was significantly increased compared to those in ADD and Control. S in DHF and ADD were significantly decreased compared to that in Control. Conclusion: LV systolic function in DHF appears to be abnormal despite preserved LV EF. S2-2 Assessment of Left Ventricular Diastolic Function by Novel Ultrasound Techniques Satoshi Nakatani. Osaka University Graduate School of Medicine, Japan Strain/strain rate imaging is the most remarkable advancement among recently developed ultrasound technologies. Strain and strain rate have been obtained based on tissue Doppler echocardiography with excellent temporal resolution but with a limitation of Doppler angle dependency. However, they can now be obtained independent of Doppler angle using speckle tracking technique. Strain and strain rate are thus obtained in longitudinal and transverse directions in the apical views and in radial and circumferential directions in the short-axis views. Longitudinal strain and strain rate well reflect global left ventricular function because most of subendocardial fibers are oriented longitudinally. Diastolic strain rate is an index of regional relaxation and has been related to global left ventricular relaxation. Further,
S13 strain rate during isovolumic relaxation time showed a good correlation with time constant of left ventricular relaxation. Speckle tracking technique can provide not only strain and strain rate but also rotational degrees and velocity at a certain short-axis image. By subtracting apical rotation from basal rotation, we can assess left ventricular twisting in systole and untwisting in diastole. The peak untwisting rate has been reported to correlate with left ventricular diastolic suction and relaxation. These new parameters are promising to assess left ventricular diastolic function independently of conventional echocardiographic parameters. S2-3 Assessment of LV Function by 3D Echo Tsui-Lieh Hsu. Taipei Veterans General Hospital, Taipei, Taiwan The advance of 3-dimensional (3D) echocardiography allows to acquiring a full volumetric dataset of the left ventricle (LV) which are using for off-line quantitative analysis of LV function. Studies have been demonstrated the accuracy of 3D method in comparison with MRI for the calculation of LV volume, ejection fraction and mass. New algorithm provides regional volume data over one cardiac cycle, which further calculation of LV dyssyncnhrony index for the selection of patients who may benefit from the cardiac resynchronization therapy. The pitfalls of current 3D technology include difficult in atrial fibrillation rhythm, loss of clear endocardium boundary in the dilated heart. The 3 layer of myocardial fiber orientation appear as a spiral, circular and longitudinal fashion. Two-dimensional speckle tracking imaging and data analysis of LV twist motion has been elucidated the importance of cardiac mechanics in normal and disease state. New modality of 3D speckle tracking technology further explores the potential clinical application of 3D volume dataset for assessing the LV function and determination of the torsion. It would have profound clinical impact for quantitative assessment of global and regional LV function. In conclusion, 3D echo could add additional diagnostic value for assessing of LV function in the diagnosis and management of failing heart. S2-4 Echo, Small Coronary Artery Stenosis in HCM Woo-Shik Kim. Kyung Hee University, Seoul, Korea The pathogenesis of myocardial ischemia in patients with hypertrophic cardiomyopathy (HCM) in the absence of epicardial coronary artery stenosis remains uncertain. Although there is growing evidence that abnormalities of the coronary microvasculature can result in myocardial ischemia in patient with HCM with normal epicardial coronary artery, clinical evaluation of the coronary microcirculation has not been fully investigated due to technical difficulties. Recent advances in transthoracic Doppler echocardiography (TTDE) allow evaluation of flow velocity not only in the left anterior descending coronary artery (LAD) but also in the intramyocardial coronary artery (IMCA, 500 1000 mm). We have observed some clinical cases of acceleration flow signal within the IMCA in patients with HCM by TTDE. Since the acceleration flow signal on color Doppler echocardiography is generally observed at the site of a segmentally narrowed portion, we hypothesized the acceleration signal observed in the IMCA might be an abnormal flow velocity which suggests a narrowed lumen in the small coronary artery. To determine whether TTDE could detect abnormal flow for a stenosis, we evaluated acceleration flow signal in IMCA. We also evaluated the