Author + information
- Received November 8, 2006
- Accepted November 21, 2006
- Published online February 6, 2007.
- ↵⁎Reprint request and correspondence:
Dr. Stephen S. Gottlieb, Division of Cardiology, University of Maryland, 22 South Greene Street, Baltimore, Maryland 21201.
The Heart Failure Society of America (HFSA) represents the first organized effort by heart failure experts from the Americas to provide a forum for all those interested in heart failure research and patient care. The annual scientific meeting brings together cardiologists, surgeons, nurses, and allied health care professionals to discuss recent advances in heart failure, including basic, translational, and clinical research and clinical care. The HFSA also seeks to promote collaborative efforts between government, industry, and academia on policy development and research. Representatives from all 3 areas participated in the 2006 annual meeting, which had more than 3,000 attendees.
The HFSA consists of professionals involved in basic science, clinical medicine, and patient management focusing on heart failure. The 10th annual scientific session, co-chaired by Drs. Stephen Gottlieb and Douglas Mann, included a variety of formats: a plenary session, debates, how-to sessions, oral abstract sessions, late breaking clinical trials, as well as a number of simultaneous sessions on new research (basic and clinical) and patient care issues. This is a report of meeting highlights.
Opening Session—Accessibility of Quality Health Care: Only If You Can Afford It?
The Opening Plenary Session began with a President’s Address by Gary S. Francis (President, HFSA 2004 to 2006) that focused on the importance of creativity in producing improvements in our understanding and treatment of heart failure. His conclusion that creativity and persistence will be required to address the still-unresolved problems of heart failure also applies to the problems of insurance and health care delivery. The next 3 speakers focused on the problem of providing insurance to all Americans. The speakers all recognized the problems produced by our present health system, but they differed on the best solution.
Kevin Grumbach (Professor and Chair, University of California San Francisco Department of Family and Community Medicine, University of California, San Francisco, California) addressed “The Promise of Universal Health Care” from the perspective of a single-payer system. Drawing an analogy to heart failure, Dr. Grumbach characterized the health care financing system in the U.S. as suffering from poor output, swollen costs, and increased afterload. We cannot “circulate health insurance to cover the entire population,” so we have poor performance with respect to health care access and ultimately outcomes. We have issues of affordability and waste and “afterload” or resistance among many special interests to the changes necessary to create a healthier finance system. More than 46 million adults in the U.S. are without health insurance, resulting in 18,000 unnecessary deaths annually according to the Institutes of Medicine. Despite the fact that we spend twice as much on health care as other developed countries, we rank 37th of 191 countries evaluated by the World Health Organization. Grumbach believes that the only definitive treatment for treating our diseased health care financing system is to remove it and “transplant” a new healthy single-payer public health insurance system. It would be “Medicare for all.” Patients could choose any provider in this capitated care system similar to that in use already in Canada and Europe. He concluded that such a system is the simplest and most effective way to ensure comprehensive care and will not involve additional expenditures.
Robert E. Moffitt (Director, Center for Health Policy Studies, The Heritage Foundation, Washington, DC) took an opposing viewpoint in “The Private Sector is the Answer.” Dr. Moffitt suggested economic discipline rather than “surgical interventions.” When attempting any reform, one must consider both cost and quality. “You can really mess things up with the best of intentions.” He emphasized that about 84% of Americans have public or private health insurance. Most, but not all, of the uninsured are young, low-income working people who are employed in small businesses and in the service and retail industries and do not get insurance through their job. Additionally, most of the uninsured are in and out of coverage. He believes that the focus should be on expanding insurance coverage options for people working in small businesses and helping people retain coverage once they have it. His answer is to tie insurance to the person and not the job. Universal coverage can be attained by changes in the tax code that would give people a credit to buy health insurance independently. People would be required to buy at least catastrophic coverage to protect themselves and their families. Tax reform would be tied to reform of the insurance market. The rules for insurance would be uniform throughout the country. This approach would create a large national insurance pool and a diversity of options.
Len M. Nichols (Director, Health Policy Program, New America Foundation, Washington, DC) addressed the “Future of Health Care” and was optimistic. He emphasized that the focus should be on value per dollar rather than on cost alone. Health insurance is growing increasingly out of reach for a growing percentage of the workforce. However, there has been no sense of urgency to make deep changes, because key incentives remain unchanged. “You could not design a system with worse incentives.” He believes that we cannot solve the cost issue without worrying about quality and access. What is required is the “brave new world of shared responsibility.” We have to develop information support tools, solve the malpractice problem, “turbocharge” incentives to pay for services that make and keep people healthy, and determine which patients should get which technologies for which diseases. Optimistically, he sees a growing consensus that something must be done, and a convergence of ideas among Democrats and Republicans. Action may result from the predicted importance of health care in the 2008 presidential elections.
The Economic Burden of Treating the Sickest of the Sick
In a session that built on the themes of the opening plenary session, the cost of health care for heart failure patients was discussed. Harlan M. Krumholz (Yale University, New Haven, Connecticut) presented data illustrating the continuing increase in health care spending in the U.S. as a percentage of gross domestic product and the various components accounting for the increase. The U.S. stands head and shoulders above other countries in health care spending, with approximately 16% of gross domestic product. Heart disease is the number one driver of the increase in health care spending. Although we have heard for years that spending has been going up with little effect on overall spending patterns, he believes that there will be changes. Because resources are finite, physicians face cuts in Medicare payments, and out-of-pocket costs for patients will increase.
Paul A. Heidenreich (Stanford University, Stanford, California) addressed the specific costs of heart failure. Close to $35 billion is spent on heart failure in the U.S. annually, accounting for approximately 1.5% of health care spending. Two-thirds of heart failure costs are for hospitalizations, with 10% of all hospitalizations in the U.S. being for heart failure; each hospitalization costs approximately $8,000 to $10,000. Drug costs are substantial as well. Heart failure drug costs have increased 22% during just 2 years. A study of the Medicare population in 2000 to 2001 found that each heart failure patient took 7.5 medications, accounting for approximately $4,000 in terms of 2006 wholesale prices. Some interventions may reduce costs, but others can be very expensive.
Gillian Sanders (Duke University, Durham, North Carolina) spoke about the cost-effectiveness of ICD and cardiac resynchronization therapy (CRT) devices for heart failure. Generally, interventions that cost less than $50,000 per life-year are considered a good value; those between $50,000 and $100,000 in a gray zone; and more than $100,000 too expensive. Depending on the study population analyzed and the projected life expectancy, the cost per life year of ICDs in a primary prevention population ranges from $34,000 to $232,000. The cost-effectiveness is more favorable the longer the patient lives, and most analyses show that the ICD is a good use of our resources in the primary prevention population. In terms of CRT, the cost per quality life year may be better than ICDs. The cost in the CARE-HF (Cardiac Resynchronization Heart Failure Study) has been estimated to be €19,319 per year and, in the COMPANION (Comparison of Medical Therapy, Resynchronization, and Defibrillation Therapies in Heart Failure) trial, it was $19,600 per year. Dr. Sanders believes that the present challenge is to do a better job of risk stratification.
In a presentation on the cost-effectiveness of disease management programs, Gregory L. Freeman (University of Texas Health Sciences Center, San Antonio, Texas) stated that although early evidence suggests these programs improve health outcomes, they do not save money. However, there may be specific steps that will improve the likelihood of fiscal success. Targeting patients for enrollment in disease-management programs more accurately, reducing expenses, and improving patient and physician buy-in can help improve cost effectiveness. He believes that the results of early studies of disease management seemed too good to be true, and they were.
Should practice guidelines mandate the management of heart failure patients?
The utility of practice guidelines was debated by Marvin Konstam (Tufts-New England Medical Center, Boston, Massachusetts) and Jay Cohn (University of Minnesota, Minneapolis, Minnesota). Dr. Konstam argued the “pro” point of view; practice guidelines are necessary to manage the increasing number of heart failure therapies that have demonstrated efficacy in clinical trials and to ensure their proper use. When you have so much to work with, a guideline is needed to determine what constitutes standard therapy. He stated that many hospitals and physicians are not following simple measures proven to improve outcomes in heart failure, such as assessment of left ventricular function and the use of angiotensin-converting enzyme (ACE) inhibitors. The way to improve compliance and care is to follow guidelines and mandate selected measures. Without guidelines, you will not have a process for improving patient care.
Dr. Cohn agreed that guidelines are a valuable source of information, but he argued that they should not mandate care. They should contribute to individual therapy decisions, but patients vary. Guidelines do not address issues such as therapeutic goals, individual differences, comorbidities, and dose-response curves. Guidelines also do not address limitations in outcomes research that forms the basis of guidelines, such as the mechanism of benefit, the relationship between efficacy and safety, and identification of who benefits from a particular therapy. Furthermore, adverse events may counteract efficacy.
Which drug should be added after a beta-blocker and ACE inhibitor?
A 3-way debate addressed the issue of what drugs should be added to heart failure patients who are receiving beta blockers and ACE inhibitors. Anne L. Taylor (University of Minnesota, Minneapolis, Minnesota) presented the case for the combination of isosorbide dinitrate and hydralazine. She argued that the population with heart failure differs from the populations in randomized clinical trials of heart failure drugs. African Americans, the elderly, and children are under-represented, and there may be heterogeneity of responses. Because clinical trials suggest a different response to drugs among African Americans, she argued that the A-HeFT (African American Heart Failure Trial) study shows that African American patients with heart failure should receive isosorbide dinitrate and hydralazine in their treatment regimen.
Bertram Pitt (University of Michigan, Ann Arbor, Michigan) presented the case for aldosterone antagonists. Animal studies and clinical trials, including the RALES (Randomized Aldactone Evaluation Study), EPHESUS (Eplerenone Post-AMI Heart Failure Efficacy and Survival Study), and EMPHASIS-HF (Effect of Eplerenone Versus Placebo on Cardiovascular Mortality and Heart Failure Hospitalization) trials, suggest an aldosterone antagonist should be added to a beta-blocker and ACE inhibitor therapy before an angiotensin II receptor blocker (ARB). He did agree that the situation with regard to African-American patients is less certain. Thus, he believes that a large-scale randomized trial is necessary to determine when isorbide nitrate and hydralazine, aldosterone antagonists, and ARBs should be added as a treatment after beta-blockers and ACE inhibitors.
Christopher B. Granger (Duke University, Durham, North Carolina) argued strongly that ARBs have the most evidence for their use. There were a small number of events in the A-HeFT study, the trial was stopped early, and the curves were converging with short follow-up. The results of the RALES trial only showed that spironolactone is great for a small number of patients who are diagnosed with New York Heart Association (NYHA) functional class IV heart failure, who have normal levels of creatinine, and who receive careful monitoring. He stated that physicians in the real world cannot follow the potassium monitoring protocol used in RALES and, thus, hyperkalemia has been a problem. In contrast, ARBs have the best evidence from the CHARM (Candesartan in Heart Failure) trial, the largest contemporary experience across the spectrum of heart failure population with long-term follow-up.
Recent and Late Breaking Trials
Six trials were presented at the late-breaking trial session. Some of them addressed analyses that showed that subgroups of large studies might benefit from the intervention. The consensus was that, although intriguing, such subgroups need to be tested prospectively.
FIX-CHF-4 (Non-Excitatory Cardiac Contractility Modulation Device for Advanced Heart Failure)
Martin Borggrefe (University Hospital Mannheim, Mannheim, Germany) presented FIX-CHF-4, a pilot study addressing whether an implantable device providing electrical stimulation during the absolute refractory period and intended to strengthen cardiac contractility can increase exercise tolerance and improve quality of life. Cardiac contractility modulation therapy is delivered via a system consisting of an implantable pulse generator and 3 transvenous pacing leads. Because of high energy requirements, the device battery must be recharged with an external unit. The multicenter, prospective, double-blind, crossover study enrolled 126 patients in NYHA functional classes II and III with an ejection fraction <35% who had medically refractory heart failure and were not eligible for CRT. All devices were switched off at implant and subsequent visits to ensure blinding. After a 2-week run-in period, patients were randomized to 2 groups. During the first 12-week phase, the patients in group 1 had the device turned on, whereas the patients in group 2 had devices that were deactivated. In the second 12-week phase, patients were crossed over. The results showed that in the first 12-week phase exercise tolerance measured by peak Vo2increased steeply in both groups of patients, suggesting a strong placebo effect. In the second 12-week crossover phase, there was further improvement in the patients whose device was switched on and a return to baseline in those with devices that were switched off (p = 0.02). A similar pattern was seen in Minnesota Living with Heart Failure scores, with both groups showing improvement during the first phase, and a divergence favoring patients with devices switched on during the second phase (p = 0.03). No significant differences in time to death or first hospitalization were seen between the 2 groups during the first phase, but there was a trend toward fewer deaths and hospitalizations in the group with the devices switched on during the second 12-week phase. There were three deaths in the study, all during the off-phase. The most common procedure-related adverse events were bleeding (4%), infection (2%), and lead dislodgement (2%), with fewer events occurring during the on-phase than during the off-phase.
ACTIVE-W (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events-W)
Akshay S. Desai (Brigham and Women’s Hospital, Boston, Massachusetts) presented this analysis of the ACTIVE-W study. The previously reported ACTIVE-W study, which was stopped early, found an overwhelming benefit for oral anticoagulation compared with a combination of clopidogrel and aspirin. Because heart failure outcomes were adjudicated in the ACTIVE-W study, there was an opportunity to look closely at the effect of aspirin on composite heart failure outcomes in a large prospective randomized trial. The question is of interest because prior randomized trials of ACE inhibitors have suggested that aspirin may attenuate the benefits of ACE inhibitors in patients with heart failure. This post-hoc analysis of the ACTIVE-W study included 2,031 patients with a previous history of heart failure. The analysis found that these patients were much more likely to reach the composite end point of death or heart failure-related hospitalization than the general ACTIVE-W study population. However, there was no significant difference between the oral anticoagulant and the aspirin/clopidogrel groups on the primary end point, components of the primary end point, and another composite end point of heart failure-related hospitalization, stroke, myocardial infarction, or vascular death. This was true regardless of the use of ACE inhibitors. This retrospective analysis suggested that there is no important interaction between ACE inhibitors and aspirin in the study population. Dr. Desai noted many limitations. The ACE inhibitor/aspirin analysis was not prespecified, patients were not randomized to ACE inhibitors, low doses of aspirin were given, and the study population included a broad spectrum of left ventricular ejection fractions.
Effects of the adenosine A1receptor antagonist KW-3902, alone or in combination with furosemide
Drs. Barry M. Massie (University of California, San Francisco, California) and Michael M. Givertz (Brigham and Women’s Hospital, Boston, Massachusetts) updated the audience on 2 studies that evaluated the dose-dependent effects of the adenosine A1receptor antagonist KW-3902 on diuresis and renal function in patients hospitalized with acute decompensated heart failure. The CKI-201 study involved patients hospitalized with acute decompensated heart failure with renal impairment, whereas the CKI-202 study involved patients refractory to high doses of conventional diuretics.
The 146 patients participating in the CKI-201 study received 1 of 4 doses of KW-3902 in a 2-h intravenous infusion for up to 3 days. KW-3902 or the placebo was given as monotherapy for the first 6 h on the first day. Thereafter, intravenous loop diuretics could be given as indicated. The primary end point of the study was 6-h urine output on the day of discharge or day 4, whichever came first. Results presented by Dr. Massie showed that patients receiving KW-3902 had increased urine volume and required less furosemide than the placebo group.
The CKI-202 study was a small dose-escalation study exploratory study with 36 patients. Of the patients, 24 were divided into 3 escalating-dose groups and 12 received placebo. After a 3- to 5-h baseline period during which diuretics were withheld, a 2- to 3-h infusion of KW-3902 was given. Rescue furosemide was allowed. The primary end point was change in hourly urine volume, and the secondary end point was change in creatinine clearance. Results presented by Dr. Givertz showed a progressive reduction in urine output in the placebo group during the 9-h period. Patients receiving KW-3902 had a trend toward increased urine output. In regard to creatinine clearance, the placebo group had a trend toward worsening renal function. The patients receiving 30 mg of KW-3902 had improved creatinine clearance, achieving statistical significance.
Combined analysis of both studies showed that approximately one-third of the patients experienced a serious adverse event. One patient receiving a 60-mg dose experienced a seizure. Dr. Givertz noted that there is a large body of evidence confirming that adenosine modulates the seizure threshold and that adenosine A1receptor antagonists may precipitate seizure in those at risk, but probably not in those who are risk-free. Results of both studies suggest that KW-3902 has diuretic properties and that the drug may have a renal protective effect in patients receiving loop diuretics, allowing lower diuretic doses and facilitating earlier discharge. An ongoing study with a target enrollment of 1,200 patients hospitalized with acute heart failure and volume overload will further assess efficacy.
Results of a first human study of a novel calcium-independent inotrope
John R. Teerlink (University of California, San Francisco, California) presented the first clinical of study the selective myosin activator CK-1827452. The drug is a small molecule activator of cardiac myosin, which has a novel mechanism of action, and was found to increase cardiac output and contractility in dog studies through an increase in left ventricular systolic ejection time. It is hoped that CK-1827452 can increase cardiac efficiency in humans without the disadvantages of current inotropes, which increase intracellular calcium, heart rate, and oxygen demand. The primary objective of the Phase 1 study was to determine the maximum tolerated dose. The study enrolled 34 healthy male volunteers who received 6-h continuous infusions of the drug or a placebo. There were 4 study days at least 1 week apart. Ascending doses of CK-1827452 ranging from 0.005 mg/kg/h to 1.0 mg/kg/h and a randomized placebo were administered. The maximum tolerated dose was 0.5 mg/kg/h. Higher doses resulted in excessive prolongation of ejection time, which decreased diastolic filling. There were 3 premature terminations at the higher doses. There was a strong dose-dependent increase in systolic ejection time. Similarly, there was a statistically significant dose-dependent increase in fractional shortening and ejection fraction. There was no evidence of QT prolongation. There were adverse events, including postural dizziness, headache, and dizziness, but there was no increase in the frequency of adverse events up to the maximum tolerated dose. The results of this study have provided the basis for initiating additional studies in patients with heart failure.
ACCLAIM (Advanced Chronic Heart Failure Clinical Assessment of Immune Modulation Therapy)
Guillermo Torre-Amione (Methodist Hospital, Houston, Texas) updated the audience on the ACCLAIM study, a trial testing whether a novel immune modulation therapy (IMT) will reduce mortality or cardiovascular hospitalization in patients with advanced systolic heart failure. The therapy involves collecting a blood sample from the patient, delivering oxidative stress to the sample with a special system, and then injecting the autologous sample intramuscularly. The trial randomized 2,426 patients with NYHA functional class II to IV heart failure and a left ventricular ejection fraction ≤30% to receive IMT or placebo. Three treatments were administered in an induction treatment phase on days 1, 2, and 14 and then followed with maintenance treatments at 4-week intervals for a minimum of 8 treatments. There was no difference between the 2 groups regarding the primary end point of all-cause mortality or cardiovascular hospitalization or in key secondary end points. There was a significant improvement in measurements of quality of life in the IMT group. IMT was safe and well-tolerated, and the number of adverse events was balanced between the 2 groups. The results of prespecified subgroup analysis found that IMT therapy was better than placebo in patients without a previous myocardial infarction and in those with a previous myocardial infarction whose symptoms had not progressed beyond NYHA functional class II. Dr. Torre-Amione concluded that the findings provide a basis for another trial to study the patient population that seemed to benefit from IMT.
OPT-CHF (Oxypurinol Therapy for Congestive Heart Failure)
Joshua M. Hare (Johns Hopkins University School of Medicine, Baltimore, Maryland) presented the OPT-CHF study, in which the safety and efficacy of oxypurinol, a xanthine oxidase inhibitor, was studied. An abundance of preclinical studies in animal models of heart failure demonstrate that xanthine oxidase inhibition reverses remodeling and improves mechanoenergetics, endothelial function, and survival. The OPT-CHF study randomized 405 patients with NYHA functional class III or IV heart failure with a left ventricular ejection fraction ≤40% who were receiving stable and optimal therapy for heart failure. Patients received either 100 mg/day of oxypurinol for 1 week followed by 600 mg/day or placebo. Patients were followed for 24 weeks. A composite clinical end point was used in which patients were classified as improved if NYHA functional class or global assessment improved; worsened if the patient died or was hospitalized for worsening heart failure, required a new heart failure medication, or if NYHA functional class or global clinical status worsened; or unchanged. Results showed no effect of oxypurinol on the primary composite end point. However, upon analysis of secondary end points, researchers found a significant decrease in serum uric acid levels starting at approximately 4 weeks into the trial and persisting throughout the follow-up period in the oxypurinol group. A subgroup analysis found that patients with high baseline levels of serum uric acid (≥9.5 mg/dl) appeared responsive to oxypurinol whereas those with lower levels did not. The findings suggest that serum uric acid levels may be a biomarker in heart failure allowing targeted therapy.
Care of Heart Failure Patients
There were numerous sessions on various aspects of caring for heart failure patients. Some of these included discussions of sleep apnea, brain natriuretic peptides (BNPs), and implantable defibrillators.
Sleep-disordered breathing and heart failure
The session on sleep apnea was very well attended, attesting to the interest in the subject. Steven M. Scharf (University of Maryland, Baltimore) discussed who should be evaluated for sleep-disordered breathing. He asked the question whether sleep apnea should be considered in every patient with heart failure. Because sleep-disordered breathing is common and may contribute to heart failure, physicians should be concerned about the possibility of sleep abnormalities. However, studying every patient with polysomnography is expensive, and there is no conclusive evidence that treatment improves mortality and quality of life. He thus recommended that all patients have clinical screening, and those with a high risk of sleep-disordered breathing be studied using polysomnography. These would include patients with obesity, daytime somnolence, snoring, and a neck circumference >43 cm. He would also consider the use of pulse oximetry for other patients and full evaluation if frequent desaturation episodes.
David White (Harvard University, Boston, Massachusetts) and Barbara Phillips (Lexington, Kentucky) talked about the treatment of sleep apnea. They acknowledged that the effects of treatment are still unclear. They showed the minimal data on oxygen and theophylline, and more extensively discussed continuous positive airway pressure (CPAP). Although there are no firm data demonstrating the long-term efficacy in heart failure of CPAP, this is the standard treatment. The risks and side effects of CPAP were discussed, including rhinorrhea, nasal congestion or dryness, epistaxis, skin abrasions and rashes, chest discomfort, claustrophobia, aerophagy, and sinus discomfort. Compliance is certainly a major problem with CPAP. Other treatments, such as oral appliances and surgery, also were discussed. Uvulopalatopharyngoplasty has not been well studied and has approximately a 50% response rate, although there is also the possibility of relapse. A review from the Cochrane Database concluded that there is insufficient evidence to recommend the use of drug therapy in the treatment of obstructive sleep apnea. However, behavioral treatment, including weight loss, lateral decubitus sleeping position, smoking cessation, avoidance of muscle relaxants, and avoidance of sleep deprivation, should be performed.
Virend K. Somers (Rochester, Minnesota) talked about possible mechanisms linking sleep apnea to heart failure. There are reasons to suspect inflammatory effects from altered oxygen tension resulting from apenic episodes, sympathetic activation, hypertension, arrhythmias, and impaired endothelium mediated vasodilation.
The utility of BNP measurements
One session addressed the latest information about natriuretic peptides. John Burnett and Margaret Redfield (Mayo Clinic, Rochester, Minnesota) addressed the different forms of BNP and N-terminal prohormone brain natriuretic peptide (NT-proBNP). Because proBNP is cleaved into NT-proBNP and BNP, different assays may not be detecting the same molecule. Thus, determining the activity of various forms and the extent to which they circulate in the blood is important. Dr. Burnett focused on the physiology of the different natriuretic peptides. He provided evidence that, although traditional assays report high measured levels of BNP-32 in advanced heart failure, a highly specific assay shows low concentrations of the usual active form. The assay may be detecting an inactive form; the studies suggest an absence of circulating BNP-32 in patients with advanced-stage heart failure and argue for the existence of altered forms of BNP that are contributing to the usual measured values. In addition, interactions among various circulating BNP forms could affect activity. He concluded that immunoreactive BNP is markedly elevated in plasma in human congestive heart failure, but this immunoreactive BNP may have reduced amounts of BNP 1-32. Other circulating forms may include pro-BNP 1-108, NT-proBNP 1-76, and BNP 3-32. These additional forms have different levels of cyclic guanosine monophosphate activity. Dr. Redfield presented additional data showing that there might be alternate BNP forms in patients with heart failure. Abnormal proBNP processing, alternate gene splicing, processing, digestion, and formation of dimers or trimers all might affect both measurement and activity of these forms. The biological activity of altered forms remains unclear. She posed the questions whether proBNP circulates in significant amounts, whether “BNP” or “NT-proBNP” assays cross react with proBNP and whether proBNP is biologically active.
The problems of measuring
Milton Packer (University of Texas Southwestern, Dallas, Texas) and Stephen Gottlieb (University of Maryland, Baltimore, Maryland) addressed the limitations of the use of BNP and NT-proBNP assays. Both emphasized that the concentrations of natriuretic peptides are affected by many factors. Although studies show that BNP and NT-proBNP concentrations can predict the presence of heart failure, its clinical utility in difficult patients not in studies is controversial. Patients in intensive care units have elevated concentrations, unrelated to volume status. Obesity lowers concentrations of BNP and NT-proBNP, whereas renal dysfunction, pulmonary disease and age elevate the concentrations. Even the chronicity or severity of disease might impact upon the concentration. Thus, it is not surprising that the relationship between left ventricular filling pressures and natriuretic peptide concentrations is poor. Both Dr. Packer and Dr. Gottlieb emphasized that these other factors must be considered when evaluating a clinically obtained value.
Limitations of ICDs
A joint session with the Heart Rhythm Society addressed a theme that has received much public scrutiny during the past year. William G. Stevenson (Brigham and Women’s Hospital, Boston, Massachusetts) opened the session with a presentation on “Who Should Get an ICD: 2006.” This presentation focused on the use of ICDs for the primary prevention of sudden cardiac death. The use of ICDs reduces mortality across the spectrum of heart failure. However, application of the American College of Cardiology/American Heart Association/European Society of Cardiology 2006 and Centers for Medicare and Medicaid Services guidelines on ICDs in primary prevention will yield an absolute annual survival benefit between 1.5% and 7%. With this potential benefit, there are concerns about cost/benefit. This has led to efforts to develop risk stratification criteria (such as the absence of T-wave alternans) to exclude patients at low-risk of sudden cardiac death. He stated that the cost/benefit case for CRT is better. We can expect to see efforts to improve the cost/benefit ratio in the coming years through reduced cost, better patient selection, and consideration of improvements in quality of life and reduced hospitalizations.
Lynne Warner Stevenson (Brigham and Women’s Hospital, Boston, Massachusetts) then addressed patient concerns about ICD therapies. Patients overestimate both the benefit of the ICD and their own life expectancy. We need to provide patients with better information about expected outcomes with heart failure therapies. The use of ICDs for primary prevention may reduce mortality by 22%, but 78% of deaths still occur. We should let patients know approximately how many patients with their condition will be saved by an ICD during the next 5 years, how many will die anyway, and how many will not need them at all. We should also present information on inappropriate shocks and other complications and listen to patients who request that their device be turned off to allow a natural death. It is difficult to talk about death and modes of death, but critical to do so.
Mark D. Carlson (Case Western Reserve University, Cleveland, Ohio) discussed a topic much in the news—ICD reliability. We experienced a “perfect storm” in 2005, as each of the 3 major ICD manufacturers issued product advisories. There were some patient deaths, thousands of devices were explanted, and patient and physician confidence in the therapy was shaken. Explanting and replacing the devices is not trivial and the risks involved may be greater than the risk of device failure. These problems resulted in many patients who could benefit from the therapy not receiving it, a problem that continues. Currently, there are guidelines being developed regarding pacemakers and ICDs. There is no such thing as a perfect guideline, but with enhanced transparency we should have better knowledge that will enable wise decisions and restore confidence and trust in this therapy.
Bruce Wilkoff (Cleveland Clinic, Cleveland, Ohio) concluded with a talk on managing the morbidity of ICD therapy. Devices are less than the perfect. When considering their use, we need to weigh the risks and benefits of ICD therapy. Risks include infections, device problems, societal restrictions, and shocks. On the other hand, ICDs are dramatically effective in reducing the mortality of ventricular arrhythmias. All of the talks emphasized that we need to help patients make informed decisions.
The Challenges and Relevance of Global Studies
One session at the annual scientific meeting provides an opportunity for industry and academia to come together to discuss issues of concern to both groups in a balanced non-threatening forum. This year’s topic focused on the advantages and disadvantages of global clinical trials. Participants included Cesare Orlandi (Otsuka Maryland Research Institute, Rockville, Maryland), Beat Knusel (Amgen, Inc., Thousand Oaks, California), Marc Pfeffer (Brigham and Women’s Hospital, Boston, Massachusetts), Robert M. Califf (Duke University, Durham, North Carolina), and John G. F. Cleland (University of Hull, Kingston upon Hull, United Kingdom). Dr. Knusel explained that global studies were needed because the pharmaceutical industry operates in a global market and global studies facilitate product registration and adoption of the drug. There is also a need to find participants amid competition from many studies in the U.S. Global studies can demonstrate robustness of the treatment effect or identify differences in treatment effect across regions and ethnic groups. Dr. Pfeffer emphasized that global trials present the opportunity to reduce morbidity and mortality as well as reduce the economic burden and enhance international collaboration. However, global studies pose limitations in terms of logistics and trial implementation, including differing treatment standards, the infrastructure to support clinical trials, translation, regulatory timelines, and patient protection.
In addressing the question of how to design a perfect global study in heart failure, Dr. Califf said that trials should be better at answering questions of importance to patients, practitioners, and the healthcare system. Trials should advance knowledge and raise new questions, and must be designed to ensure the independence of data monitoring. Dr. Cleland pointed out the need for study populations to be representative of the target populations. If a heart failure study is conducted in Russia, the patients will be 10 years younger than patients in United Kingdom or North America, and they will have fewer comorbidities. He believes we should do trials that more closely resemble clinical practice and be wary of excessively large studies; large trials that are stopped early because of statistically robust effects may nonetheless be clinically irrelevant. Dr. Cesare Orlandi concluded by stressing the need for simplicity, given the complexities involved in global clinical trials.
Basic Science Session
A special session before the meeting addressed recent advances in basic science related to heart failure. These presentations generally showed how evidence of abnormal concentrations or activity of a substance could lead to investigation in vitro or in animals and demonstrate the impact of the involved pathway on cardiac function.
Jeffery D. Molkentin (Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio) discussed growth-differentiation factor (GDF)-15, which is up-regulated in cardiomyopathic transgenic mice. The subsequent work showed that the loss of GDF-15 severely compromises the ability of the heart to adapt to stress stimulation and that the overexpression of GDF-15 in the heart protects it from stimuli that would otherwise induce hypertrophy or failure; overexpression in cardiomyocytes reduces agonist-induced hypertrophy. Systemic delivery of GDF-15 protects the heart and attenuates failure in MLP−/− mice. He further suggested that GDF-15 may exert its protective and anti-hypertrophic effect through the SMAD2/3 pathway.
Helmut Drexler (Medizinische Hochschule, Hannover, Germany) discussed CCN1. CCN1-deficient mice are embryonic lethal as the result of severe vascular defects, including disruption of vessel integrity, reduced bifurcations, and reduced vascular endothelial growth factor expression. Interestingly, CCN1 expression is elevated in the infarcted heart. Drexler further showed in multiple ways that pressure overload, stretch, ischemia, and neurohormonal factors, such as Ang II or alpha1-adrenergic stimuli, induce myocardial expression of CCN1, a potent proangiogenic factor. In turn, CCN1 promotes proliferation of endothelial cells. Furthermore, CCN1 induces release of growth factors, chemokines and cytokines from CD34+ cells.
Victor J. Dzau (Duke University, Durham, North Carolina) talked about Akt-regulated stem cell paracrine factors. After showing that mesenchynmal stem cells (MSC) modified with Akt prevented remodeling in infracted hearts, his laboratory tried to determine why. They hypothesized that Akt-MSC mediates myocardial survival and repair by secretion of factors. They showed that Akt-conditioned media induced cardiomyocyte apoptosis. To find the possible mediators, they used microarray profiling of mesenchymal stem cells with and without Akt to identify likely candidates. They then performed in vitro and in vivo functional testing of candidate genes. Dzau and colleagues showed how they have identified Sfrp2 as a candidate prosurvival factor; prosurvival effects on cardiomyocytes of Akt-MSC conditioned medium are lost upon Sfrp2 knockdown.
John M. Kyriakis, (Tufts-New England Medical Center, Boston, Massachusetts), discussed the p8 protein. He showed that there is induction of p8 protein in the failing human heart, which is reduced with mechanical unloading. He then showed that cardiomyocyte p8 is induced by endothelin-1 and p8 is required for ET-1–stimulated cardiomyocyte hypertrophy. Subsequent work showed that tumor necrosis factor (TNF) induces primary cardiac fibroblast p8 through both transcriptional and post-translational mechanisms. p8 is up-regulated and stabilized by TNF-α in cardiac fibroblasts, and p8 is required for TNF-stimulated up-regulation of MMP-13 and -9. Furthermore, p8 is required for the induction, in primary cardiac fibroblasts, of MMP-9 and -13, and p8 binds to chromatin containing the MMP-9 and -13 promoters. As with the other work presented in this session, Dr. Kyriakis showed how identification of changes of a molecule (in this case p8) can be followed by the determination of its function by careful in vitro and in vivo work.
Michael Schneider (Baylor College of Medicine, Houston, Texas) focused on the Cdk9/PGC-1 axis as a therapeutic target. Cyclin-dependent kinase-9 (Cdk9) is related to cell cycle proteins that control proliferative growth, but its chief role, instead, is in gene expression, where it acts as one of several Cdks that phosphorylate the RNA polymerase responsible for most mRNA transcription. Cdk9 activity is elevated by multiple cardiac stress signals (workload, agonist-dependent signals via the guanosine triphosphate-binding protein Gq, and calcium-dependent signals via calcineurin) and is increased in human heart failure as well. These chronic pathobiological levels of Cdk9 activity were mimicked in transgenic mice, with the result being concentric hypertrophy, plus a marked predisposition to rapidly decompensated heart failure if stressed. The mechanism for the heart becoming sensitized was shown to be the suppression of a specific transcription factor, PGC-1, that is essential for the expression of proteins involved in mitochondrial energy production. Thus, stress-induced Cdk9 activation is coupled to a master regulator of mitochondrial metabolism in heart failure. This work supports the logic of developing Cdk9 inhibitors as potential therapy. Interestingly, recent work from Dr. Schneider’s laboratory has identified the scaffold protein menage-a-trois-1 (a partner of the functionally related kinase, Cdk7) as being associated in a physical complex with PGC-1 and being essential for PGC-1 function and metabolic gene expression in cultured cells and mouse myocardium.
From basic science to clinical care, the 10th annual meeting of the Heart Failure Society provided opportunities for people from various disciplines to look at one problem (heart failure). Ideally, bringing physicians, nurses, pharmacists, basic scientists, coordinators, and industry together can lead to better understanding of the knowledge of other disciplines. The interaction should lead to improved clinical care and enhanced research.
The authors thank Harriet Guthertz for help with the writing of the manuscript. Cheryl Yano and Bart Galle were invaluable for the development and implementation of the program of the 10th Annual Meeting of the Heart Failure Society. The authors also thank them for their help with the manuscript.
Dr. Gottlieb is a consultant to Arca Discovery, Novacardia, Otsuka, and Cytokinetics and is on the speakers’ bureau for AstraZeneca. Dr. Mann is a consultant for Acorn and Wyeth, and is on the speakers’ bureau for AstraZeneca. Dr. Francis is on advisory panels for Biosite, Novartis, NitroMed, and GlaxoSmithKline. He has received honoraria from Otsuka.
- Abbreviations and Acronyms
- angiotensin-converting enzyme
- angiotensin II receptor blocker
- brain natriuretic peptide
- cyclin-dependent kinase-9
- continuous positive airway pressure
- cardiac resynchronization therapy
- growth-differentiation factor
- Heart Failure Society of America
- implantable cardioverter-defibrillator
- immune modulation therapy
- mesenchynmal stem cells
- N-terminal prohormone brain natriuretic peptide
- New York Heart Association
- tumor necrosis factor
- Received November 8, 2006.
- Accepted November 21, 2006.
- American College of Cardiology Foundation