FINAL PROGRAMME AND ABSTRACT BOOK

2014 Asia-Pacific cardiovascular symposiumManaging cardiovascular risk factors to preventthe fatal end of cardiovascular continuum1- 2 March 2014 - Guangzhou, China

General information

VenueThis live educational symposium takes place at the:Grand Hyatt Guangzhou I12 Zhujiang West Road, Pearl River New City,Guangzhou 510623, Chinahttp://guangzhou.grand.hyatt.com/en/hotel/home.html

LanguageThe official language of this live educational symposium is English.No simultaneous translation will be provided.

Scientific secretariatSerono Symposia International FoundationSalita di San Nicola da Tolentino, 1/b00187 Rome, Italy

Associate Project Manager: Simona Gaudiosi

Tel.: +39 (0)6 420 413 308Fax: +39 (0)6 420 413 677E-mail: info@seronosymposia.org

Medical Advisor: Professor Stefano Taddei

Serono Symposia International Foundation is a Swiss Foundation with headquarters in 14, Rue du Rhône, 1204 Geneva, Switzerland

Organising secretariatConnex asia consultingCongress Coordinator: Suzanna TehTel.: +65 9 776 4243 E-mail: suzanna.teh@connex-asia.com

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2014 Asia-Pacific cardiovascular symposiumManaging cardiovascular risk factors to prevent thefatal end of cardiovascular continuum

Serono Symposia International Foundation live educational symposium on:

2014 Asia-Pacific cardiovascular symposiumManaging cardiovascular risk factors to prevent the fatal end of cardiovascular continuum1 - 2 March 2014 - Guangzhou, China

AimIn spite of increased knowledge and the ongoing efforts of scientific societies, cardiovascular diseases remain the first cause ofmortality and morbidity in the Asia-Pacific regions as well as in the rest of the world. Treatment of major cardiovascular diseasesincluding acute coronary syndrome or stroke present a significant and costly challenge for the health systems - without taking intoconsideration 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 bymetabolic disease. Most hypertensive patients are still not receiving the correct pharmacological treatment and may not have theirblood pressure values suitably normalised. There is a clear need to promote clinical management of hypertension that is derivedfrom 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 “Managingcardiovascular 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 correctutilisation of the “old” drugs such as beta-blockers and the “new” therapeutic approaches such as renal denervation. Sessions willalso be devoted to discussing emerging health problems in the Asia-Pacific area and will offer possible solutions to the managementof patients with hypertension complicated by other risk factors or related diseases.

Learning objectivesBy 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 drugresponsiveness and the impact of pollution on cardiovascular disease

• Demonstrate effective treatment of hypertensive patients with specific and challenging problems including old age, diabetes orobesity

• 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, coronaryartery disease and heart failure

Target audienceCardiologists, internists and all others heath care professionals managing hypertension.

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All Serono Symposia International Foundation programmes are organized solely to promote the exchange and dissemination of scientific and medical information. Noforms of promotional activities are permitted. There may be presentations discussing investigational uses of various products. These views are the responsibility of thenamed speakers, and do not represent an endorsement or recommendation on the part of Serono Symposia International Foundation. This programme is made possiblethanks to educational grants received from: Arseus Medical, Besins Healthcare, Bristol-Myers Squibb, Celgene, Centre d’Esclerosi Multiple de Catalunya (Vall d’HebronUniversity 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, UniversitéCatholique de Louvain (UCL), University of Catania.

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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 receivingan online survey to help us to better tailor our future educational initiatives.

We thank you for participating!

AccreditationThe educational event: 2014 Asia-Pacific cardiovascular symposium “Managing cardiovascular risk factors to prevent the fatal endof cardiovascular continuum” held on 1-2 March 2014 in Guangzhou, China (Ref. 00003154), is accredited by the European Boardfor 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), www.uems.net

Serono Symposia International Foundation (SSIF) adheres to the principles of the Good CME Practice Group (gCMEp).

Scientific organisersLin ShuguangGuangdong General HospitalGuangdong, China

Brian TomlinsonDepartment of Medicine and TherapeuticsThe Chinese University of Hong KongHong Kong SAR, China

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Faculty membersClaudio BorghiDepartment of Medical and Surgical SciencesUniversity of BolognaBologna, Italy

Bambang Budi SiswantoNational Heart Center Harapan KitaJacarta Barat, Indonesia

Jamshed J. DalalCardiac SciencesKokilaben Dhirubhai Ambani Hospital and Medical Research InstituteMumbai, India

Aniruddha DharmadhikariShree Saibaba Heart Institute and Research CenterNear Kalidaskala MandirShalimar, Nasik, India

Roberto FerrariDepartment of Cardiology and LTTA CentreUniversity Hospital of FerraraFerrara, ItalyMaria Cecilia HospitalGVM Care&ResearchE.S: Health Science FoundationCotignola, Italy

Guido GrassiMedical ClinicSan Gerardo dei Tintori HospitalMonza, Italyand Milano-Bicocca UniversityMilan, Italy

Phrommintikul ArintayaDepartment of Internal MedicineFaculty of MedicineChiang Mai UniversitChiang Mai, Thailand

Gao PinjinDepartment of HypertensionRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai, China

Lin ShuguangGuangdong General HospitalGuangdong, China

Soetanto Arieska SoenartaNational Heart Center Harapan KitaJakarta, Indonesia

Piyamitr SritaraDepartment of MedicineRamathibodi HospitalMahidol UniversityBangkok, Thailand

Stefano TaddeiDepartment of Clinical and Experimental MedicineUniversity of PisaPisa, Italy

Brian TomlinsonDepartment of Medicine and TherapeuticsThe Chinese University of Hong KongHong Kong SAR, China

Hung-Fat TseCardiology DivisionDepartment of MedicineThe University of Hong KongHong Kong SAR, China

Marlon T. CoChong Hua HospitalCebu City, Philippines

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Scientific programme1- 2March 2014

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Chairman: Lin Shuguang (China)

Real time survey

09.35 L2: Does a first-choice treatment exist? Stefano Taddei (Italy)

09.55 D1: Debate on beta blockers: - Pro Soetanto Arieska Soenarta (Indonesia)- Cons Jamshed J. Dalal (India)

10.25 CC1: Clinical caseSoetanto Arieska Soenarta (Indonesia)

11.00 Real time survey and questions time

11.10 Coffee break

Chairman: Jamshed J. Dalal (India)

Real time survey

11.30 L3: Burden of cardio metabolic diseasesPiyamitr Sritara (Thailand)

11.50 L4: Differences in drug responsiveness tohypertensive drugsBrian Tomlinson (China)

12.15 L5: Pollution factorsStefano Taddei (Italy)

12.35 Real time survey and questions time

12.45 Lunch

Specific issues in the pharmacological treatment ofhypertensionSession I

Specific problems in APACSession II

Chairman: Roberto Ferrari (Italy)

Real time survey

CC2: Clinical cases

14.00 Diabetic populationHung-Fat Tse (China)

14.30 Young and middle age obese populationBambang Budi Siswanto (Indonesia)

15.00 Real time survey and questions time

15.15 Coffee break

Chairman: Hung-Fat Tse (China)

Real time survey

15.30 L6: Beta-blockers in Asian patients:pharmacodynamics, pharmacokinetics,pharmacogeneticsBrian Tomlinson (China)

15.50 L7: Comparing two beta-blockers in patients withhypertensionAniruddha Dharmadhikari (India)

16.10 L8: Comparison of two beta-blockers onsympathetic nervous activity and central aorticpressure in hypertensive patientsGao Pinjin (China)

16.30 Panel discussion: Which criteria for theselection of a beta-blocker should beconsidered?

16.50 Real time survey and questions time

17.00 End of the first day

Hypertension in special populationSession III

Beta blockers for management of cardiovasculardiseases: are all beta- blockers the same?Session IV

Saturday, 1 March 2014

08.45 Serono Symposia International Foundation(SSIF) welcome and introduction Brian Tomlinson (China)

09.00 Introductory lecture Lin Shuguang (China)

09.15 L1: Novelties from recent guidelines inhypertensionMarlon T. Co (Philippines)

Legend

L : Lecture; D : Debate; CC : Clinical case; : Questions time;

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Sunday, 2 March 2014

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Chairman: Stefano Taddei (Italy)

Real time survey

09.00 L9: Sympathetic nervous system andhypertension: an overview Guido Grassi (Italy)

09.20 D2: Debate: is heart rate a target in hypertensivetreatment?- Pro Guido Grassi (Italy)- Cons Phrommintikul Arintaya (Thailand)

10.00 Real time survey and questions time

10.15 Coffee break

New therapeutic approach in hypertension: the roleof heart rateSession V

Chairman: Brian Tomlinson (China)

Real time survey

10.45 L10: Hypertension and atrial fibrillationClaudio Borghi (Italy)

11.15 L11: Coronary artery disease Roberto Ferrari (Italy)

11.45 L12: Heart failureRoberto Ferrari (Italy)

12.15 Real time survey and questions time

12.20 Concluding remarks

12.30 End of the live educational symposium

Hypertension and related diseasesSession VI

Disclosure of faculty relationships

Serono Symposia International Foundation adheres to guidelines of the European Accreditation Council for Continuing MedicalEducation (EACCME) and all other professional organizations, as applicable, which state that programmes awarding continuingeducation credits must be balanced, independent, objective, and scientifically rigorous. Investigative and other uses for pharmaceuticalagents, medical devices, and other products (other than those uses indicated in approved product labeling/package insert for theproduct) may be presented in the programme (which may reflect clinical experience, the professional literature or other clinical sourcesknown to the presenter). We ask all presenters to provide participants with information about relationships with pharmaceutical ormedical equipment companies that may have relevance to their lectures. This policy is not intended to exclude faculty who haverelationships with such companies; it is only intended to inform participants of any potential conflicts so that participants may form theirown judgements, based on full disclosure of the facts. Further, all opinions and recommendations presented during the programmeand all programme-related materials neither imply an endorsement nor a recommendation on the part of Serono SymposiaInternational 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 ornon-EMEA/FDA approved (off-label) uses of drugs:

Claudio Borghi Declared receipts of grants and contract from Manarini international. Declared receipt ofhonoraria 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 groupof: Ely-Lilly, Menarini. Declared participation in a company sponsored speakers’ bureau of: Menarini, Servier, St. Judemedical.

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 groupof: Amgen, Janssen and Merck Serono. Declared participation in a company sponsoredspeakers’ 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 discussionof investigational or non-EMEA/FDA approved (off-label) uses of drugs as of 18 February 2014. Bambang Budi SiswantoMarlon T. CoPhrommintikul ArintayaLin Shuguang

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Abstracts

The followig abstracts were available at the time of printing.

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L2. Does a first-choice treatment exist?

Clear evidence demonstrates that the administration of blood pressure (BP)-lowering drugs reduces the risk of major clinical CVoutcomes (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 nonfataloutcomes.

Guidelines reviewing the large number of randomized trials of antihypertensive therapy concluded that the main benefits ofantihypertensive 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 patientsneeded, trials commonly enrol high-risk patients (old age, concomitant or previous disease) and for practical reasons, the durationof controlled trials is necessarily short (from 3 to 6 years). Thus recommendations for life-long intervention are based onconsiderable 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 andmaintenance 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 eachsingle patient and the knowledge of the different pharmacological and therapeutic characteristics of drugs classes. Compellingevidence exists for antihypertensive drugs and the choice of first-choice agent should derive from specific indications such as thepresence 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 inmost cases it is necessary to use drug combination, it is evident that the issue of first-choice treatment is not so relevant for theclinical practice.

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Stefano TaddeiDepartment of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

D1. Debate on beta blockers

1 - National Heart Center Harapan Kita, Jakarta, Malaysia;2 - Cardiac Sciences, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Mumbai, India.

ProBeta-blockers In the management of hypertensionSoetanto Arieska Soenarta

The discovery of beta-blockers (BB) as anti-ischemic agents dated about 45 years ago, as anti-hypertensive- agents about 40 yearsago and as anti-heart failure agents about 30 years ago. Today the anti-ischemic as well as the anti heart failure role remainsunchallenged, while the anti-hypertensive role is being questioned. BB’s were used as one of the first line drugs in hypertension (HT)management since 1971. Controversy occurred, which is provoked by the publications of trials and meta-analysis suggesting thatBB’s have less effect on cardiovascular (CV) morbidity/mortality than other anti-HT agents, resulting in the 2006 guideline of theNational Institute for Health and Clinical Excellence (NICE) and the British Hypertension Society Guidelines, removing BB’s from thecurrent first line treatment of HT. Metabolic changes caused by some BB’s, the inability to reverse left ventricular hypertrophy andto reduce CV events in the elderly, all these concerns are not unreasonable, but “modern BB’s” seem to discard these negativeproperties of BB’s mostly used in the trials. The hydrophilic BB atenolol was used in most trials as a reference BB. Atenolol have aplasma 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 ofefficacy of the BB atenolol is responsible for the results of the meta-analysis. Besides this, BB’s have been used together withthiazide diuretics in many trials including the largest and most recent ones; it is difficult to discriminate between the favorable andthe adverse role one over the other drug class. The ESH/ESC 2007 guidelines also withdrew endorsement of BB’s as first –linetherapy for primary HT, however, the 2009 and 2013 guidelines of the European Society of HT state that large–scale meta-analysesof available data confirm that diuretics, beta-blockers, ACE-Inhibitors, ARB’s and calcium channel blockers do not significantly differin their ability to lower BP and to provide cardiovascular protection, in elderly as well as in younger hypertensives. Finally, there arePros and Cons of BB’s as anti HT agents; however, all other classes of anti HT drugs have their Pros as well their Cons. TheESH/ECC HT guidelines list the conditions in which some drugs should be preferred, and others they should be avoided.

ConsBeta blockers in hypertension: Not drugs of first choiceJamshed J. Dalal

All antihypertensive drugs reduce blood pressure, however one needs to look beyond that and concentrate on the vascular benefitsand the reduction of cardiovascular events. When you put aside compelling indications such as ischemia or heart failure, the use ofbeta 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 , whichmay be related to either lesser overall blood pressure lowering or due to lesser reduction of central aortic pressure. Beta blockersare also associated with higher side effects, in particular fatigue and sexual dysfunction. One may suggest that newer beta blockerswhich do not have these negative attributes, may be better than atenolol, which has been the standard drug used in trials. Howeverno cardiovascular benefits or mortality reduction has been confirmed with the new generation beta blockers in clinical trials. Settingaside these negative aspects of beta blockers, one has to consider the specific advantages of other anti hypertensive drugs, such asendothelial 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 ofmortality reduction (Diuretics). These mechanism of actions have clearly been shown to be associated significant clinical benefits inlarge trials like LIFE and ASCOT. The NICE guidelines and the 2014 JNC guidelines also state that beta blockers should not beconsidered as first line drugs for treatment of hypertension. Even ESC 2013 which allows use of beta blockers as first line, excludestheir use for the elderly, and those with diabetes, chronic kidney disease or even proteinuria. Clearly, better anti hypertensive drugsare available, and should be used as first line drugs instead of beta blockers.

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Soetanto Arieska Soenarta, Indonesia 1

Jamshed J. Dalal, India 2

References:1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction6 1206-1212.

2 - Filicori M, Cognigni GE, Pocognoli P et al. 2003 Current concepts and novel applications of LH activity in ovarian stimulation. Trends in Endocrinology andMetabolism 14, 267-273.

L4. Differences in drug responsiveness to hypertensive drugs

The blood pressure response to any antihypertensive medication differs between individuals and some patients will show a betterresponse 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 onsimple phenotypic factors such as age or ethnicity. These phenotypes in turn show some relationship with underlyingpathophysiological mechanisms such as the degree of activity of the renin-angiotensin-aldosterone system (RAAS) or thesympathetic nervous system (SNS) and the salt intake or degree of salt sensitivity. Assessment of the activation of the RAAS bymeasuring plasma renin activity (PRA) or the salt intake by measuring 24 hour urinary sodium excretion can help to refine theunderstanding of the pathogenesis of hypertension in the individual but these measurements may not predict the response toantihypertensive 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 receptorblocker (ARB) in younger patients and with a calcium channel blocker (CCB) in older patients or in black people of African orCaribbean family origin, as this approach may result in greater blood pressure reductions [1]. However, other guidelines do notrecommend this practice [2]. It is commonly thought that Asian patients respond well to CCBs, but this group of drugs producesgreater blood pressure reductions than other classes in most ethnic groups. Whilst there may be differences in the mean bloodpressure 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 forindividualized therapy. At present, this is most useful to predict the pharmacokinetics for drugs that undergo extensive metabolismby a polymorphic enzyme such as metoprolol which is influenced by cytochrome P450 (CYP) 2D6 polymorphisms. The genotyperelated 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 berelevant 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 mostguidelines if the baseline blood pressure is well above the target and combinations of a CCB with an ACEI, ARB or a beta-blockerusually produce reliable blood pressure reductions [2].

In conclusion, there are considerable differences in the drug responsiveness to antihypertensive drugs but these are not accuratelypredictable with current phenotyping or genotyping procedures. This may improve with better understanding of thepharmacogenetics of these drugs. In the meantime the use of appropriate drug combinations may result in the most reliable bloodpressure response.

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Brian TomlinsonDepartment of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China

References:1 - National Institute for Health and Clinical Excellence (NICE). Hypertension (update): full guideline. Available from:

http://www.nice.org.uk/guidance/index.jsp?action=download&o=54727 2011.2 - 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): 2159-219.3 - 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):767-90.4 - Johnson JA, Zineh I, Puckett BJ, et al., Beta 1-adrenergic receptor polymorphisms and antihypertensive response to metoprolol. Clin Pharmacol Ther 2003;74(1): 44-52.

5 - 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): 715-21.

L6. Beta-blockers in Asian patients: pharmacodynamics,pharmacokinetics, pharmacogenetics

Asian patients may show a difference in response with some beta-blockers compared to other ethnic groups. The influence ofpharmacodynamic, 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 doseshave typically been used. This was confirmed in a study which compared the blood pressure and heart rate responses betweenChinese and Caucasian healthy subjects at different propranolol plasma concentrations [1]. This difference could have been relatedto differences in protein binding of propranolol isomers between ethnic groups and subsequent studies have shown that propranololpharmacokinetics are highly dependent on polymorphisms in cytochrome P450 (CYP) 2D6 [2]. The CYP2D6*10 variant is common inChinese and other Asian populations and results in higher blood concentrations of propranolol and also metoprolol [3]. Propranololis not commonly used for systemic hypertension, but metoprolol is used for several indications throughout the cardiovascularcontinuum 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 haveshown that higher metoprolol plasma concentrations are associated with more adverse effects. Genotyping the CYP2D6*10polymorphism may help to predict the most appropriate dose of metoprolol in Asian patients or alternatively a beta-blocker whichis 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 commonpolymorphisms in the beta1-adrenoceptor have a similar frequency in Asian and Caucasian subjects but are more common in peopleof African origin and this may provide a partial explanation why black patients respond less well on average to beta-blockerscompared to Caucasians. Genotyping for these polymorphisms may help to predict the blood pressure response and cardiovascularoutcome 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 commonpolymorphism in the CYP2D6 enzyme. Whether this influences the pharmacodynamics of these drugs is not clearly established andthe role of pharmacogenetic testing to predict beta-blocker responses requires further clarification.

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Brian TomlinsonDepartment of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China

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): 565-70.2 - Lai ML, Wang SL, Lai MD, et al., Propranolol disposition in Chinese subjects of different CYP2D6 genotypes. Clin Pharmacol Ther 1995; 58(3): 264-8.3 - 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): 402-7.4 - Johnson JA, Zineh I, Puckett BJ, et al., Beta 1-adrenergic receptor polymorphisms and antihypertensive response to metoprolol. Clin Pharmacol Ther 2003;74(1): 44-52.

5 - Pacanowski MA, Gong Y, Cooper-Dehoff RM, et al., Beta-adrenergic receptor gene polymorphisms and beta-blocker treatment outcomes in hypertension. ClinPharmacol Ther 2008; 84(6): 715-21.

L9. Sympathetic nervous system and hypertension: an overview

Following the demonstration that autonomic cardiovascular influences play a fundamental role in homeostatic control of thecardiovascular system, the hypothesis that hypertension is due to a derangement of sympathetic and parasympatheticcardiovascular regulation has been one of the most widely accredited and tested Iin cardiovascular research. To-date this hypothesishas found confirmation in animal studies which have shown that an increased sympathetic nerve activity, as well as a reduction ofvagal cardiac tone, are associated with and responsible for the appearance and maintenance of high blood pressure in severalexperimental models of hypertension , their role expanding to hypertension-related sequelae. Albeit through a longer and moredifficult journey, evidence is now available that similar autonomic alterations may characterize human hypertension as well, and thatlike 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 humanhypertension. It will then discuss the possible approaches to assess human sympathetic neural function in research and in clinicalpractice. Finally, the contribution of the adrenergic overdrive to the functional and structural changes of the heart and the systemiccirculation that accompany a chronic hypertensive state and lead to its overt complications will be discussed.

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Guido Grassi, ItalyMedical Clinic, San Gerardo dei Tintori Hospital, Monza, Italy and Milano-Bicocca University, Milan, Italy

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D2. Debate: is heart rate a target in hypertensive treatment?

1 - 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.

ProHeart rate as target of treatment in hypertension: a pros positionGuido Grassi

More than 40 epidemiological studies, including the Framingham study, have provided evidence that heart rate is independentlyassociated with cardiovascular and all-cause mortality. In several studies, the heart rate displays a positive relationship with bloodpressure values, body weight, triglycerides, insulin and glucose metabolism. This raises the possibility that the ability of thishaemodynamic variable to predict cardiovascular events is somewhat aspecific and at least in part dependent on other well knowncardiovascular risk factors. However, in the follow-up of two recent surveys, an association between heart rate sudden death andacute coronary events has been reported, and it remained significant even after adjustment for age, body mass index, smoking, bloodpressure, lipid profile, diabetes and history of cardiovascular disease. Interestingly, in these studies the predictive power of heart ratefor fatal cardiovascular and non cardiovascular events was often greater than that of hypertension and/or hypercholesterolemia . Itis manifested not only in ischaemic heart disease, but also in heart failure, hypertension and diabetes. This presentation will reviewcurrent knowledge on the role of elevated heart rate as a cardiovascular risk factor highlighting the potential factors that favourtreatment of this haemodynamic variable.

Guido Grassi, Italy 1

Phrommintikul Arintaya, Thailand 2

References:1 - Chappel SC, Howles C 1991 Reevaluation of the roles of luteinizing hormone and follicle-stimulating hormone in the ovulatory process. Human Reproduction6 1206-1212.

2 - Filicori M, Cognigni GE, Pocognoli P et al. 2003 Current concepts and novel applications of LH activity in ovarian stimulation. Trends in Endocrinology andMetabolism 14, 267-273.

L10. Hypertension and atrial fibrillation

Cardiovascular diseases are the first cause of death in the industrialized countries mainly because of the negative impact of clearrisk factors. Arterial hypertension plays a primary role and is reponsible for a large proportion of cardiovascular complicationsobserved in the general population. The negative impact of hypertension is strictly related to its capacity to promote atherosclerosisas well as target organ damage chiefly at the cardiac, cerebrovascular and renal levels. Among the possible complications ofhypertension, atrial fribillation is certainly a growing problem that involves a remarkable proportion of the hypertensive populationparticularly among the elderly. The onset of atrial fibrillation is frequently associated with left ventricular hypertrophy and diastolicdysfunction with associated atrial dilatation. More recently an interesting association has been reported between the new onset ofatrial fibrillation and the increase in vascular stiffness that support some degree of intercation between cardiac and vascular organdamage in patients with hypertension. From the clinical point of view, the presence of atrial fibrillation is leading to a significantincrease in the risk of embolic stroke that may sinergistically interact with the higher probability of ischemic stroke associated withthe presence of hypertension. An effective blood pressure control and management of target organ damage is however mandatoryfor the prevention of atrial fibrillation in patients with hypertension. In patients where permanent atrial fibrillation is co-existing withhypertension, the effective blood pressure control should be combined with an effective control of heart rate as well as with ananticoagulant treatment with warfarin or NOAC. This is particularly so in those hypertensive patients where the risk ofthromboembolic events is not associated with an excessive risk of bleeding.

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Claudio BorghiDepartment of Medical and Surgical Sciences, University of Bologna, Bologna, Italy

L11. Coronary artery disease

The so called “continuum” of cardiovascular disease describes a series of events leading, in some individuals, to differentmanifestations of cardiovascular diseases. The initial steps of the continuum are several well-known modifiable risk factors such assmoking, dyslipidaemia, insulin resistance, diabetes, hypertension and, as recently suggested, elevated heart rate. All of thesefactors in one way or another cause alteration of the endothelium of the vessels and in particular a modification of the endotheliumlife/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 marrowproducing the so called endothelial progenitor cells (EPCs). If a mismatch between the rate of endothelial apoptosis / regenerationoccurs, or whenever the first exceeds the second, the result is loss of endothelial continuity, allowing all of the biochemicalprocesses of atherosclerosis to start and progress with time, in turn leading to the formation of the atheroma. If this series of eventstakes place in the coronaries or in the brain arteries, the final result will be, depending on several co-factors, one of the pathologicalmanifestations of the cardiovascular continuum. Hypertension and elevated heart rate (above 70 b/m) are known to negatively affectendothelial function and more specifically to increase its rate of apoptosis, thus facilitating its discontinuity which is the prerequisitefor the atheroma formation and progression. It is not surprising therefore that there is a close link between high blood pressure andheart 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 preventingcardiovascular 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 generictreatment! The existing data, however, provides some indication on which drug should be preferred. For example, in hypertensionpatients 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 andoverwhelming evidence that only ACEi (particularly some of them) and not ARBs reduce total and cardiovascular mortality as wellas hospitalisation for acute myocardial infarction. Thus, prescribing ARBs for hypertension not only will not protect the patient fromCAD but will deprive them of the benefits of ACEi.

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Roberto FerrariDepartment of Cardiology and LTTA Centre, University Hospital of Ferrara, Ferrara, ItalyMaria Cecilia Hospital, GVM Care&Research, E.S: Health Science Foundation, Cotignola, Italy

L12. Heart failure

Therapeutic approaches for the treatment of heart failure (HF) have evolved over recent decades, starting in the early 1950s whenHF was treated with digitalis, diuretics and bed rest. In the 1980s, in the wake of the first vasodilator HF trial (V-HeFT), blood pressurereduction 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 ofangiotensin-converting-enzyme inhibitors (ACEi) and β-blockers and the value of training programmes for HF patients. Today, ACEiand β-blockers are the first therapeutic approach for patients with HF. β-blockers reduce heart rate, remodelling the burden of lethalarrhythmias and, importantly, the negative effects of increased catecholamine levels on the myocytes. Current guidelines alsosuggest anti-aldosterone agents and Ivabradine as a second stage of intervention if heart rate remains elevated despite β-blockertreatment. 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 leftventricular ejection fraction (LVEF), a condition referred to as diastolic HF or HF with preserved EF (HFpEF). Schematically, twopathophysiological hypotheses of the development of the HFpEF have been formulated. One proposing a model of progressiveabnormalities in left ventricular (LV) diastolic function first, followed by systolic dysfunction underlying HF along with a progressivedeclining of LVEF, being the clinical syndrome able to occur at any point along this continuum. An alternative hypothesis is based onthe 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 andfunctional 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 pro-inflammatory state (shown to be predictive of incident HFpEF but not of incident HFrEF), causing coronary microvascular endothelialinflammation. In turn this would inflammatory oxidative stress, endothelial dysfunction, and organ-level dysfunction in patients withHFpEF. Such a complex systemic process should probably require an individual susceptibility leading to a cardiovascular vulnerabilityto 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 beseen as a primary multimorbid systemic syndrome with a prominent cardiovascular component, and cardiac dominantabnormalities 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 absenceof specific treatment, β-blockers and ACEi are the preferred treatment.

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Roberto FerrariDepartment of Cardiology and LTTA Centre, University Hospital of Ferrara, Ferrara, ItalyMaria Cecilia Hospital, GVM Care&Research, E.S: Health Science Foundation, Cotignola, Italy

NOTES

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