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Rethinking of Metabolic Approach in Heart Failure
The 16th Annual Scientific Meeting
JHFS
S121
Special Lectures SL1 Lessons from the ESC Guidelines of the Management of Heart Failure (TBA) JOHN MCMURRAY University of Glasgow, Medical Cardiology, UK
SL2 New Drug Therapies for Heart Failure HENRY KRUM Centre of Cardiovascular Research & Education in Therapeutics, Monash University, Australia Despite susbtantial advances in the pharmacological management of heart failure, the prognosis of these patients remains poor. Additionally, the treatments and clinical outcomes of patients with acute decompensated heart failure have not changed substantially over the past few decades. Consequently, there is a critical need for new drug therapies that can improve clinical outcomes. In the setting of acute heart failure, new inotropic agents such as cardiac myosin activators and new vasodilators such as relaxin have been developed. For chronic heart failure with reduced ejection fraction, there are several new approaches that target multiple pathophysiological mechanisms including novel blockers of the renin-angiotensin-aldosterone system (direct renin inhibitors, dual-acting inhibitors of the angiotensin II receptor and neprilysin, aldosterone synthase inhibitors), ryanodine receptor stabilizers, If channel blockers and SERCA activators. Heart failure with preserved ejection fraction represents a substantial therapeutic problem as no therapy has been demonstrated to improve symptoms or outcomes in this condition. Newer treatment strategies target specific structural and functional abnormalities that lead to increased myocardial stiffness. Finally, new therapies for the treatment of heart failure complications and associated co-morbidities and such as pulmonary hypertension, anemia, and iron deficiency have been developed that may provide symptomatic benefit complementary to standard therapies.
SL3 Control of Heart Rate and Neurohormonal Activation in Chronic Heart Failure - Important Targets to Improve Outcomes KARL SWEDBERG Sahlgrenska Academy, University of Gothenburg, Sweden Neurohormonal antagonism: Since 1987 with the publication of CONSENSUS, neurohormonal antagonism by ACE-inhibition has been an established life-prolonging option in the treatment of chronic systolic heart failure (CHF)(1). When the effect of enalapril could be associated with the degree of neurohormonal activation (2), the mechanism was further clarified. An alternative to ACE-inhibition emerged with angiotensin receptor blockers (ARBs) where life-prolonging options where documented in VALHeFT and CHARM (3, 4). In all international guidelines, these therapies have recommendation class I and evidence levels A and are the modes of therapies which should be initiated first when systolic HF is diagnosed (5). The associated activation of the renin-angiotensin-aldosterone system (RAAS) can be blocked by mineralocorticoid antagonism (MRA). This has been important in severe HF but more recently, the EMPHASIS-HF study demonstrated that also in mild-moderate HF eplerenone was important and associated with lifeprolongation (6). A beta-blocker should also be considered in all patients with systolic HF. These therapies counteract the intense sympathetic activation bombarding the myocardium in CHF. Beta-blockers cause reduction in heart rate and it has been unclear how important the reduced heart arte is compared to other effects of beta-blockers. Pure heart rate modification: Ivabradine, which acts on the sinus node through a mechanism completely different from a beta-blocker, can reduce heart rate in patients in sinus rhythm above and beyond a beta-blocker. In SHIFT (The Systolic Heart failure Treatment with the If inhibitor Ivabradine Trial), 6505 patients with symptomatic CHF and with left ventricular ejection fraction #35%, who were in sinus rhythm with heart rate $70 bpm, and were on stable background therapy, were randomized to placebo or ivabradine and followed for 23 months, The primary composite end-point, cardiovascular mortality or hospitalization for HF, was reduced by 18% in the ivabradine group (p!0.0001). The effects were driven mainly by hospitalizations for worsening HF, which were reduced by 26% (p!0.0001) and deaths due to HF (p50.014). Patients with the highest heart rate at baseline had the highest benefit from ivabradine (7). We have recently presented results which indicates that the magnitude of the reduction in heart rate by ivabradine above and beyond what can be achieved by a beta-blocker, regardless of doe level, is the most important therapeutic effect (8). Conclusions: In the pharmacological treatment of CHF and left ventricular systolic dysfunction, neurohormonal blockade should be initiated with a combination of agents. This combination should include that in all patients consideration is given to an ACE-inhibitor and/or an ARB, a beta-receptor blocker and aldosterone antagonist.
Recent experience suggests that this strategy should include the addition of a pure heart rate reducing agent in those patients who remain symptomatic, in sinus rhythm and with an elevated heart rate. References: 1. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med 1987; 316:1429-1435. 2. Swedberg K, Eneroth P, Kjekshus J, Wilhelmsen L. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. CONSENSUS Trial Study Group. Circulation 1990; 82:1730-1736. 3. Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003; 362:759-766. 4. Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001; 345:1667-1675. 5. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012. 6. Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011; 364:11-21. 7. Swedberg K, Komajda M, Bohm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010; 376:875-885. 8. Swedberg K, Komajda M, Bohm M, et al. Effects on Outcomes of Heart Rate Reduction by Ivabradine in Patients With Congestive Heart Failure: Is There an Influence of Beta-Blocker Dose?: Findings From the SHIFT (Systolic Heart failure treatment with the I(f) inhibitor ivabradine Trial) Study. J Am Coll Cardiol 2012.
SL4 Regulation of Myocardial Survival and Death by Autophagy during Myocardial Stress and Aging JUNICHI SADOSHIMA University of Medicine and Dentistry of New Jersey, New Jersey Medical School, USA Autophagy is a bulk degradation process in which cytosolic proteins and organelles are sequestered into double membrane vesicles, termed autophagosomes, and degraded in lysosomes. Although autophagy is generally protective, excessive autophagy may induce myocardial damage. Autophagy is protective during myocardial ischemia, whereas it promotes myocardial injury during reperfusion. The former is mediated through an AMP-dependent protein kinase-dependent mechanism, while the latter through Beclin-1-dependent mechanisms. Thus, the function and the signaling mechanism of autophagy are stimulus-dependent. Interestingly, recent evidence suggests that, besides (Atg-7-dependent) conventional autophagy (CA), alternative autophagy (AA) which utilizes distinct signaling mechanisms for autophagosome formation and distinct intracellular membranes as sources of autophagosomes, may exist. Here I will present 1) that there are two forms of autophagy, namely CA and AA, in the heart, 2) that although CA plays an important role in maintaining cardiac function at baseline, AA plays an essential role in maintaining cardiac function during nutrient deprivation, 3) that AA is mediated through an Ulk1-dependent mechanism, 4) that CA and AA degrade distinct proteins/organelles, and 5) that AA plays an important role in preventing aging in the heart. Thus, selective modulation of CA and AA should allow us to better control survival and death of cardiomyocytes in response to ischemia, hemodynamic overload and aging, which may lead to better control of heart failure in patients.
SL5 Rethinking of Metabolic Approach in Heart Failure SANG HONG BAEK Division of Cardiovascular Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Korea Although neurohumoral antagonism has successfully reduced HF morbidity and mortality, the residual risk remains unacceptably high. The concept of myocardial energetic deficiency in the pathogenesis of HF, and the consequent rationale for treating this energy deficiency clinically by metabolic modulation using long-chain 3-ketoacyl coenzyme A thiolase inhibitior (e.g., trimetazidine), late sodium current inhibitor (e.g., ranolazine), carnitine palmitoyl transferase inhibitior (e.g., perhexiline) and carnitine palmitoyl transferase I and/or II inhibitors (e.g., etomoxir) would be recognized. Trimetazidine (TMZ) shifts myocardial energy production from free fatty acids to glucose oxidation, a more efficient metabolic pathway. Previous small studies in patients with chronic HF have shown that TMZ can improve contractile left ventricular function, exercise capacity and NYHA class compared to placebo. However, no data on the effects of TMZ on survival in patients with CHF have ever been produced. Recently we have conducted the international multicentre retrospective cohort study. The 669 patients from the CHF clinics of our institutions were
S122 Journal of Cardiac Failure Vol. 18 No. 10S October 2012 recruited. 362 patients were on TMZ due to symptoms persistence despite up titration of optimal CHF medical therapy, while the remaining patients continued conventional CHF therapy alone. In conclusion, TMZ is effective in reducing both global and cardiovascular mortality and event-free survival in patients with CHF. The addition of TMZ on top of optimal medical therapy improves long term survival in CHF patients.
SL6 Donor-related Characteristics in Patients with Mechanical Circulatory Support Undergoing Heart Transplantation: Factors that Really Influence Survival SIMON MALTAIS, NIKHIL P. JAIK, IRENE FEURER, MARK A. WIGGER Vanderbilt Heart, Vanderbilt University Medical Center, USA Introduction: Mechanical circulatory support (MCS) is an accepted strategy to bridge patients with advanced heart failure to heart transplantation (HTxp). Despite established guidelines for HTxp without MCS, there is no consensus regarding optimal donor criteria in patients undergoing HTxp with an implanted MCS device. Methods: Using the Scientific Registry for Transplant Recipients (SRTR) database, we analyzed adult HTxp recipients who previously had 1 of 4 long-term MCS devices. Kaplan-Meier and multivariate Cox regression models evaluated associations of device type and donor-related characteristics with graft survival. Results: Between January 1997 and February 2012, 2785 patients were identified. 2674 patients had a LVAD (HeartMate XVE5724, HeartMate II51882, HeartWare568), while 111 had a TAH. Follow-up averaged 25624 (range !1 to 183) months. Graft survival didn’t differ between LVAD groups. TAH was associated with reduced graft survival compared to LVAD (p!0.001). The multivariate model demonstrates that after controlling for device type (LAVD/TAH), pulmonary vascular resistance (PVR), ischemia time, decreased donor age, donor to recipient gender match and increased body mass index (BMI) ratio were independent predictors of survival. Conclusion: The type of LVAD did not influence survival in patients undergoing HTxp. Donor age, recipient PVR, short ischemic time, gender match and higher BMI ratio are associated with graft survival. Considering these donor-related characteristics may improve outcomes in those undergoing HTxp with MCS.
SL7 Current Overview of Transplantation JIGNESH K. PATEL Heart Transplant Program, Cedars-Sinai Heart Institute/UCLA, USA Since inception, the number of heart transplants performed globally has plateaued due to limited donor supply despite a progressive increase in the number of patients requiring treatment for end-stage heart disease. Mechanical circulatory support (MCS) systems are emerging as a possible alternative to bridge the gap between the demand and availability of organs. However, due to excellent long-term outcomes, with median survival now exceeding 11 years, heart transplantation remains the preferred therapy of choice for the majority of appropriately selected patients. The advent of effective immunosuppressive therapy, initially with calcineurin inhibitors (CNIs) and subsequently mycophenolate mofetil (MMF), has substantially decreased cellular rejection rates and improved survival. Current challenges in heart transplantation include a focus of research in 3 areas: 1) Management of an increasing number of sensitized patients (predominantly due to increased use of MCS) referred for transplant 2) Treatment of antibody-mediated rejection, an emerging entity with greater impact on outcomes than cellular rejection, and 3) Management of cardiac allograft vasculopathy (CAV). CAV has generally not been significantly impacted by the use of CNIs or MMF. The introduction of proliferation signal inhibitors (everolimus) promises to be a major advance in the prevention and treatment of CAV. It also shows some promise of attenuating antibody responses and therefore may play a role in the management of AMR.
SL8 The Coronary Circulation and Blood Flow in Left Ventricular Hypertrophy and in the Transition to Heart Failure PAOLO G CAMICI Vita-Salute University San Raffaele and San Raffaele Scientific Institute Milan, Italy Two distinct types of left ventricular hypertrophy (LVH) have been described: the so called “physiologic” hypertrophy, which is normally found in professional athletes, and “pathologic” LVH which is found in patients with inherited heart muscle disease such as hypertrophic cardiomyopathy (HCM) or patients with cardiac and systemic diseases characterized by pressure or volume overload. Patients with pathologic LVH have often symptoms and signs suggestive of myocardial ischaemia despite normal coronary angiograms. Under these circumstances ischemia is due to coronary microvascular dysfunction (CMD). The abnormalities of the coronary microcirculation may be unrelated to the degree of LVH and cause a reduction in maximum myocardial blood flow which, in the absence of epicardial stenoses, is suggestive of CMD.
There is no technique that enables direct visualization of coronary microcirculation in vivo in humans. Therefore, its assessment relies on the measurement of parameters which reflect its functional status, such as myocardial blood flow and coronary flow reserve which is an integrated measure of flow through both the large epicardial coronary arteries and the microcirculation. In my presentation I will discuss the pathophysiological mechanisms responsible for CMD in patients with primary and secondary LVH and how this phenomenon plays a role in the transition to heart failure in these patients.
SL9 Present Status and Future Perspectives of CRT ANGELO AURICCHIO Clinical Electrophysiology Unit, Fondazione Cardiocentro Ticino, Switzerland/ Division of Cardiology, University Hospital in Madgeburg, Germany
JHFS
S121
Special Lectures SL1 Lessons from the ESC Guidelines of the Management of Heart Failure (TBA) JOHN MCMURRAY University of Glasgow, Medical Cardiology, UK
SL2 New Drug Therapies for Heart Failure HENRY KRUM Centre of Cardiovascular Research & Education in Therapeutics, Monash University, Australia Despite susbtantial advances in the pharmacological management of heart failure, the prognosis of these patients remains poor. Additionally, the treatments and clinical outcomes of patients with acute decompensated heart failure have not changed substantially over the past few decades. Consequently, there is a critical need for new drug therapies that can improve clinical outcomes. In the setting of acute heart failure, new inotropic agents such as cardiac myosin activators and new vasodilators such as relaxin have been developed. For chronic heart failure with reduced ejection fraction, there are several new approaches that target multiple pathophysiological mechanisms including novel blockers of the renin-angiotensin-aldosterone system (direct renin inhibitors, dual-acting inhibitors of the angiotensin II receptor and neprilysin, aldosterone synthase inhibitors), ryanodine receptor stabilizers, If channel blockers and SERCA activators. Heart failure with preserved ejection fraction represents a substantial therapeutic problem as no therapy has been demonstrated to improve symptoms or outcomes in this condition. Newer treatment strategies target specific structural and functional abnormalities that lead to increased myocardial stiffness. Finally, new therapies for the treatment of heart failure complications and associated co-morbidities and such as pulmonary hypertension, anemia, and iron deficiency have been developed that may provide symptomatic benefit complementary to standard therapies.
SL3 Control of Heart Rate and Neurohormonal Activation in Chronic Heart Failure - Important Targets to Improve Outcomes KARL SWEDBERG Sahlgrenska Academy, University of Gothenburg, Sweden Neurohormonal antagonism: Since 1987 with the publication of CONSENSUS, neurohormonal antagonism by ACE-inhibition has been an established life-prolonging option in the treatment of chronic systolic heart failure (CHF)(1). When the effect of enalapril could be associated with the degree of neurohormonal activation (2), the mechanism was further clarified. An alternative to ACE-inhibition emerged with angiotensin receptor blockers (ARBs) where life-prolonging options where documented in VALHeFT and CHARM (3, 4). In all international guidelines, these therapies have recommendation class I and evidence levels A and are the modes of therapies which should be initiated first when systolic HF is diagnosed (5). The associated activation of the renin-angiotensin-aldosterone system (RAAS) can be blocked by mineralocorticoid antagonism (MRA). This has been important in severe HF but more recently, the EMPHASIS-HF study demonstrated that also in mild-moderate HF eplerenone was important and associated with lifeprolongation (6). A beta-blocker should also be considered in all patients with systolic HF. These therapies counteract the intense sympathetic activation bombarding the myocardium in CHF. Beta-blockers cause reduction in heart rate and it has been unclear how important the reduced heart arte is compared to other effects of beta-blockers. Pure heart rate modification: Ivabradine, which acts on the sinus node through a mechanism completely different from a beta-blocker, can reduce heart rate in patients in sinus rhythm above and beyond a beta-blocker. In SHIFT (The Systolic Heart failure Treatment with the If inhibitor Ivabradine Trial), 6505 patients with symptomatic CHF and with left ventricular ejection fraction #35%, who were in sinus rhythm with heart rate $70 bpm, and were on stable background therapy, were randomized to placebo or ivabradine and followed for 23 months, The primary composite end-point, cardiovascular mortality or hospitalization for HF, was reduced by 18% in the ivabradine group (p!0.0001). The effects were driven mainly by hospitalizations for worsening HF, which were reduced by 26% (p!0.0001) and deaths due to HF (p50.014). Patients with the highest heart rate at baseline had the highest benefit from ivabradine (7). We have recently presented results which indicates that the magnitude of the reduction in heart rate by ivabradine above and beyond what can be achieved by a beta-blocker, regardless of doe level, is the most important therapeutic effect (8). Conclusions: In the pharmacological treatment of CHF and left ventricular systolic dysfunction, neurohormonal blockade should be initiated with a combination of agents. This combination should include that in all patients consideration is given to an ACE-inhibitor and/or an ARB, a beta-receptor blocker and aldosterone antagonist.
Recent experience suggests that this strategy should include the addition of a pure heart rate reducing agent in those patients who remain symptomatic, in sinus rhythm and with an elevated heart rate. References: 1. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med 1987; 316:1429-1435. 2. Swedberg K, Eneroth P, Kjekshus J, Wilhelmsen L. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. CONSENSUS Trial Study Group. Circulation 1990; 82:1730-1736. 3. Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003; 362:759-766. 4. Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001; 345:1667-1675. 5. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012. 6. Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011; 364:11-21. 7. Swedberg K, Komajda M, Bohm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010; 376:875-885. 8. Swedberg K, Komajda M, Bohm M, et al. Effects on Outcomes of Heart Rate Reduction by Ivabradine in Patients With Congestive Heart Failure: Is There an Influence of Beta-Blocker Dose?: Findings From the SHIFT (Systolic Heart failure treatment with the I(f) inhibitor ivabradine Trial) Study. J Am Coll Cardiol 2012.
SL4 Regulation of Myocardial Survival and Death by Autophagy during Myocardial Stress and Aging JUNICHI SADOSHIMA University of Medicine and Dentistry of New Jersey, New Jersey Medical School, USA Autophagy is a bulk degradation process in which cytosolic proteins and organelles are sequestered into double membrane vesicles, termed autophagosomes, and degraded in lysosomes. Although autophagy is generally protective, excessive autophagy may induce myocardial damage. Autophagy is protective during myocardial ischemia, whereas it promotes myocardial injury during reperfusion. The former is mediated through an AMP-dependent protein kinase-dependent mechanism, while the latter through Beclin-1-dependent mechanisms. Thus, the function and the signaling mechanism of autophagy are stimulus-dependent. Interestingly, recent evidence suggests that, besides (Atg-7-dependent) conventional autophagy (CA), alternative autophagy (AA) which utilizes distinct signaling mechanisms for autophagosome formation and distinct intracellular membranes as sources of autophagosomes, may exist. Here I will present 1) that there are two forms of autophagy, namely CA and AA, in the heart, 2) that although CA plays an important role in maintaining cardiac function at baseline, AA plays an essential role in maintaining cardiac function during nutrient deprivation, 3) that AA is mediated through an Ulk1-dependent mechanism, 4) that CA and AA degrade distinct proteins/organelles, and 5) that AA plays an important role in preventing aging in the heart. Thus, selective modulation of CA and AA should allow us to better control survival and death of cardiomyocytes in response to ischemia, hemodynamic overload and aging, which may lead to better control of heart failure in patients.
SL5 Rethinking of Metabolic Approach in Heart Failure SANG HONG BAEK Division of Cardiovascular Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Korea Although neurohumoral antagonism has successfully reduced HF morbidity and mortality, the residual risk remains unacceptably high. The concept of myocardial energetic deficiency in the pathogenesis of HF, and the consequent rationale for treating this energy deficiency clinically by metabolic modulation using long-chain 3-ketoacyl coenzyme A thiolase inhibitior (e.g., trimetazidine), late sodium current inhibitor (e.g., ranolazine), carnitine palmitoyl transferase inhibitior (e.g., perhexiline) and carnitine palmitoyl transferase I and/or II inhibitors (e.g., etomoxir) would be recognized. Trimetazidine (TMZ) shifts myocardial energy production from free fatty acids to glucose oxidation, a more efficient metabolic pathway. Previous small studies in patients with chronic HF have shown that TMZ can improve contractile left ventricular function, exercise capacity and NYHA class compared to placebo. However, no data on the effects of TMZ on survival in patients with CHF have ever been produced. Recently we have conducted the international multicentre retrospective cohort study. The 669 patients from the CHF clinics of our institutions were
S122 Journal of Cardiac Failure Vol. 18 No. 10S October 2012 recruited. 362 patients were on TMZ due to symptoms persistence despite up titration of optimal CHF medical therapy, while the remaining patients continued conventional CHF therapy alone. In conclusion, TMZ is effective in reducing both global and cardiovascular mortality and event-free survival in patients with CHF. The addition of TMZ on top of optimal medical therapy improves long term survival in CHF patients.
SL6 Donor-related Characteristics in Patients with Mechanical Circulatory Support Undergoing Heart Transplantation: Factors that Really Influence Survival SIMON MALTAIS, NIKHIL P. JAIK, IRENE FEURER, MARK A. WIGGER Vanderbilt Heart, Vanderbilt University Medical Center, USA Introduction: Mechanical circulatory support (MCS) is an accepted strategy to bridge patients with advanced heart failure to heart transplantation (HTxp). Despite established guidelines for HTxp without MCS, there is no consensus regarding optimal donor criteria in patients undergoing HTxp with an implanted MCS device. Methods: Using the Scientific Registry for Transplant Recipients (SRTR) database, we analyzed adult HTxp recipients who previously had 1 of 4 long-term MCS devices. Kaplan-Meier and multivariate Cox regression models evaluated associations of device type and donor-related characteristics with graft survival. Results: Between January 1997 and February 2012, 2785 patients were identified. 2674 patients had a LVAD (HeartMate XVE5724, HeartMate II51882, HeartWare568), while 111 had a TAH. Follow-up averaged 25624 (range !1 to 183) months. Graft survival didn’t differ between LVAD groups. TAH was associated with reduced graft survival compared to LVAD (p!0.001). The multivariate model demonstrates that after controlling for device type (LAVD/TAH), pulmonary vascular resistance (PVR), ischemia time, decreased donor age, donor to recipient gender match and increased body mass index (BMI) ratio were independent predictors of survival. Conclusion: The type of LVAD did not influence survival in patients undergoing HTxp. Donor age, recipient PVR, short ischemic time, gender match and higher BMI ratio are associated with graft survival. Considering these donor-related characteristics may improve outcomes in those undergoing HTxp with MCS.
SL7 Current Overview of Transplantation JIGNESH K. PATEL Heart Transplant Program, Cedars-Sinai Heart Institute/UCLA, USA Since inception, the number of heart transplants performed globally has plateaued due to limited donor supply despite a progressive increase in the number of patients requiring treatment for end-stage heart disease. Mechanical circulatory support (MCS) systems are emerging as a possible alternative to bridge the gap between the demand and availability of organs. However, due to excellent long-term outcomes, with median survival now exceeding 11 years, heart transplantation remains the preferred therapy of choice for the majority of appropriately selected patients. The advent of effective immunosuppressive therapy, initially with calcineurin inhibitors (CNIs) and subsequently mycophenolate mofetil (MMF), has substantially decreased cellular rejection rates and improved survival. Current challenges in heart transplantation include a focus of research in 3 areas: 1) Management of an increasing number of sensitized patients (predominantly due to increased use of MCS) referred for transplant 2) Treatment of antibody-mediated rejection, an emerging entity with greater impact on outcomes than cellular rejection, and 3) Management of cardiac allograft vasculopathy (CAV). CAV has generally not been significantly impacted by the use of CNIs or MMF. The introduction of proliferation signal inhibitors (everolimus) promises to be a major advance in the prevention and treatment of CAV. It also shows some promise of attenuating antibody responses and therefore may play a role in the management of AMR.
SL8 The Coronary Circulation and Blood Flow in Left Ventricular Hypertrophy and in the Transition to Heart Failure PAOLO G CAMICI Vita-Salute University San Raffaele and San Raffaele Scientific Institute Milan, Italy Two distinct types of left ventricular hypertrophy (LVH) have been described: the so called “physiologic” hypertrophy, which is normally found in professional athletes, and “pathologic” LVH which is found in patients with inherited heart muscle disease such as hypertrophic cardiomyopathy (HCM) or patients with cardiac and systemic diseases characterized by pressure or volume overload. Patients with pathologic LVH have often symptoms and signs suggestive of myocardial ischaemia despite normal coronary angiograms. Under these circumstances ischemia is due to coronary microvascular dysfunction (CMD). The abnormalities of the coronary microcirculation may be unrelated to the degree of LVH and cause a reduction in maximum myocardial blood flow which, in the absence of epicardial stenoses, is suggestive of CMD.
There is no technique that enables direct visualization of coronary microcirculation in vivo in humans. Therefore, its assessment relies on the measurement of parameters which reflect its functional status, such as myocardial blood flow and coronary flow reserve which is an integrated measure of flow through both the large epicardial coronary arteries and the microcirculation. In my presentation I will discuss the pathophysiological mechanisms responsible for CMD in patients with primary and secondary LVH and how this phenomenon plays a role in the transition to heart failure in these patients.
SL9 Present Status and Future Perspectives of CRT ANGELO AURICCHIO Clinical Electrophysiology Unit, Fondazione Cardiocentro Ticino, Switzerland/ Division of Cardiology, University Hospital in Madgeburg, Germany