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Journal of the American College of Cardiology Vol. 43, No. 6, 2004© 2004 by the American College of Cardiology Foundation ISSN 0735-1097/04/$30.00Published by Elsevier Inc. doi:10.1016/j.jacc.2004.01.026

EETING HIGHLIGHTS

ighlights of the 2003 Scientificessions of the Heart Failure Society of Americaas Vegas, Nevada, September 21 to 24, 2003eter Liu, MD,* Marvin A. Konstam, MD,† Thomas Force, MD†‡oronto, Canada; and Boston, Massachusetts

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he Annual Scientific Meeting of the Heart Failure Societyf America (HFSA) brings together health care profession-ls who are dedicated to improving the diagnosis, treatment,nd quality of life for individuals affected by heart failureHF). During the 2.5-day meeting, attendees had an op-ortunity to hear about the latest developments in researchboth basic and clinical), learn about the latest technologiessed to treat HF, attend small “how to” sessions on focusedopics, and hear about the latest clinical trials and guide-ines. The attendance at this year’s 7th annual meetingroke a new record with 3,400 registrants, compared with,500 registrants for last year. This is a testament of theuccess of the meeting in addressing the needs of thisedicated community. The meeting had over 30 sessionsnd obviously not all can be highlighted. This paperrovides an overview of four clinical sessions, as well as theasic science portions of the scientific program.

PENING PLENARY SYMPOSIUM—HEARTAILURE 2003: FROM CELLS TO POPULATION

tem and progenitor cells for repair. Dr. Michael Schnei-er (Baylor College of Medicine, Houston, Texas) openedhe plenary symposium on the topic of stem and progenitorells for cardiac repair. Intrinsic cardiac restorative growth isoo meager to match the demands after acute cell death inyocardial infarction (MI) or chronic sporadic cell death inF. Currently, a variety of cell types show promise foryocardial regeneration, although the biologic understand-

ng of this process is still primitive. Skeletal muscle cells haveeen used in clinical trials. They improve ventricular func-ion, but without transdifferentiating into cardiomyocytes oronnecting with cardiomyocytes, and are a source of ar-hythmias. Bone marrow-derived cells—hematopoietic andesenchymal stem cells and circulating endothelial progen-

tor cells or hemangioblasts—are also promising as sourcesf autologous cells. The phase I trials to date are encour-ging, but it is unclear whether benefits are related to

From the *Heart and Stroke/Richard Lewar Centre of Excellence, University oforonto, and Division of Cardiology, Toronto General Hospital, University Healthetwork, Toronto, Canada; †Division of Cardiology, and the ‡Cardiomyocyteiology Laboratory of the Molecular Cardiology Research Institute, Tufts–Newngland Medical Center and Tufts University School of Medicine, Boston, Massa-

husetts.

Manuscript received January 6, 2004; accepted January 14, 2004.

yocyte formation or, alternatively, to angiogenesis or anltered remodeling process. Human embryonic stem cells havehe best proven ability to form all cell types and holdremendous promise for therapy, but studies on these cellsave been limited by religious or ethical objections.Therefore, the most intriguing question is whether the

eart actually has its own reservoir of repair cells that mighte exploited to replace damaged myocardium more effec-ively. The answer appears to be “yes,” and the possibleandidates to date are the side-population (SP) cells, c-kit�ells, and Sca-1� cells. Dr. Schneider’s laboratory hasocused on the latter, identified using the Sca-1 markerstem cell antigen-1). These are small interstitial cells thatxpress many cardiac transcription factors, but not cardiactructural genes, and are viewed as predisposed to convertnto cardiac muscle itself. This can be triggered in cellulture by using a drug (azacytidine), partly dependent on aeceptor for growth factors with known importance forardiac development in the embryo, called “bone morpho-enic proteins.” Given systemically, cardiac Sca-1� cellsome specifically to the infarct border zone and differentiatefficiently in vivo.

The future challenge for stem cell research will be to focusn stem cell mobilization and stem cell engineering, in anttempt to identify control systems for proliferation, differ-ntiation, myocyte connectivity, and ultimately organ func-ion and host survival.

ellular apoptosis and survival in HF. Dr. Richard KitsisAlbert Einstein College of Medicine, Bronx, New York)hen presented a discussion on cell survival and apoptosis.he ability to prevent apoptosis or programmed cell death,articularly in ischemia-reperfusion, will have importantalutary effects on HF development. During a typicalnfarction, 5% to 30% of myocytes in the infarct zone and.1% to 0.3% in the remote zone undergo apoptosis. This isn contrast to the baseline apoptosis rate of 0.01% to 0.001%n the normal myocardium. Apoptotic pathways in myo-ytes can be triggered by death receptor signals coupled torocaspase-8. Additional triggers can arise from an extra-ellular stimulus that activates Bax and releasesytochrome-c from mitochondria. This, in turn, activatespaf-1 and procaspase-9 and, together with caspase-8,

eads to caspase-3 activation and execution of cell death. Inhe setting of ischemia-reperfusion, inhibition of apoptosis,

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1104 Liu et al. JACC Vol. 43, No. 6, 2004Highlights of 2003 Heart Failure Society of America March 17, 2004:1103–9

sing genetic manipulations, reduces the infarct size by 50%o 60% and improves cardiac function. Similar results arebtained with the newer caspase inhibitors, where sustainedeductions in infarct size and improvements in cardiacunction are observed, even when administration of the drugs delayed 1 h from the onset of ischemia.

Does apoptosis directly contribute to HF? Conditionalctivation of a caspase gene in the mouse myocardium leadso cardiomyopathy. Conversely, inhibition of apoptosis withaspase inhibitors improves cardiac dysfunction and reducesortality in several models of HF. Thus, at least in rodentodels, there is a causal link between apoptosis and HF.So could anti-apoptosis therapies be used to treat acuteI (ischemia-reperfusion) and chronic HF? Given long-

erm safety concerns associated with chronic apoptosisnhibition, the first realistic clinical target for apoptosisnhibition is likely to be acute ischemia-reperfusion. Later,t may be possible to assess the risk/benefit ratio of apoptosisnhibition for chronic HF. In either case, it may be possibleo combine anti-apoptosis inhibition with the cell-basedherapy discussed earlier.

linical cell therapy in the HF patient. Dr. Richardeisel (University of Toronto Faculty of Medicine, To-

onto, Canada) provided an overview of clinical develop-ents in clinical applications of regenerative medicine to

ate. The pioneering efforts of skeletal myoblast transplanta-ion has led to ventricular arrhythmias in 4 of 12 patients,equiring placement of an implantable cardioverter-efibrillator, but the cells improved regional wall motion,ven though they did not beat with the surroundingyocytes. The major clinical issues to resolve are the modes

f delivery of cells: intracoronary, endocardial, or the novelpproach of using coronary venous access to deliver cellsnto the mid-myocardium of the infarct region.

Currently, the most promising sources of stem cells orrogenitor cells are from the bone marrow or the heart.uccessful implantation improved myocardial perfusion tohe ischemic region and prevented dilation of the ventricle.he other challenges are the optimal cell types, the timingf engraftment, and how to improve the survival of theraft. The combination of the cells with gene transfer ofurvival factors may be a promising approach.

Future approaches to the cellular remodeling may includeurgical resection, such as that being tested in the Surgicalreatment for Intra-Cerebral Hemorrhage STICH trial,

ogether with a cellular patch graft into the infarct zone.he salutary mechanisms of these cellular grafts likely reside

n their ability to increase matrix metalloproteinases andecrease their inhibitors (tissue inhibitors of metalloprotein-se [TIMP]). This leads to stabilization of matrix, cellreservation, prevention of apoptosis, improvement of an-iogenesis, and ultimately improvement in cell survival.

ap for the future care of patients with HF. Dr. Harlanrumholz (Yale University, New Haven, Connecticut) ex-ressed concern about the state of the health care system for

ur HF patients, as it is currently unsafe, ineffective, (

nequitable, inefficient, and non–patient-centered. We needo rapidly evolve to a safe and patient-centered health careystem to deliver better care to our patients.

To do so, we first need to expand our knowledge base. Weeed new insights from efficacy trials to effectively preventF; we need new information on means of delivering

ffective clinical care to prevent HF. We need to havenowledge of what treatments actually improve outcomes,s well as what systems to implement to maximize benefitnd efficiency.

We also need knowledge derived from outcomes research,enerating evidence that can support clinical decision-aking, improve clinical practice, and guide health policy.ow are we doing now, and how can we do it better?urrently, there is no national surveillance database for HF.e need to have ongoing monitoring of HF outcomes,

long with associated costs, manpower, and other resourcesequired. For example, disease management can achieve a6% reduction in the relative risk of combined mortality andorbidity for the HF patient. However, it is not seen as a

riority within the medical community. Indeed, HF carenterdisciplinary teams are at the leading edge of thisoncept of care, but the health care system must appreciatehe value of this paradigm and accommodate this change inoncept.

To move health care to the next level, we also need toractice preference sensitive care, whereby a patient’s personalhoices, such as tradeoffs in quality versus quantity of life,ust be individually decided. We also need to practice

esource sensitive care, whereby the balance of societal,ommunity, and individual patient needs is carefullyeighed, and efforts toward increased standardization of

ccess and expenditure should be made.We need to realize the need to change and take actions to

hange the culture of our health care system. We mustecognize the need for change, seek ways to improve ourutcomes, and move from a paradigm of individual maverickhysician to integrated teams. We can enhance system per-ormance through a concerted effort, and this is not a sign ofeakness or a threat to the science and art of medicine. Weeed to start now.

ASIC SCIENCE SYMPOSIUM

he inaugural Basic Science Symposium on Sunday focusedrimarily on the role of regulators of gene transcription inormal and pathologic growth of the heart. Presentations byr. Eric Olson (Keynote Address; University of Texas,

outhwestern Medical Center, Dallas, Texas) and Dr.onathan Epstein (University of Pennsylvania School of

edicine, Philadelphia, Pennsylvania) helped clarify seem-ngly contradictory reports on the role of histone de-cetylases (HDACs) in regulating cardiac hypertrophy. TheDACs are enzymes that remove acetyl groups from

istones, proteins associated with deoxyribonucleic acid

DNA). De-acetylation of histones blocks gene transcrip-

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1105JACC Vol. 43, No. 6, 2004 Liu et al.March 17, 2004:1103–9 Highlights of 2003 Heart Failure Society of America

ion, and thus HDACs are negative regulators of transcrip-ion. In the heart, HDACs were initially identified asnhibitors of hypertrophy, as deletion of HDAC-5 and -9 inhe mouse led to spontaneous hypertrophy. Similarly, Joan

eller Brown’s work with a transgenic mouse expressingaMKII�B, a protein kinase that, when activated by hyper-

rophic stimuli, leads to the export of class II HDACs fromhe nucleus, thus inactivating them, also suggests a criticalole for HDACs in blocking hypertrophy, as her mouse alsoad spontaneous hypertrophy. However, pharmacologic

nhibitors of HDACs, which might have been predicted toimic the phenotype of the knockouts and to increase

ypertrophy, have recently been reported to block hypertro-hic growth in cardiomyocytes in culture. The Olson andpstein laboratories have found that these seemingly con-

radictory results may relate to the fact that HDAC-5 and9, which are class II HDACs, repress transcription ofrohypertrophic gene programs, whereas class I HDACsay repress transcription of antihypertrophic genes. This

electivity may be mediated, at least in part, by a proteinalled Hop (homeodomain only protein), which recruitslass I HDACs specifically to antihypertrophic genes regu-ated by the transcription factor called serum responseactor. In agreement with this, a transgenic mouse express-ng Hop in the heart has severe hypertrophy and fibrosis andies suddenly. Importantly, trichostatin A, an HDAC

nhibitor, blocked isoproterenol-induced hypertrophy. Be-ause HDAC inhibitors are currently in clinical trials forancer and appear to be well tolerated, this sets up theossibility of employing HDAC inhibitors as potentiallyery important antihypertrophic therapies. However, class-r isoform-specific inhibitors may be required.The study of cardiac development has largely focused on

enetic determinants. In a departure from the main themef the session, Dr. Scott Fraser (California Institute ofechnology, Pasadena, California) reviewed emerging evi-ence that intracardiac fluid forces function as an epigeneticactor to critically regulate embryonic development of theeart. Fraser and his co-workers have used remarkable inivo imaging technologies to demonstrate high levels ofhear forces and vortical flow in the developing zebrafisheart, which is approximately the size of a coarse humanair. They found that the levels of shear forces were wellbove the threshold for induction of gene expression intudies of endothelial cells in culture. By physically inter-ering with inflow or outflow of the heart at 37 h afterertilization, they were able to test the hypothesis that thesehear forces might modulate embryonic development of theeart. They found that the reduction in shear stress led to aailure of one of the chambers of the heart to develop, aailure of the heart to loop (a necessary step in cardiacevelopment), collapse and fusion of the walls of the inflownd outflow tracts, and abnormal valve development. Thesetudies demonstrate that direct interference with intracar-iac fluid forces has profound effects on valve formation,

hamber differentiation, and organ morphology. Because

pproximately 40% of congenital heart defects involve aalvular abnormality, these studies raise the possibility thathese valvular abnormalities worsen the phenotype of theirth defect via altering intracardiac fluid forces.Dr. Michael Schneider (Baylor College of Medicine,ouston, Texas) in the Sunday Morning Symposium, and

is fellow, Dr. Motoaki Sano (finalist in the Jay Cohn Newnvestigator Award Basic Science competition), presentedata implicating two novel pathways in the regulation ofardiac hypertrophy and cardiomyocyte apoptosis. One ofhese involves a cyclin-dependent kinase, Cdk9, which plays

role in activating ribonucleic acid polymerase II, anssential element in the basal machinery for transcription ofenes. They reported that kinase activity of Cdk9 (and theelated Cdk7) was increased in the hearts of patients withilated cardiomyopathy. To evaluate the significance of this,hey studied a transgenic mouse expressing the Cdk9ctivator, cyclin T1. The mouse demonstrated spontaneousypertrophy, but after imposition of a pressure load, leftentricular (LV) contractility deteriorated, and the mouseied within a few weeks. These studies suggest that thencreased activity of Cdk9 in the failing human heart maylay a role in the progression of HF and thus could serve asnovel target in the treatment of the disorder.The second pathway involves the DNA damage-sensing

rotein kinase, checkpoint 2 (Chk2), which Schneider ando-workers have found to be markedly activated in theearts of patients with advanced HF. Furthermore, thisinase is also activated by imposition of an acute pressureoad (aortic banding) in the mouse. Schneider presentedvidence that activation of Chk2 may play a significant rolen the enhanced apoptosis seen in the failing heart. This isurprising, because this pathway has been believed to pri-arily function in cycling cells, not terminally differentiated

ardiomyocytes. In addition, the findings identify this path-ay as a possible therapeutic target to block apoptosis inatients with HF.Dr. Helmut Drexler (Hannover Medical School, Han-

over, Germany) has previously reported that signalingown the JAK/STAT pathway is down-regulated in pa-ients with advanced HF. This pathway is activated byytokines, growth factors, and some vasoactive peptides,ncluding angiotensin II. Drexler presented his group’snalysis of the phenotypes resulting from cardiac-specificeletion in mice with STAT3 (signal transducer and acti-ator of transcription 3), a transcription factor that inducesene expression after cytokine stimulation. The most strik-ng phenotype of this mouse was marked impairment ofngiogenesis. In addition, the mouse had depressed systolicunction and late development of HF, which was signifi-antly accelerated by pregnancy. These findings indicate aritical role for STAT3 and the JAK/STAT pathway inardiac angiogenesis and in the maintenance of LV func-ion.

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1106 Liu et al. JACC Vol. 43, No. 6, 2004Highlights of 2003 Heart Failure Society of America March 17, 2004:1103–9

ASIC SCIENCE: GENERAL SESSIONS

egulating myocardial growth, survival, and function.r. Kenneth Walsh (Boston University School of Medi-

ine, Boston, Massachusetts) and his postdoctoral fellow,r. Ichiro Shiojima (winner of the Jay Cohn New Investi-

ator Award for Basic Science), in their study of a mouse,resented striking findings that tell us about the reversibilityf hypertrophic responses of the heart. In this mouse,xpression of the prohypertrophic/anti-apoptotic proteininase, Akt, can be suppressed by doxycycline and inducedy withdrawing the drug. Short-term induction of Akt (forwo weeks) led to a 70% increase in heart weight, which,emarkably, completely reverted to baseline within threeays of turning off Akt expression with doxycycline. Pro-

onged induction (six weeks) induced marked cardiac hy-ertrophy with severe cardiac dysfunction, and turning offkt expression at this point led to a further decline in

ontractility. These studies demonstrate remarkably rapideversibility of short-term hypertrophy (though the molec-lar mechanism is not known at this point) and also suggestn important role for Akt in maintaining contractility inypertrophic/failing hearts.Dr. John Kyriakis (Tufts University School of Medicine,

oston, Massachusetts) has identified a new mechanism byhich growth-promoting stimuli lead to entry of cells,

ncluding vascular smooth muscle cells, into the cell cycle.his involves a novel pathway in which a protein kinase,ixed lineage kinase-3 (MLK-3), is essential for both

ctivation of the mitogen-activated protein kinases andntry into the cell cycle by growth-promoting stimuli. Theseata have important implications for the treatment ofisorders that involve unrestrained growth of vascularmooth muscle cells and other cells, including restenosisfter percutaneous coronary intervention (PCI). Further-ore, they establish MLK-3 as a potential target for therapy

o block post-PCI restenosis.ovel therapeutic strategies in HF. Dr. Elizabeth Mur-

hy (Duke University School of Medicine, Durham, Northarolina) outlined potential approaches to blocking apopto-

is in ischemic syndromes and in the hearts of patients withF, using inhibitors of caspases and of molecular compo-

ents upstream of caspase activation. Dr. Min Nian (Uni-ersity of Toronto, Toronto, Canada) discussed in detailne of these putative targets, cFLIP, in her presentation forhe Jay N. Cohn New Investigator Award competition.

Dr. Douglas Mann (Baylor College of Medicine, Hous-on, Texas) reviewed recent data to help clarify the molec-lar mechanisms which may have accounted for the failuref anticytokine therapies targeting tumor necrosis factor-lpha with etanercept (RENEWAL) and infliximab (AT-ACH) to improve outcomes in chronic HF patients, asell as the mechanisms by which these therapies worsenedF in patients in the trials.olecular imaging. Dr. Mike Modo (Institute of Psychi-

try, London, United Kingdom) reviewed his group’s work A

n serial in vivo imaging of transplanted stem cells withagnetic resonance imaging. Using his work on the brain as

n example, he highlighted the importance of being able torack the migration, survival, proliferation, and differentia-ion of stem cells after their injection into diseased regions,o that these could eventually be correlated with functionalecovery (or lack thereof).

etabolic dysregulation in HF. Dr. David Carling (Im-erial College, London, United Kingdom) reviewed recentrogress in the regulation and function of a protein kinasehat is believed to be a central sensing mechanism to protectells in the setting of adenosine triphosphate (ATP) deple-ion, such as occurs with ischemia or intensive exercise. Thisinase, the adenosine monophosphate (AMP)-activatedrotein kinase, AMPK, has become of major interest to theharmaceutical industry, as it is believed that activators of itay be of benefit in the treatment of patients with meta-

olic syndrome, diabetes, and hyperlipidemia. Mutations inMPK lead to familial hypertrophic cardiomyopathy, orig-

nally identified by Dr. Hugh Watkins and co-workers,hich is also associated with pre-excitation and is charac-

erized by inappropriate deposition of glycogen in the heart.arling reviewed the functional effects of these mutations

nd presented data showing that the mutations appear toead to partial inactivation of AMPK.

In the same session, Dr. Daniel Kelly (Washingtonniversity School of Medicine, St. Louis, Missouri) pre-

ented data on novel mechanisms possibly underlying theyocardial dysfunction seen in patients with HF, implicat-

ng metabolic abnormalities downstream of the peroxisomalroliferator-activated receptor (PPAR)-alpha pathway andlipotoxicity” in the development of hypertrophy and LVysfunction. Kelly has found that PPAR-alpha activity isown-regulated in HF. To explore the significance of this,he PPAR-alpha knockout mouse was crossed with aardiac-specific transgenic mouse overexpressing acyl coen-yme A synthetase. This produced lipotoxicity that wasssociated with apoptosis, fibrosis, LV dilation, and de-ressed systolic function. This lipotoxicity could be partiallyrevented by substituting medium-chain triglycerides for

ong-chain triglycerides (the normal component of ouriet). These data raise the intriguing possibility that manip-lation of dietary fat content and of PPAR-alpha activityould potentially alter the progression of HF in patients.roteomics. There were two sessions focusing on pro-

eomics, the first of which was jointly sponsored by theational Heart, Lung, and Blood Institute (NHLBI, Na-

ional Institutes of Health, Bethesda, Maryland) and in-luded speakers from the NHLBI (Dr. John Fakunding)nd from four of the proteomics centers recently establishedy the NHLBI—Boston University School of MedicineDr. Wilson Colucci), Medical University of South Caro-ina, Charleston (Drs. Daniel Knapp and Merry Lindsey),ohns Hopkins University, Baltimore (Dr. Jennifer vanyck), and Medical College of Wisconsin, Milwaukee (Dr.

ndrew Greene), as well as a review of the technology (Dr.

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1107JACC Vol. 43, No. 6, 2004 Liu et al.March 17, 2004:1103–9 Highlights of 2003 Heart Failure Society of America

eipei Ping, UCLA School of Medicine, Los Angeles,alifornia) and a commentary on the proteomics initiative

Dr. Bruce McManus, McDonald Research Lab, Vancou-er, Canada). In the second session, Dr. Hayes McDonaldScripps Institute, La Jolla, California) and Dr. Don HuntUniversity of Virginia, Charlottesville, Virginia) reviewedechnologic advances in the field that will allow the identi-cation of proteins present at �10�15 mol/l concentrations

n complex mixtures of proteins (the so-called “shotgun”pproach) and will also allow the identification of post-ranslational modifications of these proteins (e.g., phos-horylation, oxidation). Because so much of a cell’s responseo stimuli involves post-translational modifications of pro-eins that are present at very low levels in the cell, theensitivity of these technologies should allow a much moreomprehensive understanding of the range of a cell’s re-ponses. Importantly, these approaches take an unbiasedpproach and do not rely on “candidates” (i.e., one does noteed to know what one is looking for before one can lookor it). These approaches may well revolutionize the field ofroteomics.alcium regulation and arrhythmias. This session in-

luded talks by Drs. Steven Pogwizd (University of Illinois,hicago, Illinois), Hector Valdivia (University of Wiscon-

in, Madison, Wisconsin), and Steven Houser (Templeniversity, Philadelphia, Pennsylvania), characterizing the

ellular alterations in calcium transport and ion channelshat contribute to depressed systolic function and triggeredrrhythmias seen in humans and animals with HF. Aeduced sarcoplasmic reticulum (SR) calcium content (andonsequent reduced calcium transients) seems to be a mainulprit in systolic dysfunction. This is caused by a combi-ation of reduced SR Ca-ATPase, increased Na/Ca ex-hange, and increased SR calcium leak. Up-regulation ofa/Ca exchange and depression of potassium currents also

ncrease the propensity for triggered arrhythmias. Dr. Alanarfinkel (University of California at Los Angeles) showedhole-heart re-entry data and models, indicating how thereakup of stable, spiral waves can occur, even if all cells aredentical, and that it depends on the steepness of theestitution of action potential duration versus cardiac cycleength. Finally, Dr. Rui-Ping Xiao (National Institute ofging, Bethesda, Maryland) showed that there is complex

ross-talk between how cAMP- and calcium-calmodulin–ependent protein kinases (PKA and CaMKII) modulateardiac myocyte function. This session highlighted nicelyow understanding the cellular and molecular bases forltered electrophysiologic, calcium transport, and signalingrocesses in HF may lead to novel molecular targets andherapeutic strategies to combat acute systolic dysfunctionnd arrhythmias in HF.

ene therapy. Several presentations in this session offeredope that gene therapy might one day offer novel therapeu-ic approaches to patients with HF. Recombinant adeno-ssociated viruses (rAAV) have appeared promising because

f their ability to transduce nonreplicating or slowly repli- s

ating cells, such as cardiomyocytes, and because they areot human pathogens. Dr. Jude Samulski (University oforth Carolina, Chapel Hill, North Carolina) presented

tudies documenting the different tropisms of various rAAVerotypes. By making use of these tropisms, as well asngineered, cardiac-specific promoters, Samulski showedmpressive cardiac transduction achieved through intraperi-oneal delivery of such vectors in animal models. Dr.duardo Marban (Johns Hopkins University, Baltimore,aryland) discussed genetic interventions targeted to both

radyarrhythmias and tachyarrhythmias. Proof-of-conceptxperiments were presented, documenting the ability ofectors to specifically slow atrioventricular (AV) conductionr, alternatively, to restore pacemaker function toardiomyocytes.

OCUSED SYMPOSIUM ON DIABETES AND HF

urden of diabetes and impact on HF. The global in-rease in diabetes is also affecting HF epidemiology andathophysiology. A symposium on this new topic wasntroduced by Dr. Michael Fowler (Stanford University,tanford, California). Currently, obesity is present in 20%f the U.S. population (defined as a body mass index �30g/m2), and obesity increases the odds of developing dia-etes to 3.44:1. In turn, the odds of developing HF isncreased fourfold in young diabetic males and eightfold inoung diabetic females. Conversely, the incidence of diabe-es in HF patients is 20% to 25%.

The associated elevations of serum insulin and insulinrowth factor-1 directly predict cardiovascular complica-ions. Conversely, poor HF control also aggravates theiabetic state. The utilization of angiotensin-convertingnzyme inhibitors, angiotensin receptor blockers, and beta-lockers delays the onset or decreases the incidence of newiabetes.nsulin resistance and diabetic cardiomyopathy. Dr.ale Abel (University of Utah, Salt Lake City, Utah)

iscussed insulin resistance and mitochondrial dysfunctionn diabetic cardiomyopathy. Normal insulin signaling isequired for the metabolic adaptation of the heart toressure overload, which includes increased glycolysis, glu-ose oxidation, and expression of GLUT1. Insulin signalingn the heart is impaired in diabetes, and in the context ofressure overload, these hearts develop mitochondrial andetabolic dysfunction and early HF. These observationsay explain why diabetes and hypertension are a potent

ombination leading to rapid development of HF.F and PPARs. Dr. Wilson Tang (Cleveland Clinic,leveland, Ohio) said that PPAR-gamma plays a distinct

ole in inhibiting cardiac hypertrophy and attenuates LVemodeling after experimental MI. Thiazolidinediones arePAR agonists, but have been associated with fluid reten-

ion in patients with HF. Indeed, thiazolidinedione users

how an increased risk of HF diagnosis, according to the

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1108 Liu et al. JACC Vol. 43, No. 6, 2004Highlights of 2003 Heart Failure Society of America March 17, 2004:1103–9

nternational Classification of Diseases-9th Revision (ICD-), from 5.5% to 8.1%, but this is only associated witheripheral edema and actually less pulmonary edema. Thisisk versus benefit should be carefully weighed in individualatients.ole of diabetes in acute MI. Dr. Scott Solomon (Har-

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ncluding infarct size and ventricular remodeling. Theost-MI diabetic patient also develops more fibrosis andorse compliance.anaging diabetes in the presence of HF. Dr. James

oung (Cleveland Clinic, Cleveland, Ohio) suggested thatight glycemic control in patients with HF and diabetesakes the HF easier to control. Each 1% increase in

lycosylated hemoglobin is directly associated with an 8%ncrease in HF. Even if the patient does not have frankiabetes, it is worthwhile to screen for abnormal glucoseolerance in patients with HF, as the prevalence is so high.ggressive use of angiotensin-converting enzyme inhibitors,

ngiotensin receptor blockers, or beta-blockers will facilitatehe prevention and treatment of HF.

ARDIAC RESYNCHRONIZATION THERAPY (CRT)

ow does resynchronization work? Dr. David KassJohns Hopkins University, Baltimore, Maryland) demon-trated that ventricular dyssynchrony in bundle branch blockctually worsens LV function by requiring a higher localnergy expenditure, inducing local molecular and metabolichanges in the high-stress regions of the myocardium. Thepplication of resynchronization provides immediate en-ancement of systolic function, thus reducing wall stress andnergy cost.

A recent detailed evaluation suggested that the LV pacingite has a major impact on the improvement of patients,hereas AV delay and right ventricular/LV timing couplinglay a relatively minor role in most patients. Resynchroni-ation is also associated with a reduced degree of mitralegurgitation. Resynchronization enhances the rate of LVressure rise, thus reducing the effective orifice area, leadingo better coordination of papillary muscles and improvedhronic chamber remodeling.ew insights from clinical trials. Dr. William Abraham

Ohio State University, Columbus, Ohio) reported thatRT can improve indexes of quality of life, as well as Nework Heart Association (NYHA) functional class, as seen in

he Multicenter InSync Randomized Clinical EvaluationMIRACLE), CONTAK-CD, and Multicenter InSyncandomized Clinical Evaluation-Implantable Cardioverterefibrillator (MIRACLE-ICD) trials. Consistently, CRT

mproves exercise capacity in trials where this was tested. It p

lso improves cardiac function and structure, with improve-ent in LV ejection fraction, change in mitral regurgitation

et area, and reduction in LV end-diastolic diameter.To date, the CRT trials have shown a reduction in

ospitalization for worsening HF, but not significantlyeduced mortality. Meta-analysis shows that the overalldds ratio for hospitalization was 0.49 (95% confidencenterval 0.25 to 0.93), in favor of CRT compared withonventional medical therapy. In the most recently reportedomparison of Medical Therapy, Pacing and Defibrillation

n Chronic Heart Failure (COMPANION) trial, the all-ause mortality at 12 months was reduced by 23.9% (p �.12) in the CRT group and 43.4% in the CRT withefibrillation (CRT-D) group (p � 0.002), as comparedith the conventional medical therapy group. In summary,RT reduces HF and CRT-D reduces morbidity andortality.ho is a candidate for resynchronization? Dr. John

arker (University of Toronto, Toronto, Canada) discussedhich patients with HF are the most suitable candidates forRT, in view of the high cost and ancillary resources

equired for its use. Data from clinical trials to date suggesthat patients in NYHA functional class III/IV, with LVjection fraction �35%, who are already maximized onedical therapy and remain in normal sinus rhythm, are theost ideal candidates. On the other hand, clinical experi-

nce also suggests that patients with severe symptoms withecent hospitalization, low blood pressure, dilated LV end-iastolic diameter with mitral regurgitation, high diureticequirement, and rising creatinine and dyssynchrony on thechocardiogram will likely benefit.

Potential indications that are emerging on the horizon areor patients with HF who need right ventricular pacing forraditional indications or atrial fibrillation and right bundleranch block.ow to look after resynchronization devices. Dr. Leslie

axon (University of Southern California, Los Angeles)mphasized that attention to details in terms of short- andong-term programming is essential to optimize a clinicalesponse to CRT. This includes lead positioning, rate, andime interval considerations. The pending availability ofight-sided hemodynamic monitoring facilities will greatlymprove the ease with which these devices are followed.s there still a role for the traditional pacemaker? Dr.ony Tang (University of Ottawa, Ottawa, Canada) dis-

ussed the issue of what to do with HF patients who requireacing according to traditional indications. If the HFatient needs a pacemaker because of bradycardia, and if theatient has good AV conduction, then either the VVI orDD/R mode will do. However, if AV conduction is poor,

hen the DDD/R mode will be required. If the patient hastrial fibrillation but needs only backup pacing, then theVI/R mode may be sufficient. However, if the patient iseing paced most of the time, then CRT with biventricular

acing will be much more appropriate.

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1109JACC Vol. 43, No. 6, 2004 Liu et al.March 17, 2004:1103–9 Highlights of 2003 Heart Failure Society of America

LINICAL TRIALS

here were a number of new or updated clinical trialsresented at the meeting; only two with data not presentedefore at an international forum are summarized here.he TEN-HMS trial. The purpose of the Trans-Europeanetwork-Home Management System (TEN-HMS) trial,

resented by Dr. John G. F. Cleland (University of Hull,ingston-Upon-Hull, United Kingdom) is to compare

hree different strategies for following HF patients who haveeen recently discharged from the hospital. They wereandomized to either: 1) usual care (traditional physician-ased program); 2) nurse telephone service (monthly nurseelephone call plus usual care); or 3) home telemonitoringith patient-initiated recording of blood pressure, weight,

nd electrocardiographic recording with automatic trans-ission of data via a modem to a care team twice per day.The primary outcome of the study was days lost to death

r hospitalization. The secondary end points were death,ospitalization, or changes in medications. Ultimately, 85atients were randomized to the usual care group, 173atients to the nurse-managed care group, and 168 patientso the device-monitored group. At baseline, 60% of theatients were in NYHA functional class I or II (mean age 67ears, mean LV ejection fraction 25%).

The percentage of days in which the patients were deadr hospitalized was reduced from 19.5% with usual care to5.9% for nurse-managed care and 12.7% for the combinedevice- and nurse-managed care groups. There was also anbsolute reduction of 16.4% in mortality when comparinghe intervention versus usual care groups (p � 0.05). Theean duration of hospitalization was reduced from 17.5

ays with nurse telephone support versus 11 days withelemonitoring (p � 0.05). Patients in the telemonitoringroup were more likely to have evidence-based medicationsuccessfully implemented than were patients in either of thether groups. Therefore, the investigators concluded thatncreased patient support and monitoring reduced mortality,nd when compared with usual care, the monitoring devicetrategy reduced hospital length of stay and days lost due toeath or hospitalization and was also associated with lowerosts.he RED-HOT trial. The Rapid Emergency Depart-ent Heart Failure Outpatient Trial (RED-HOT), pre-

ented by Dr. Alan Maisel (San Diego VA Healthcareystem, San Diego, California) was designed to evaluate therognostic and triage role of point-of-care brain natriureticeptide (BNP) determination in the emergency room inriaging a patient presenting with suspected HF, as com-ared with the physician’s judgment alone. The hypothesis

s that BNP determination may fare better than clinicaludgment.

In the RED-HOT study, 464 patients presenting withyspnea to the emergency department with suspected HFere enrolled. Patients with BNP �100 pg/ml, MI, or renal

ailure were excluded. The BNP level was determined onrrival and thereafter every 3 h, but the attending physiciansere blinded to the values.The patients’ average age was 63 years; 54% were males

nd �50% were African-Americans. The physician-erceived clinical status was used to categorize 76% of theatients as being in NYHA functional class III/IV, but 90%ere ultimately admitted. There was a significant discrep-

ncy in the physician’s assessment versus BNP measure-ents. For example, 11% of the patients were admitted with

ctual BNP values �200 pg/ml, yet 66% were perceived byhe physician to be very sick. In contrast, in the patientsith BNP �200 pg/ml, 76% of those were perceived to beery sick.

On follow-up, those patients who had initial BNP �200g/ml had 0% and 0% mortality at 30 and 90 days,espectively. However, those who had BNP �200 pg/mlccrued 4% and 7% mortality at 30 and 90 days, respectively.he average BNP values were 976 pg/ml in those who wereischarged versus 767 pg/ml in those who were admitted.t 30 days, those who were alive had an average BNP valuef 764 pg/ml, as compared with an initial value of �2,000g/ml in those who died.The investigators concluded that patients with initial

NP values �100 pg/ml can be discharged home, whereashose with BNP values between 100 and 400 pg/ml shoulde considered for emergency department treatment, fol-owed by discharge if clinically stable.

UMMARY

n addition to the sessions highlighted herein, the meetingncluded debates, “how to” sessions, young investigatorward competitions, late-breaking clinical trials, case dis-ussions, bench-to-bedside sessions, as well as moderatedoster and regular poster sessions. The next Annual Scien-ific Meeting of the Heart Failure Society of America will beeld September 12 to 15, 2004, in Toronto, Canadahttp://www.hfsa.org).

eprint requests and correspondence: Cheryl Yano, Executiveirector, Heart Failure Society of America, Court International

uite 240 South, 2550 University Avenue West, St. Paul,innesota 55114. E-mail: cyano@hfsa.org.