1-2 March Guangzhou, China

Transcription

1 FINAL PROGRAMME AND ABSTRACT BOOK 2014 Asia-Pacific cardiovascular symposium Managing cardiovascular risk factors to prevent the fatal end of cardiovascular continuum 1-2 March Guangzhou, China

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3 General information Venue This live educational symposium takes place at the: Grand Hyatt Guangzhou I12 Zhujiang West Road, Pearl River New City, Guangzhou , China Language The official language of this live educational symposium is English. No simultaneous translation will be provided. Scientific secretariat Serono Symposia International Foundation Salita di San Nicola da Tolentino, 1/b Rome, Italy Associate Project Manager: Simona Gaudiosi Tel.: +39 (0) Fax: +39 (0) Medical Advisor: Professor Stefano Taddei Serono Symposia International Foundation is a Swiss Foundation with headquarters in 14, Rue du Rhône, 1204 Geneva, Switzerland Organising secretariat Connex asia consulting Congress Coordinator: Suzanna Teh Tel.: suzanna.teh@connex-asia.com 1

4 2014 Asia-Pacific cardiovascular symposium Managing cardiovascular risk factors to prevent the fatal end of cardiovascular continuum Serono Symposia International Foundation live educational symposium on: 2014 Asia-Pacific cardiovascular symposium Managing cardiovascular risk factors to prevent the fatal end of cardiovascular continuum 1-2 March Guangzhou, China Aim In spite of increased knowledge and the ongoing efforts of scientific societies, cardiovascular diseases remain the first cause of mortality and morbidity in the Asia-Pacific regions as well as in the rest of the world. Treatment of major cardiovascular diseases including acute coronary syndrome or stroke present a significant and costly challenge for the health systems - without taking into consideration that the most effective therapy for these diseases is prevention based on effective control of risk factors. Essential hypertension remains an unsolved problem in cardiovascular medicine, not least because it is often complicated by metabolic disease. Most hypertensive patients are still not receiving the correct pharmacological treatment and may not have their blood pressure values suitably normalised. There is a clear need to promote clinical management of hypertension that is derived from evidence-based medicine and scientific guidelines, and to ensure that scientific knowledge is transformed into clinical practice. Serono Symposia International Foundation is proud to organize the 2014 Asia-Pacific Cardiology Symposium Managing cardiovascular risk factors to prevent the fatal end of cardiovascular continuum. This live educational symposium will examine recent evidence in the treatment of hypertension with a specific focus on the correct utilisation of the old drugs such as beta-blockers and the new therapeutic approaches such as renal denervation. Sessions will also be devoted to discussing emerging health problems in the Asia-Pacific area and will offer possible solutions to the management of patients with hypertension complicated by other risk factors or related diseases. Learning objectives By attending this live educational symposium the learners will be able to: Discuss the evidence supporting a first-choice drug in the treatment of hypertension and the specific role for beta-blockers Evaluate the impact in the Asia-Pacific area of the merging health problems including metabolic alterations, differences in drug responsiveness and the impact of pollution on cardiovascular disease Demonstrate effective treatment of hypertensive patients with specific and challenging problems including old age, diabetes or obesity Actively participate in the debate about the real effectiveness of renal denervation in the treatment of essential hypertension Manage the complexity of treating hypertension associated to crucial cardiovascular diseases such as atrial fibrillation, coronary artery disease and heart failure Target audience Cardiologists, internists and all others heath care professionals managing hypertension. All Serono Symposia International Foundation programmes are organized solely to promote the exchange and dissemination of scientific and medical information. No forms of promotional activities are permitted. There may be presentations discussing investigational uses of various products. These views are the responsibility of the named speakers, and do not represent an endorsement or recommendation on the part of Serono Symposia International Foundation. This programme is made possible thanks to educational grants received from: Arseus Medical, Besins Healthcare, Bristol-Myers Squibb, Celgene, Centre d Esclerosi Multiple de Catalunya (Vall d Hebron University Hospital), Centre Hépato-Biliaire (Hôpital Paul Brousse), Croissance Conseil, Cryo-Save, Datanalysis, Dos33, Esaote, Ferring, Fondazione Humanitas, Fundación IVI, GE Healthcare, GlaxoSmithKline Pharmaceuticals, IPSEN, Italfarmaco, International Society for Fertility Preservation, Johnson & Johnson Medical, K.I.T.E., Karl Storz, Lumenis, Merck Serono Group, PregLem, Richard Wolf Endoscopie, Sanofi-Aventis, Stallergenes, Stopler, Teva Pharma, Toshiba Medical Systems, Université Catholique de Louvain (UCL), University of Catania. 2

5 Accreditation The educational event: 2014 Asia-Pacific cardiovascular symposium Managing cardiovascular risk factors to prevent the fatal end of cardiovascular continuum held on 1-2 March 2014 in Guangzhou, China (Ref ), is accredited by the European Board for Accreditation in Cardiology (EBAC ) for 9 (nine) CME credit hour(s). Each participant should claim only those hours of credit that have actually been spent in the educational activity. EBAC works according to the quality standards of the European Accreditation Council for Continuing Medical Education (EACCME ), which is an institution of the European Union of Medical Specialists (UEMS), Serono Symposia International Foundation (SSIF) adheres to the principles of the Good CME Practice Group (gcmep). We value your opinion! We are continually trying to develop and improve our educational initiative to provide you with cutting-edge learning activities. During this symposium you will be asked to answer a real-time survey and after this educational event you will be receiving an online survey to help us to better tailor our future educational initiatives. We thank you for participating! 3

6 Scientific organisers Lin Shuguang Guangdong General Hospital Guangdong, China Brian Tomlinson Department of Medicine and Therapeutics The Chinese University of Hong Kong Hong Kong SAR, China Faculty members Claudio Borghi Department of Medical and Surgical Sciences University of Bologna Bologna, Italy Bambang Budi Siswanto National Heart Center Harapan Kita Jacarta Barat, Indonesia Jamshed J. Dalal Cardiac Sciences Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute Mumbai, India Aniruddha Dharmadhikari Shree Saibaba Heart Institute and Research Center Near Kalidaskala Mandir Shalimar, Nasik, India Roberto Ferrari Department of Cardiology and LTTA Centre University Hospital of Ferrara Ferrara, Italy Maria Cecilia Hospital GVM Care&Research E.S: Health Science Foundation Cotignola, Italy Guido Grassi Medical Clinic San Gerardo dei Tintori Hospital Monza, Italy and Milano-Bicocca University Milan, Italy Phrommintikul Arintaya Department of Internal Medicine Faculty of Medicine Chiang Mai Universit Chiang Mai, Thailand 4

7 Gao Pinjin Department of Hypertension Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai, China Lin Shuguang Guangdong General Hospital Guangdong, China Soetanto Arieska Soenarta National Heart Center Harapan Kita Jakarta, Indonesia Piyamitr Sritara Department of Medicine Ramathibodi Hospital Mahidol University Bangkok, Thailand Stefano Taddei Department of Clinical and Experimental Medicine University of Pisa Pisa, Italy Brian Tomlinson Department of Medicine and Therapeutics The Chinese University of Hong Kong Hong Kong SAR, China Hung-Fat Tse Cardiology Division Department of Medicine The University of Hong Kong Hong Kong SAR, China Marlon T. Co Chong Hua Hospital Cebu City, Philippines 5

8 Scientific programme 1-2 March 2014 Saturday, 1 March Serono Symposia International Foundation (SSIF) welcome and introduction Brian Tomlinson (China) Introductory lecture Lin Shuguang (China) L1: Novelties from recent guidelines in hypertension Marlon T. Co (Philippines) Session I Specific issues in the pharmacological treatment of hypertension Chairman: Lin Shuguang (China) Real time survey L2: Does a first-choice treatment exist? Stefano Taddei (Italy) D1: Debate on beta blockers: - Pro Soetanto Arieska Soenarta (Indonesia) - Cons Jamshed J. Dalal (India) CC1: Clinical case Soetanto Arieska Soenarta (Indonesia) Real time survey and questions time Coffee break Session II Specific problems in APAC Chairman: Jamshed J. Dalal (India) Real time survey L3: Burden of cardio metabolic diseases Piyamitr Sritara (Thailand) L4: Differences in drug responsiveness to hypertensive drugs Brian Tomlinson (China) L5: Pollution factors Stefano Taddei (Italy) Session III Chairman: Roberto Ferrari (Italy) CC2: Real time survey Clinical cases Diabetic population Hung-Fat Tse (China) Young and middle age obese population Bambang Budi Siswanto (Indonesia) Real time survey and questions time Coffee break Session IV Hypertension in special population Beta blockers for management of cardiovascular diseases: are all beta- blockers the same? Chairman: Hung-Fat Tse (China) Real time survey L6: Beta-blockers in Asian patients: pharmacodynamics, pharmacokinetics, pharmacogenetics Brian Tomlinson (China) L7: Comparing two beta-blockers in patients with hypertension Aniruddha Dharmadhikari (India) L8: Comparison of two beta-blockers on sympathetic nervous activity and central aortic pressure in hypertensive patients Gao Pinjin (China) Panel discussion: Which criteria for the selection of a beta-blocker should be considered? Real time survey and questions time End of the first day Real time survey and questions time Lunch Legend L : Lecture; D : Debate; CC : Clinical case; : Questions time; 6

9 Sunday, 2 March Session V New therapeutic approach in hypertension: the role of heart rate Session VI Hypertension and related diseases Chairman: Stefano Taddei (Italy) Real time survey L9: Sympathetic nervous system and hypertension: an overview Guido Grassi (Italy) D2: Debate: is heart rate a target in hypertensive treatment? - Pro Guido Grassi (Italy) - Cons Phrommintikul Arintaya (Thailand) Real time survey and questions time Coffee break Chairman: Brian Tomlinson (China) Real time survey L10: Hypertension and atrial fibrillation Claudio Borghi (Italy) L11: Coronary artery disease Roberto Ferrari (Italy) L12: Heart failure Roberto Ferrari (Italy) Real time survey and questions time Concluding remarks End of the live educational symposium 7

10 Disclosure of faculty relationships Serono Symposia International Foundation adheres to guidelines of the European Accreditation Council for Continuing Medical Education (EACCME) and all other professional organizations, as applicable, which state that programmes awarding continuing education credits must be balanced, independent, objective, and scientifically rigorous. Investigative and other uses for pharmaceutical agents, medical devices, and other products (other than those uses indicated in approved product labeling/package insert for the product) may be presented in the programme (which may reflect clinical experience, the professional literature or other clinical sources known to the presenter). We ask all presenters to provide participants with information about relationships with pharmaceutical or medical equipment companies that may have relevance to their lectures. This policy is not intended to exclude faculty who have relationships with such companies; it is only intended to inform participants of any potential conflicts so that participants may form their own judgements, based on full disclosure of the facts. Further, all opinions and recommendations presented during the programme and all programme-related materials neither imply an endorsement nor a recommendation on the part of Serono Symposia International Foundation. All presentations represent solely the independent views of the presenters/authors. The following faculty provided information regarding significant commercial relationships and/or discussions of investigational or non-emea/fda approved (off-label) uses of drugs: Claudio Borghi Declared receipts of grants and contract from Manarini international. Declared receipt of honoraria or consultation fees from Manarini, St. Jude medical, Servier, Berlin Chemie. Declared to be member of a company advisory board, board of directors or other similar group of: Ely-Lilly, Menarini. Declared participation in a company sponsored speakers bureau of: Menarini, Servier, St. Jude medical. Jamshed J. Dalal Declared no potential conflict of interest. Aniruddha Dharmadhikari Declared no potential conflict of interest. Roberto Ferrari Declared receipt of research grant from: Boehringer Ingelheim, Novartis, Servier, Irbtech. Declared receipt of honoraria or consultation fees from: Boehringer Ingelheim, Servier. Declared participation in a company sponsored speakers bureau of: Boehringer Ingelheim, Servier and Merck Serono. Guido Grassi Declared receipt of honoraria or consultation fees from: Medtronic, Boston, Scientific, Malesci. Declared participation in a company sponsored speakers bureau of: Medtronic. Gao Pinjin Declared no potential conflict of interest. Soetanto Arieska Soenarta Declared no potential conflict of interest. Piyamitr Sritara Declared no potential conflict of interest. Stefano Taddei Declared receipt of grants and contracts from Novartis, Servier, Boehringer. Declared participation in a company sponsored speakers bureau of Servier, Stroder, Pfizer, Bayer, Msd and Boehringer. Brian Tomlinson Declared receipts of research funding from Amgen, AstraZeneca, Bristol-Mayers Squibb, Genzyme, GlaxoSmith Kline, Merck Serono and Dohme, Novartis, Roche and Tajeda. Declared receipt of honoraria or consultation fees from: Amgen, Janssen and Merck Serono. Declared to be member of a company advisory board, board of directors or other similar group of: Amgen, Janssen and Merck Serono. Declared participation in a company sponsored speakers bureau of: Merck Serono, Merck Sharp and Dohme, Ranbaxy, Servier. Hung-Fat Tse Declared no potential conflict of interest. The following faculty have provided no information regarding significant relationship with commercial supporters and/or discussion of investigational or non-emea/fda approved (off-label) uses of drugs as of 18 February Bambang Budi Siswanto Marlon T. Co Phrommintikul Arintaya Lin Shuguang 8

11 Abstracts

12 The followig abstracts were available at the time of printing. 10

13 L2. Does a first-choice treatment exist? Stefano Taddei Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy Clear evidence demonstrates that the administration of blood pressure (BP)-lowering drugs reduces the risk of major clinical CV outcomes (fatal and nonfatal stroke, myocardial infarction, heart failure and other CV deaths) in hypertensive individuals. In addition, BP induced regression of OD, such as LVH and urinary protein excretion, may be accompanied by a reduction of fatal and nonfatal outcomes. Guidelines reviewing the large number of randomized trials of antihypertensive therapy concluded that the main benefits of antihypertensive treatment are due to lowering of BP per se and are largely independent of the drugs employed. However, randomized trials based on hard clinical CV outcomes have the following limitations: to limit the number of patients needed, trials commonly enrol high-risk patients (old age, concomitant or previous disease) and for practical reasons, the duration of controlled trials is necessarily short (from 3 to 6 years). Thus recommendations for life-long intervention are based on considerable extrapolation from data obtained over periods much shorter than the life expectancy of most patients. Basically, first-choice antihypertensive drugs should include diuretics (thiazides, chlorthalidone and indapamide), beta-blockers, calcium antagonists, ACE-inhibitors and angiotensin receptor blockers. These drug classes are all suitable for the initiation and maintenance of antihypertensive treatment, either as monotherapy or in some combinations. In the clinical practive choice of antihypertensive drugs should derive from a carefull evaluation of the clinical characteristics of each single patient and the knowledge of the different pharmacological and therapeutic characteristics of drugs classes. Compelling evidence exists for antihypertensive drugs and the choice of first-choice agent should derive from specific indications such as the presence of target organ damage, associated clinical events, methabolic disorders or side effects. However, if we consider that monotherapy can normalize BP values in no more than 30% of hypertensive patients and therefore in most cases it is necessary to use drug combination, it is evident that the issue of first-choice treatment is not so relevant for the clinical practice. 11

14 D1. Debate on beta blockers Soetanto Arieska Soenarta, Indonesia 1 Jamshed J. Dalal, India National Heart Center Harapan Kita, Jakarta, Malaysia; 2 - Cardiac Sciences, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Mumbai, India. Pro Beta-blockers In the management of hypertension Soetanto Arieska Soenarta The discovery of beta-blockers (BB) as anti-ischemic agents dated about 45 years ago, as anti-hypertensive- agents about 40 years ago and as anti-heart failure agents about 30 years ago. Today the anti-ischemic as well as the anti heart failure role remains unchallenged, while the anti-hypertensive role is being questioned. BB s were used as one of the first line drugs in hypertension (HT) management since Controversy occurred, which is provoked by the publications of trials and meta-analysis suggesting that BB s have less effect on cardiovascular (CV) morbidity/mortality than other anti-ht agents, resulting in the 2006 guideline of the National Institute for Health and Clinical Excellence (NICE) and the British Hypertension Society Guidelines, removing BB s from the current first line treatment of HT. Metabolic changes caused by some BB s, the inability to reverse left ventricular hypertrophy and to reduce CV events in the elderly, all these concerns are not unreasonable, but modern BB s seem to discard these negative properties of BB s mostly used in the trials. The hydrophilic BB atenolol was used in most trials as a reference BB. Atenolol have a plasma half life of 6 to 7 hours and is only moderately beta-1 selective, and at 100mg blocks about 80% of beta-1 receptors and 25% of beta-2 receptors in contrast to the zero occupancy of beta-2 receptors of bisoprolol 5-10mg (not all BB s are equal) The lack of efficacy of the BB atenolol is responsible for the results of the meta-analysis. Besides this, BB s have been used together with thiazide diuretics in many trials including the largest and most recent ones; it is difficult to discriminate between the favorable and the adverse role one over the other drug class. The ESH/ESC 2007 guidelines also withdrew endorsement of BB s as first line therapy for primary HT, however, the 2009 and 2013 guidelines of the European Society of HT state that large scale meta-analyses of available data confirm that diuretics, beta-blockers, ACE-Inhibitors, ARB s and calcium channel blockers do not significantly differ in their ability to lower BP and to provide cardiovascular protection, in elderly as well as in younger hypertensives. Finally, there are Pros and Cons of BB s as anti HT agents; however, all other classes of anti HT drugs have their Pros as well their Cons. The ESH/ECC HT guidelines list the conditions in which some drugs should be preferred, and others they should be avoided. Cons Beta blockers in hypertension: Not drugs of first choice Jamshed J. Dalal All antihypertensive drugs reduce blood pressure, however one needs to look beyond that and concentrate on the vascular benefits and the reduction of cardiovascular events. When you put aside compelling indications such as ischemia or heart failure, the use of beta blockers as first choice can no longer be recommended. Firstly they have deleterious metabolic effects on diabetes and lipids, two factors that have considerable negative effects on the vascular system. Beta blockers also have lesser reduction in stroke, which may be related to either lesser overall blood pressure lowering or due to lesser reduction of central aortic pressure. Beta blockers are also associated with higher side effects, in particular fatigue and sexual dysfunction. One may suggest that newer beta blockers which do not have these negative attributes, may be better than atenolol, which has been the standard drug used in trials. However no cardiovascular benefits or mortality reduction has been confirmed with the new generation beta blockers in clinical trials. Setting aside these negative aspects of beta blockers, one has to consider the specific advantages of other anti hypertensive drugs, such as endothelial and renal protection, reduction of proteinuria and left ventricular hypertrophy (Renin Angiotensin System blockers), arterial vasodilatation and reduction of peripheral resistance ( Calcium Channel blockers) and historic and strong evidence of mortality reduction (Diuretics). These mechanism of actions have clearly been shown to be associated significant clinical benefits in large trials like LIFE and ASCOT. The NICE guidelines and the 2014 JNC guidelines also state that beta blockers should not be considered as first line drugs for treatment of hypertension. Even ESC 2013 which allows use of beta blockers as first line, excludes their use for the elderly, and those with diabetes, chronic kidney disease or even proteinuria. Clearly, better anti hypertensive drugs are available, and should be used as first line drugs instead of beta blockers. References: 1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction Filicori M, Cognigni GE, Pocognoli P et al Current concepts and novel applications of LH activity in ovarian stimulation. Trends in Endocrinology and Metabolism 14,

15 L4. Differences in drug responsiveness to hypertensive drugs Brian Tomlinson Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China The blood pressure response to any antihypertensive medication differs between individuals and some patients will show a better response to one drug than to another. This presentation will discuss the factors which influence this variability. Currently, in the absence of specific indications or contra-indications, the choice of initial antihypertensive therapy may be based on simple phenotypic factors such as age or ethnicity. These phenotypes in turn show some relationship with underlying pathophysiological mechanisms such as the degree of activity of the renin-angiotensin-aldosterone system (RAAS) or the sympathetic nervous system (SNS) and the salt intake or degree of salt sensitivity. Assessment of the activation of the RAAS by measuring plasma renin activity (PRA) or the salt intake by measuring 24 hour urinary sodium excretion can help to refine the understanding of the pathogenesis of hypertension in the individual but these measurements may not predict the response to antihypertensive drugs very accurately and are not widely used in clinical practice. Some guidelines recommend starting treatment with an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) in younger patients and with a calcium channel blocker (CCB) in older patients or in black people of African or Caribbean family origin, as this approach may result in greater blood pressure reductions [1]. However, other guidelines do not recommend this practice [2]. It is commonly thought that Asian patients respond well to CCBs, but this group of drugs produces greater blood pressure reductions than other classes in most ethnic groups. Whilst there may be differences in the mean blood pressure response with different drugs according to age or ethnicity, these do not predict the response in individuals very well. Predicting blood pressure response or cardiovascular outcome according to genotype appears a more attractive proposition for individualized therapy. At present, this is most useful to predict the pharmacokinetics for drugs that undergo extensive metabolism by a polymorphic enzyme such as metoprolol which is influenced by cytochrome P450 (CYP) 2D6 polymorphisms. The genotype related to the pharmacokinetics may influence cardiovascular response but studies have not been consistent in this finding [3]. Polymorphisms in receptors or enzymes involved in drug response may also predict the blood pressure response [4] and may be relevant to cardiovascular outcomes [5], but again findings have not always been consistent. The use of combinations of drugs with complimentary modes of action is an attractive approach and is recommended by most guidelines if the baseline blood pressure is well above the target and combinations of a CCB with an ACEI, ARB or a beta-blocker usually produce reliable blood pressure reductions [2]. In conclusion, there are considerable differences in the drug responsiveness to antihypertensive drugs but these are not accurately predictable with current phenotyping or genotyping procedures. This may improve with better understanding of the pharmacogenetics of these drugs. In the meantime the use of appropriate drug combinations may result in the most reliable blood pressure response. References: 1 - National Institute for Health and Clinical Excellence (NICE). Hypertension (update): full guideline. Available from: Mancia G, Fagard R, Narkiewicz K, et al., 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013; 34(28): Chan SW, Hu M, Tomlinson B. The pharmacogenetics of beta-adrenergic receptor antagonists in the treatment of hypertension and heart failure. Expert Opin Drug Metab Toxicol 2012;8(7): Johnson JA, Zineh I, Puckett BJ, et al., Beta 1-adrenergic receptor polymorphisms and antihypertensive response to metoprolol. Clin Pharmacol Ther 2003; 74(1): Pacanowski MA, Gong Y, Cooper-Dehoff RM, et al., Beta-adrenergic receptor gene polymorphisms and beta-blocker treatment outcomes in hypertension. Clin Pharmacol Ther 2008; 84(6):

16 L6. Beta-blockers in Asian patients: pharmacodynamics, pharmacokinetics, pharmacogenetics Brian Tomlinson Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China Asian patients may show a difference in response with some beta-blockers compared to other ethnic groups. The influence of pharmacodynamic, pharmacokinetic, and pharmacogenetic factors will be discussed in this presentation. Empirical observations identified that Chinese patients were more sensitive to propranolol than Caucasians and lower starting doses have typically been used. This was confirmed in a study which compared the blood pressure and heart rate responses between Chinese and Caucasian healthy subjects at different propranolol plasma concentrations [1]. This difference could have been related to differences in protein binding of propranolol isomers between ethnic groups and subsequent studies have shown that propranolol pharmacokinetics are highly dependent on polymorphisms in cytochrome P450 (CYP) 2D6 [2]. The CYP2D6*10 variant is common in Chinese and other Asian populations and results in higher blood concentrations of propranolol and also metoprolol [3]. Propranolol is not commonly used for systemic hypertension, but metoprolol is used for several indications throughout the cardiovascular continuum and plasma metoprolol levels will vary considerably in Asian patients according to the CYP2D6*10 polymorphism. Whether this polymorphism influences the haemodynamic response to metoprolol remains controversial but several studies have shown that higher metoprolol plasma concentrations are associated with more adverse effects. Genotyping the CYP2D6*10 polymorphism may help to predict the most appropriate dose of metoprolol in Asian patients or alternatively a beta-blocker which is not dependent on this pathway such as atenolol or bisoprolol could be chosen. Polymorphisms in the beta1-adrenoceptor may also influence the response to most of the beta-blockers. The two common polymorphisms in the beta1-adrenoceptor have a similar frequency in Asian and Caucasian subjects but are more common in people of African origin and this may provide a partial explanation why black patients respond less well on average to beta-blockers compared to Caucasians. Genotyping for these polymorphisms may help to predict the blood pressure response and cardiovascular outcome with beta-blocker treatment in hypertension [4,5], but more data are required to confirm these findings. In conclusion, Asian patients show differences in the pharmacokinetics for propranolol and metoprolol related to the common polymorphism in the CYP2D6 enzyme. Whether this influences the pharmacodynamics of these drugs is not clearly established and the role of pharmacogenetic testing to predict beta-blocker responses requires further clarification. References: 1 - Zhou HH, Koshakji RP, Silberstein DJ, et al., Altered sensitivity to and clearance of propranolol in men of Chinese descent as compared with American whites. N Engl J Med 1989; 320(9): Lai ML, Wang SL, Lai MD, et al., Propranolol disposition in Chinese subjects of different CYP2D6 genotypes. Clin Pharmacol Ther 1995; 58(3): Huang J, Chuang SK, Cheng CL, et al., Pharmacokinetics of metoprolol enantiomers in Chinese subjects of major CYP2D6 genotypes. Clin Pharmacol Ther 1999; 65(4): Johnson JA, Zineh I, Puckett BJ, et al., Beta 1-adrenergic receptor polymorphisms and antihypertensive response to metoprolol. Clin Pharmacol Ther 2003; 74(1): Pacanowski MA, Gong Y, Cooper-Dehoff RM, et al., Beta-adrenergic receptor gene polymorphisms and beta-blocker treatment outcomes in hypertension. Clin Pharmacol Ther 2008; 84(6):

17 L9. Sympathetic nervous system and hypertension: an overview Guido Grassi, Italy Medical Clinic, San Gerardo dei Tintori Hospital, Monza, Italy and Milano-Bicocca University, Milan, Italy Following the demonstration that autonomic cardiovascular influences play a fundamental role in homeostatic control of the cardiovascular system, the hypothesis that hypertension is due to a derangement of sympathetic and parasympathetic cardiovascular regulation has been one of the most widely accredited and tested Iin cardiovascular research. To-date this hypothesis has found confirmation in animal studies which have shown that an increased sympathetic nerve activity, as well as a reduction of vagal cardiac tone, are associated with and responsible for the appearance and maintenance of high blood pressure in several experimental models of hypertension, their role expanding to hypertension-related sequelae. Albeit through a longer and more difficult journey, evidence is now available that similar autonomic alterations may characterize human hypertension as well, and that like in animals these alterations can have a causative or a co-causative role in the generation of this condition. This presentation will describe the alterations of autonomic cardiovascular control that have been reported to occur in human hypertension. It will then discuss the possible approaches to assess human sympathetic neural function in research and in clinical practice. Finally, the contribution of the adrenergic overdrive to the functional and structural changes of the heart and the systemic circulation that accompany a chronic hypertensive state and lead to its overt complications will be discussed. 15

18 D2. Debate: is heart rate a target in hypertensive treatment? Guido Grassi, Italy 1 Phrommintikul Arintaya, Thailand Medical Clinic, San Gerardo dei Tintori Hospital, Monza, Italy and Milano-Bicocca University, Milan, Italy; 2 - Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. Pro Heart rate as target of treatment in hypertension: a pros position Guido Grassi More than 40 epidemiological studies, including the Framingham study, have provided evidence that heart rate is independently associated with cardiovascular and all-cause mortality. In several studies, the heart rate displays a positive relationship with blood pressure values, body weight, triglycerides, insulin and glucose metabolism. This raises the possibility that the ability of this haemodynamic variable to predict cardiovascular events is somewhat aspecific and at least in part dependent on other well known cardiovascular risk factors. However, in the follow-up of two recent surveys, an association between heart rate sudden death and acute coronary events has been reported, and it remained significant even after adjustment for age, body mass index, smoking, blood pressure, lipid profile, diabetes and history of cardiovascular disease. Interestingly, in these studies the predictive power of heart rate for fatal cardiovascular and non cardiovascular events was often greater than that of hypertension and/or hypercholesterolemia. It is manifested not only in ischaemic heart disease, but also in heart failure, hypertension and diabetes. This presentation will review current knowledge on the role of elevated heart rate as a cardiovascular risk factor highlighting the potential factors that favour treatment of this haemodynamic variable. References: 1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction Filicori M, Cognigni GE, Pocognoli P et al Current concepts and novel applications of LH activity in ovarian stimulation. Trends in Endocrinology and Metabolism 14,

19 L10. Hypertension and atrial fibrillation Claudio Borghi Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy Cardiovascular diseases are the first cause of death in the industrialized countries mainly because of the negative impact of clear risk factors. Arterial hypertension plays a primary role and is reponsible for a large proportion of cardiovascular complications observed in the general population. The negative impact of hypertension is strictly related to its capacity to promote atherosclerosis as well as target organ damage chiefly at the cardiac, cerebrovascular and renal levels. Among the possible complications of hypertension, atrial fribillation is certainly a growing problem that involves a remarkable proportion of the hypertensive population particularly among the elderly. The onset of atrial fibrillation is frequently associated with left ventricular hypertrophy and diastolic dysfunction with associated atrial dilatation. More recently an interesting association has been reported between the new onset of atrial fibrillation and the increase in vascular stiffness that support some degree of intercation between cardiac and vascular organ damage in patients with hypertension. From the clinical point of view, the presence of atrial fibrillation is leading to a significant increase in the risk of embolic stroke that may sinergistically interact with the higher probability of ischemic stroke associated with the presence of hypertension. An effective blood pressure control and management of target organ damage is however mandatory for the prevention of atrial fibrillation in patients with hypertension. In patients where permanent atrial fibrillation is co-existing with hypertension, the effective blood pressure control should be combined with an effective control of heart rate as well as with an anticoagulant treatment with warfarin or NOAC. This is particularly so in those hypertensive patients where the risk of thromboembolic events is not associated with an excessive risk of bleeding. 17

20 L11. Coronary artery disease Roberto Ferrari Department of Cardiology and LTTA Centre, University Hospital of Ferrara, Ferrara, Italy Maria Cecilia Hospital, GVM Care&Research, E.S: Health Science Foundation, Cotignola, Italy The so called continuum of cardiovascular disease describes a series of events leading, in some individuals, to different manifestations of cardiovascular diseases. The initial steps of the continuum are several well-known modifiable risk factors such as smoking, dyslipidaemia, insulin resistance, diabetes, hypertension and, as recently suggested, elevated heart rate. All of these factors in one way or another cause alteration of the endothelium of the vessels and in particular a modification of the endothelium life/death cycle. It is relevant to recall that human endothelial cells, like all other cells of the body, commit a programmed death (apoptosis) throughout our entire lifetime. They are also continuously regenerated from the emopoietic lineage of the bone marrow producing the so called endothelial progenitor cells (EPCs). If a mismatch between the rate of endothelial apoptosis / regeneration occurs, or whenever the first exceeds the second, the result is loss of endothelial continuity, allowing all of the biochemical processes of atherosclerosis to start and progress with time, in turn leading to the formation of the atheroma. If this series of events takes place in the coronaries or in the brain arteries, the final result will be, depending on several co-factors, one of the pathological manifestations of the cardiovascular continuum. Hypertension and elevated heart rate (above 70 b/m) are known to negatively affect endothelial function and more specifically to increase its rate of apoptosis, thus facilitating its discontinuity which is the prerequisite for the atheroma formation and progression. It is not surprising therefore that there is a close link between high blood pressure and heart rate and cardiovascular disease such as angina and/or infarction and, consequently cardiovascular mortality. The recent ESC/ESH Guidelines do not provide any specific rank or preferred drug for treating hypertension and preventing cardiovascular mortality. The guidelines suggest that benefit is due to blood pressure reduction per se, no matter how it is obtained, leading to doctors choosing the drugs that are considered the more suitable for the patient. A sort of revival of tailored vs generic treatment! The existing data, however, provides some indication on which drug should be preferred. For example, in hypertension patients with high heart rate, which is an index of increased sympathetic activity, β-blockers should be considered. Equally, β- blockers should be preferred in hypertensive patients with left ventricular dysfunction and/or overt heart failure as in this condition, circulating catecholamines are increased and free to exert their negative effects on the myocytes. Equally, ACE inhibitors (ACEi) should always be preferred to angiotensin II receptor blockers (ARBs) as there is clear and overwhelming evidence that only ACEi (particularly some of them) and not ARBs reduce total and cardiovascular mortality as well as hospitalisation for acute myocardial infarction. Thus, prescribing ARBs for hypertension not only will not protect the patient from CAD but will deprive them of the benefits of ACEi. 18

21 L12. Heart failure Roberto Ferrari Department of Cardiology and LTTA Centre, University Hospital of Ferrara, Ferrara, Italy Maria Cecilia Hospital, GVM Care&Research, E.S: Health Science Foundation, Cotignola, Italy Therapeutic approaches for the treatment of heart failure (HF) have evolved over recent decades, starting in the early 1950s when HF was treated with digitalis, diuretics and bed rest. In the 1980s, in the wake of the first vasodilator HF trial (V-HeFT), blood pressure reduction became the most popular treatment. The 1990s saw a consensus (Cooperative North Scandinavian enalapril Survival Trial) reached about the neuro-hormonal hypothesis. Subsequently, clinical trials confirmed the hypothesis demonstrating the benefit of angiotensin-converting-enzyme inhibitors (ACEi) and β-blockers and the value of training programmes for HF patients. Today, ACEi and β-blockers are the first therapeutic approach for patients with HF. β-blockers reduce heart rate, remodelling the burden of lethal arrhythmias and, importantly, the negative effects of increased catecholamine levels on the myocytes. Current guidelines also suggest anti-aldosterone agents and Ivabradine as a second stage of intervention if heart rate remains elevated despite β-blocker treatment. All of these drugs have been proven to be successful in those patients with HF with reduced ejection fraction (HFrEF). During the last 15 years or so it has been increasingly recognised that many patients with HF have normal or nearly normal left ventricular ejection fraction (LVEF), a condition referred to as diastolic HF or HF with preserved EF (HFpEF). Schematically, two pathophysiological hypotheses of the development of the HFpEF have been formulated. One proposing a model of progressive abnormalities in left ventricular (LV) diastolic function first, followed by systolic dysfunction underlying HF along with a progressive declining of LVEF, being the clinical syndrome able to occur at any point along this continuum. An alternative hypothesis is based on the principle that HFrEF and HFpEF are distinct conditions developing through different processes. In essence, a systemic pro-inflammatory state would be induced by common cardiovascular risk factors and comorbidities, representing the biological background of the cardiovascular abnormalities in HFpEF and particularly of myocardial structural and functional alterations. According to this paradigm, a high prevalence of comorbidities such as overweight/obesity, diabetes mellitus, chronic obstructive pulmonary disease and particularly salt sensitive hypertension would induce a systemic permanent proinflammatory state (shown to be predictive of incident HFpEF but not of incident HFrEF), causing coronary microvascular endothelial inflammation. In turn this would inflammatory oxidative stress, endothelial dysfunction, and organ-level dysfunction in patients with HFpEF. Such a complex systemic process should probably require an individual susceptibility leading to a cardiovascular vulnerability to the cumulative mechanical load of hypertension and biological insults of metabolic comorbidities and aging. Thus, we might consider the HFrEF as a primarily cardiac syndrome with complex, prevalently neuro-hormonal, systemic responses, being dominant cardiac abnormalities in systolic function, left ventricular dilation, and eccentric remodelling. The HFpEF may be seen as a primary multimorbid systemic syndrome with a prominent cardiovascular component, and cardiac dominant abnormalities in diastolic function, normal left ventricular size, and concentric remodelling. This clinical research aimed at finding effective therapeutic tools was successful in HFrEF but not in HFpEF so far. In the absence of specific treatment, β-blockers and ACEi are the preferred treatment. 19

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