Author + information
- Received November 2, 2007
- Accepted November 8, 2007
- Published online January 22, 2008.
- ↵⁎Reprint requests and correspondence:
Dr. Mandeep R. Mehra, Cardiology, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, Maryland 21201.
The Heart Failure Society of America (HFSA) is a multidisciplinary organization of health care professionals dedicated to promoting research and education, with the primary goal of prevention and treatment of heart failure. Furthermore, the HFSA engages in the development of comprehensive patient care guidelines and serves as a resource for the government, health care industry, and providers to affect heart failure-related policy. Importantly, the HFSA has established a fellowship program to support young academic physicians focusing on heart failure and has supported the development of a professional certification program in advanced heart failure and transplant cardiology.
The 11th Annual Scientific Meeting, co-chaired by Drs. Mandeep R. Mehra and Howard A. Rockman, was attended by approximately 2,700 cardiologists, surgeons, nurses, pharmacists, and allied health professionals representing academia, government, and industry. The program included presentations on advances and controversies in basic, translational, and clinical research, clinical care, and public policy related to heart failure. This is a report of the meeting highlights.
Opening Session: Empowering Innovation in Research
The opening plenary session focused on the challenges facing progress in research. Gail D. Pearson, Branch Chief, Heart Development and Structural Diseases Division, National Heart, Lung, and Blood Institute (NHLBI), discussed “The National Institutes of Health (NIH) Road Map as an Optimal Heart Failure Research Catalyst.” The NIH blueprint for facilitating research over the next decade was developed by a conglomeration of 23 work groups, including one on heart failure. The plan’s overarching goal is to improve our understanding of the molecular and physiologic basis of disease, the clinical mechanisms of disease, and the process of translating research into clinical practice. Priorities in the arena of heart failure include study of the triggers and modifiers of heart failure, the effects of treatment on disease progression, and improving our understanding of the heart failure epidemic. As an example, specific NHLBI-supported heart failure studies will seek to explore the rationale for diuretic dosing in acute heart failure, the use of ultrafiltration in acute decompensated heart failure with cardiorenal syndrome, and surgical techniques for mitral valve repair in severe left ventricular failure. Dr. Pearson stressed that the NHLBI shares the goals, mission, and sense of urgency of the HFSA.
Andrew R. Marks (Columbia University, New York, New York) acknowledged the important partnership of the NHLBI with basic scientists but also critiqued the funding crisis at the NIH in his talk, “Challenges Facing the Basic Science Investigator.” Despite the importance of basic science research for the identification of mechanisms of disease and novel therapeutic targets, Dr. Marks underscored the difficulties for researchers who are “riding the NIH funding roller coaster.” He said that it was ironic to observe that because the NIH budget doubled to fund the roadmap, it has been significantly harder for individual investigators to get grants. Junior investigators and under-represented minorities, including women, have been particularly hard hit. In this environment, research needs to be virtually certain of success to be funded. Creative or risky proposals will not be funded. This policy diminishes scientific advances. To solve the funding problem, Dr. Marks proposed shelving the roadmap and streamlining the application process for NIH funding. The issue is not the roadmap, but the importance of restoring funds to individual-initiated research. Large clinical studies that require hundreds of millions of dollars should be supported in partnership with industry, he said.
Robert M. Califf (Duke University, Durham, North Carolina) addressed research challenges from the perspective of a clinical investigator. These challenges include lack of acceptance as a concrete valued discipline, shortage of capable mentoring, bureaucratic hurdles and sparse infrastructure, and inadequate funding. He asked for a renewed focus on development of clear definitions of what constitutes excellence and expertise in clinical research. He quipped that clinical researchers suffer from “a Rodney Dangerfield syndrome” and feel undervalued. Academic institutions prize basic research, whereas clinical research is relegated to the realm of a “bystander hobby.” Top academic centers often fail to grant tenure to clinical researchers, leading to a culture that does not nourish clinical research. The problem is further compounded because efforts toward clinical research remain unfunded and require subsidy via additional clinical activity. In fact, by virtue of awarding greater funding to basic science, the NIH has reinforced this situation. Thus, a strong NIH is needed—one willing to stand up to bureaucracy and industry and to facilitate effective partnerships. Public–private partnerships in which resources are pooled are critical to the success of clinical research, Dr. Califf concluded.
Recent and Late-Breaking Trials
This session highlighted results from 4 trials: 2 on implantable heart failure devices, one on use of transtelephonic monitoring in the management of heart failure patients, and one on the use of a vasopressin V2 receptor blocker in decompensated heart failure.
Results of the PROSPECT (Predictors of Response to CRT) trial
Eugene S. Chung (Ohio Heart and Vascular Center, Cincinnati, Ohio) presented the results of the PROSPECT trial, which studied the ability of echocardiography measurements to predict response to cardiac resynchronization therapy (CRT). Although CRT has been shown to reduce morbidity and mortality in well-selected patients (with systolic heart failure and a widened QRS interval on the surface electrocardiogram) who remain persistently symptomatic despite optimal medical therapy, as many as 30% demonstrate poor to no response to this therapy. Single-center studies support the use of echocardiographic measures of mechanical dyssynchrony to identify responders to CRT and to optimize therapeutic implementation. The PROSPECT trial studied 12 pre-defined echocardiography parameters of mechanical dyssynchrony in the setting of a prospective, observational, nonrandomized, multicenter trial. The primary end points, analyzed separately at 6 months were: 1) improvement in clinical composite score defined as survival without heart failure hospitalizations or heart failure-related CRT discontinuation and New York Heart Association (NYHA) functional class improvement or improved patient global assessment; or 2) reduction of left ventricular end-systolic volume of ≥15%.
The trial enrolled 426 patients with NYHA functional class III or IV heart failure, a left ventricular ejection fraction ≤35%, and QRS duration ≥130 ms who were implanted with either a CRT or a CRT-defibrillator device. Patients were followed at 1, 3, and 6 months, and echocardiography measurements were made at baseline and at the 6-month follow-up. Each participating center was trained in a protocol for echo assessments, and analysis was adjudicated by a core laboratory. Results demonstrated that 69% improved, 15% were unchanged, and 16% clinically worsened. With regard to left ventricular end-systolic volume, 56% showed a ≥15% reduction, 9% increased in size, and 15% fell in between. The rate of clinical improvement was 76% among patients with nonischemic disease and 64% in patients with ischemic heart failure (p = 0.01). Reverse remodeling was seen in 56% overall, 63% among nonischemic patients, and 50% among ischemic patients (p = 0.03). More important, however, was the finding of a lack of predictive value of individual measures of echocardiographic dyssynchrony to define these clinical responses observed. Furthermore, marked discrepancy was observed between the core laboratory adjudication and local centers in their interpretation of tissue Doppler imaging measurements and those pertaining to interventricular delay (varied by 50% and 90%, respectively). This result affirmed the contention that until better standardization and test–test reliability of echocardiography parameters of dyssynchrony can be developed, this technique is not ready for prime time use to guide decisions for CRT.
Randomized clinical trial of the clinical effects of enhanced heart failure monitoring using a computer-based telephonic monitoring system in older minorities and women
Ozlem Z. Soran (University of Pittsburgh, Pittsburgh, Pennsylvania) presented the results of this study assessing the efficacy of a home monitoring system on heart failure outcomes. Although several earlier studies have expressed ebullience for the use of home telemonitoring, they have not enrolled elderly patients, women, and minorities with reasonable penetration to draw conclusions for efficacy in these populations. This multicenter, randomized, controlled clinical trial enrolled 315 Medicare-eligible patients—more than 60% women, one-third Hispanics, and more than 40% African Americans—with heart failure secondary to systolic dysfunction. All had been hospitalized for heart failure within 6 months of randomization and had symptoms despite optimal medical treatment. The patients, who were cared for by primary care physicians in community-based clinics, were randomized 1:1 to either the Alere Day Link Heart Failure Monitoring System (Alere Medical, Inc., Reno, Nevada) or standard heart failure care. Patients in both groups received optimal medical care (over 75% were taking beta-blockers, and over 90% were taking diuretics). The monitoring system consisted of an electronic scale with a response system, programmed to ask patients heart failure questions. Patient weight data and answers to the questions were transmitted via telephone line to a remote database monitored by trained nurses. The nurses reported significant changes directly to the primary care physicians. Standard care consisted of one-on-one education, an effort to use evidenced-based optimal medical treatment, and use of a digital home scale. Patients were followed in the clinic at baseline and at 6 months as well as by telephone contact at 30 days and 3 months by nonmedical personnel blinded to treatment assignment. The primary end point was cardiovascular death or rehospitalization for heart failure within 6 months of enrollment. Among rehospitalized patients, length of stay was also considered to be a primary end point. Secondary end points included 6-month all-cause hospitalization, 6-month heart failure hospitalization, emergency room visits, change in functional status, and quality-of-life measurements.
The study showed that use of the system had no significant impact on the primary or secondary end points. The results were surprising to Sharon A. Hunt (Stanford University, Palo Alto, California) session co-chair, who said, “We really want to hear that heart failure management systems work and are accustomed to hearing that they do work.” Dr. Ozlem said that although remote monitoring might be efficacious in a different setting, the results are not universal. She also suggested that because both groups were already receiving optimal medical care and good patient education, there was little room for improved outcomes through a disease management program.
Acute hemodynamic effects of tolvaptan, a vasopressive V2-receptor blocker, in patients with symptomatic heart failure and systolic dysfunction: the ECLIPSE (Effect of Tolvaptan on Hemodynamic Parameters in Subjects with Heart Failure) international, multicenter, randomized, placebo-controlled trial
James E. Udelson (Tufts University, Boston, Massachusetts) presented the results of the ECLIPSE trial, which studied the effects of tolvaptan, a V2 vasopressin-receptor antagonist, on hemodynamics and fluid balance in patients with advanced heart failure and left ventricular dysfunction. In the previously reported EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Trial) study, tolvaptan was shown to improve the signs and symptoms of congestion (dyspnea, orthopnea, and edema) and reduce body weight without adversely affecting long-term outcomes. The ECLIPSE trial was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study of a single administration of tolvaptan. The primary objective was to compare the effects of tolvaptan and placebo on pulmonary capillary wedge pressure (PCWP). Secondary objectives were the effects of tolvaptan compared with placebo on a number of pharmocodynamic variables. A total of 181 patients with NYHA functional class III to IV heart failure, who were on a stable regimen of heart failure drug therapy and had a baseline PCWP ≥18 mm, were randomized to receive an oral dose of 15, 30, or 60 mg tolvaptan or placebo. Patients received their concomitant heart failure medications no longer than 2 h before insertion of a pulmonary artery catheter. The catheter could be inserted from 2 to 20 h before administration of the study dose. Urine output measurements were also started 2 h before drug administration. Hemodynamic assessments were made at varying points up to 12 h, and safety was assessed out to 7 days.
Results showed an early reduction in PCWP in all of the groups, but the placebo group drifted back to baseline. There was a statistically significant reduction in the PCWP in all of the tolvaptan groups, but no clear dose–response relationship. The peak change in PCWP at any time between 3 and 8 h was statistically significant but modest compared with the placebo group. Similarly, there were significant though modest reductions in the mean pulmonary artery pressure compared with placebo, again with no dose–response curve. Dr. Udelson surmised that placement of the pulmonary artery catheter itself had a vasodilator effect, resulting in the drop in PCWP in the placebo group. There were modest reductions in right atrial pressure in the tolvaptan groups. There was a dose-dependent and highly significant increase in urine output. Urine osmolality decreased significantly in the tolvaptan groups with no dose response. Tolvaptan was generally well tolerated, with adverse effects slightly higher in the higher-dose groups.
In summary, the results of the ECLIPSE study demonstrated that acute antagonism of vasopressin V2 receptors results in favorable, although often modest, hemodynamic and renal effects in heart failure patients. They also provide a mechanistic explanation for the changes in dyspnea seen in the EVEREST trial but create new questions about the long-term significance of such short-term gains, because the EVEREST trial demonstrated no difference in primary outcomes between tolvaptan- and placebo-treated groups at 24 months.
Impact of atrial pacing on quality of life in the DAVID (Dual-Chamber and VVI Implantable Defibrillator) II Trial
James R. Cook (Baystate Medical Center, Springfield, Massachusetts) presented the DAVID II study, a prospective, multicenter, noninferiority study in which the effect of atrial pacing was compared with ventricular pacing in patients with an implantable cardioverter-defibrillator (ICD) in the setting of left ventricular dysfunction but with no indication for bradycardia pacing. The primary end point was death or heart failure hospitalization; the secondary end point was quality of life. The DAVID II study was predicated on the results of the DAVID I study, which suggested dual-chamber pacing resulted in more heart failure-related hospitalizations.
A total of 600 patients with primary and secondary indications for an ICD and a left ventricular ejection fraction ≤40% were randomized to receive either atrial pacing at AAI-70 or ventricular backup pacing at VVI-40. Almost all of the patients were NYHA functional class I or II at the time of enrollment. Background medical therapy was excellent. Results of the study found that at 24-month follow-up there was very little ventricular pacing in the VVI group and approximately 50% atrial pacing in the AAI group. There was no significant difference between the 2 groups for the primary end point of death or rehospitalization for new or worsened heart failure. Similarly, there was no difference when subgroup results were considered. There were no significant differences in the quality-of-life secondary end point results. In conclusion, the DAVID II study found that atrial-based pacing (AAI-70) is not substantially worse and is likely equivalent to ventricular back-up pacing (VVI-40) in patients with an LV dysfunction and an ICD and no indication for antibradycardia pacing.
Are stem cells to repair the broken heart ready for prime time?
The use of stem cells to treat heart failure was hotly debated by Steven R. Houser (Temple University, Philadelphia, Pennsylvania) and Charles E. Murry (University of Washington, Seattle, Washington). Dr. Houser argued that current dogma that the heart has no renewal capacity is fundamentally incorrect. Experiments in his laboratory have demonstrated that bone marrow-derived stem cells can be transformed into truly functioning myocytes in a rat tissue model. Although it is not known if this would occur in human hearts, it does provide a paradigm for new myocyte formation in the heart. Dr. Houser remarked that animal and human studies involving bone marrow cell therapies are safe, and there is emerging evidence for efficacy signals. In his opinion, the question should be not whether stem cell therapy is ready for prime time, but rather what should we try next?
Dr. Murry argued that “prime time” should mean that safety has been convincingly demonstrated and that the therapy is ready for widespread clinical use. Both safety and efficacy must be demonstrated in randomized, blinded, placebo-controlled trials using hard end points. His contention was that current clinical trials have fallen short of allowing us to develop a conviction about stem cell therapy. Questions remain about the right cell type as well as the appropriate patient in whom these cells should be used. He pointed out that as yet, we do not know exactly how this therapy works. He asserted that it is a fallacy to assume that stem cells re-muscularize the heart. It is also a fallacy that stem cell therapy is safe and easy. Complications include ventricular arrhythmias with skeletal muscle grafts, calcification with bone marrow stem cells, and microemboli with intracoronary administration of stem cells. Phase I clinical trials of stem cells have not been sufficiently powered to demonstrate efficacy. Randomized controlled clinical trials have yet to demonstrate a robust proof of concept, Dr. Murry concluded.
Should “functional” mitral regurgitation in severe heart failure be repaired?
James S. Gammie (University of Maryland, Baltimore, Maryland) presented the case in favor of surgical repair of secondary mitral regurgitation (MR). Mitral regurgitation (i.e., geometric MR occurring as a consequence of ventricular remodeling, not degenerative MR) is common in patients with heart failure and is associated with a poor prognosis. Mitral regurgitation begets more MR which in turn worsens ventricular function. The cycle can be interrupted with an annular ring in a procedure that takes about 1.5 to 2 h to perform and can be accomplished with low morbidity and mortality in experienced hands. Use of a rigid ring and undersizing has also been shown to provide a durable repair in more recent studies. These studies provide convincing evidence that mitral valve repair is safe, effective, and durable and improves patient symptoms. However, we do not know if the procedure increases survival, Dr. Gammie concluded.
Michael A. Acker (University of Pennsylvania, Philadelphia, Pennsylvania) opened his opposing arguments by stating that amelioration of MR in heart failure was a seductive hypothesis because of the negative prognostic implications associated with its presence. However, beneficial outcomes have not been clearly documented. We do not know if the ventricle is continuing to dilate, causing new MR, or if the reverse is true and recurrent MR is causing additional ventricular remodeling. We need objective data on symptom improvement, reverse remodeling, and recurrence. The surgical literature on MR repair is limited and predominantly anecdotal. Studies are generally small, there is no control group, they are not randomized, and they have short follow-up. In studies where MR has been corrected, the coronary vessels have also been concomitantly revascularized, and therefore we cannot claim that improvements were due to mitral valve repair alone. Recurrence is a problem with ring repairs, and the benefits on survival remain uncertain. Mitral valve replacement, rather than repair, may eliminate recurrence. The current state of affairs argues for the development of well-constructed randomized trials designed to answer these questions.
Progress in the HFSA Practice Guidelines
The HFSA published its “Comprehensive Heart Failure Practice Guidelines” in 2006 and is committed to updating the document annually. The guidelines session detailed aspects of the evaluation and revision process, including efforts to improve the usability and accessibility of the guidelines. It also introduced the new initiatives of the guidelines process, focusing on the development of guidelines for the genetic evaluation of inheritable cardiomyopathy and for chemotherapy-related cardiotoxicity.
The HFSA Guidelines Committee Chair, JoAnn Lindenfeld (University of Colorado, Denver, Colorado), began by addressing the question, “Have We Met the Guidelines for Guidelines?” The HFSA has initiated the revision and update process by systematically reviewing the recent literature related to each of the 16 sections of the 2006 guidelines. This literature forms the basis for reviewing sections in a timely manner using an evidence-based approach. In addition, the HFSA is using a policy to avoid conflicts, not just declare them. Access has been provided through an easily navigated website and a Pocket Guide (1). The HFSA hopes to include primary care and greater patient access to the guidelines as we move forward, especially by using the Internet portal capability.
Alan B. Miller (University of Florida, Jacksonville, Florida) reported on updates and additions to the 2006 guidelines. Subjects currently under discussion for changes include: heart failure prevention, endocarditis prophylaxis, prophylactic ICD placement, cautions about the use of echocardiographic measures of dyssynchrony in heart failure device therapy, the role of ultrafiltration in fluid removal, and additional discharge criteria.
Ray E. Hershberger (University of Miami, Miami, Florida) reported on the current initiatives of a practice guideline for the genetic evaluation of inheritable cardiomyopathy. This complex area will be made “user friendly” by describing clinical phenotypes that require consideration for genetic testing (such as a cardiomyopathy with skeletal muscle weakness or a unique echocardiography pattern such as left ventricular noncompaction). The single most important recommendation may be to undertake a careful family history for 3 or more generations for all patients with an “idiopathic” cardiomyopathy. Topics still under active discussion include the frequency and components of genetic screening and the therapeutic decision following such discovery.
Daniel J. Lenihan (MD Anderson, Houston, Texas) presented the development of guidelines on cardiac toxicity related to anticancer therapy. This issue is likely to become increasingly important, because cancer is no longer the death sentence that it once was. He highlighted proposed guidelines for therapy before, during, and after anticancer therapy, with a focus on recommendations that may be controversial or less familiar to practitioners. Guidelines under active development include: recommendations for the detection of cardiac toxicity during cancer chemotherapy by screening for left ventricular dysfunction with echocardiography or multiple gaited acquisition scan; blood pressure monitoring (because new anticancer agents cause hypertension); evaluation of biomarkers such as troponin and B-type natriuretic protein (to detect subtle cardiac injury and stress); and the use of an angiotensin-converting enzyme inhibitor or beta-blocker for the prevention of cardiac toxicity before chemotherapy. Close collaboration between cardiology and oncology is recommended to avoid the unnecessary discontinuation of anticancer therapy.
“Common” Rare Causes of Heart Failure
With the increased survival of cancer patients, the role of radiation and chemotherapy in the development of heart failure has become increasingly important. Similarly, because children with congenital heart disease have now reached adulthood, the role of pediatric “cures” as a cause of heart failure has been recognized. The treatment and management of these populations were among the topics discussed in a session on rare causes of heart failure. Barry L. Karon (Mayo Clinic, Rochester, Minnesota) discussed that irradiation is injurious to the cardiac structure and is particularly an issue in the treatment of lymphomas and breast, lung, and esophageal cancer, although the effect varies by type of cancer. A review of meta-analyses, randomized controlled trials, and registry data of breast cancer survivors treated with pre-modern techniques showed an increase in cardiovascular death, all-cause mortality, or fatal myocardial infarction. The data on cardiovascular morbidity and mortality in breast cancer survivors irradiated with modern techniques are mixed: some studies show an effect, whereas others show none. The case for the injurious effect is more conclusive with lymphoma survivors. Lymphoma patients are younger when treated and receive more radiation exposure to the heart. Overall, conclusions about the significance of radiation-induced cardiac disease are confounded by factors such as the location of the tumor in relation to the heart, whether chemotherapy is involved, the amount of cardiac tissue in the radiation field and cardiac protective maneuvers. However, Dr. Karon concluded that radiation affects all cardiac structures, there is a long latency period, the risk is increased by cardiotoxic chemotherapy and the presence of conventional risk factors, and there are increased risks associated with performing cardiac surgery on these patients.
In his talk on adults with congenital heart disease and heart failure, John T. Berger (Children’s National Medical Center, Washington, DC) said the prevalence of congenital heart disease patients is increasing as more patients are diagnosed and corrective surgeries enable these patients to live into adulthood. Studies suggest that approximately one-fourth of patients go on to develop heart failure late after congenital heart surgery. Dr. Berger focused on single ventricle abnormality and the impact of various surgical correction strategies on the later development of heart failure. Current thinking is that heart failure can be prevented or minimized with different surgical methods. However, we still have questions about such issues as the role of medications in preventing abnormal remodeling in this situation, the role of anticoagulants, and the specifics of particular corrective procedures. He advocated the continued collaboration between pediatric and adult specialists as the best way to determine the consequences of current treatment strategies.
Jean-Bernard Durand (University of Texas, Houston, Texas) spoke on drug-induced heart disease, a topic of much recent interest and discussion. The leading cause of death of cancer survivors is secondary cancer, but cardiovascular complications are close behind. More than 20 new drugs for cancer have been approved in the past 5 years, but the cardiovascular toxicities of chemotherapy drugs are not captured, evaluated, or addressed in oncology clinical trials. Furthermore, cardiovascular toxicities may be more frequent as a result of expanded indications of approved cancer drugs. Dr. Durand said that all patients with exposure to cardiotoxic agents should be considered “at risk” for heart failure. To maximize the potential of new cancer therapies, he advocated that cardiologists be included in oncology trial design and that potential cardiotoxicity be identified and addressed from the start.
John B. O’Connell (Northwestern University, Chicago, Illinois) spoke on viral inflammatory disease with a focus on myocarditis. Viral myocarditis should be suspected in newly onset heart failure in a patient without other known comorbidities, particularly if the patient is young and has had antecedent flu-like symptoms. Confirming a diagnosis of myocarditis, however, can be problematic. Biopsy is the gold standard for diagnosis, but routine biopsies for unexplained heart failure are not justified. Magnetic resonance imaging (MRI) may be the best imaging modality, because a normal MRI may reliably exclude myocarditis. He stressed that when considering treatment one must remember that there is a high incidence of spontaneous recovery, even when the patient is in dire hemodynamic condition. Antiviral agents are currently being examined in clinical trials. All other options, including mechanical circulatory support, should be used before transplant.
Gender, Hormones, and Heart Failure
A session featuring basic science and clinical presentations examined the effect of gender differences on heart failure.
Richard D. Patten (Tufts University, Boston, Massachusetts) discussed estrogen-receptor signaling in the heart in remodeling. The survival advantage of women in clinical and experimental studies supports the hypothesis that sex hormones may favorably influence cardiac structure and function. Data from animal studies support the conclusion that estrogen replacement affects cardiac remodeling, but the response depends on the nature of the hypertrophic stimulus. In response to myocardial injury, estrogen replacement has the potential for benefit by decreasing infarct size and inhibiting cardiomyocyte apoptosis, but also the potential for harm by worsening left ventricular remodeling and increasing mortality. In response to pressure overload, estrogen limits left ventricular hypertrophy by inhibiting cardiomyocyte elongation.
Leslie A. Leinwand (University of Colorado, Boulder, Colorado) discussed the impact of phytoestrogens on cardiomyopathy. There is increasing interest in soy dietary products, which have phytoestrogens and isoflavones, and male mice fed the traditional soy diet tend to have a worse cardiac phenotype with reference to myocardial infarction, hypertrophic cardiomyopathy, and hypertension compared with those fed a casein diet. In a mouse model destined to develop hypertrophic cardiomyopathy, male mice fed a casein diet with added phytoestrogens had reduced contractile function. The phytoestrogens also activated hypertrophic markers and caused fibrosis in males. Diet did not matter as much in females. Leinwand hypothesized that phytoestrogens impact males disproportionately because males do not normally have endogenous estrogens. Therefore, phytoestrogens do not have to compete with estrogens to activate genes. Thus, it may be prudent to urge caution with the use of soy-rich diets in men with a hypertrophic cardiomyopathy.
Frederick A. Masoudi (University of Colorado, Denver, Colorado) presented on gender-based differences in the presentation, care, and outcomes of heart failure. Women with heart failure predominately have preserved left ventricular systolic function (LVSF). Heart failure with preserved LVSF is not a benign condition and is associated with increased readmission and mortality and poor functional outcomes. The lack of inclusion of women in heart failure clinical trials has led to a critical gap in the evidence base about the care and treatment of women with heart failure. The gap is worse in evidence for the treatment of heart failure with preserved LVSF. Although women with heart failure tend to have better survival than men, better does not mean good, said Dr. Masoudi, who emphasized that there is a critical need to address the evidence gap concerning women with heart failure.
Jalal K. Ghali (Wayne State University, Detroit, Michigan) concluded the session with a presentation on the differences in the response to heart failure therapies between men and women. He reviewed the clinical literature regarding response of women to heart failure medical therapy, including angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and beta-blockers, concluding that guidelines recommending the similar treatment of men and women are appropriate. He concluded with the recommendation that consideration should be given to conduct clinical trials of heart failure drugs exclusively in women or to take measures to ensure a larger representation.
Evaluating Drugs and Devices for Acute Decompensated Heart Failure (ADHF)
At each annual scientific meeting, representatives of industry, government, and academia hold a joint session to discuss an issue of global concern in a balanced forum. The topic at this year’s meeting concerned end points in trials of drugs and devices for ADHF. Participants included Uri Elkayam (University of Southern California, Los Angeles, California), Mark D. Carlson (St. Jude Medical, Sylmar, California), Jay N. Cohn (University of Minnesota, Minneapolis, Minnesota), Clyde W. Yancy (Baylor University, Dallas, Texas), Robert M. Califf (Duke University, Durham, North Carolina), James B. Young (Cleveland Clinic, Cleveland, Ohio), Bram D. Zuckerman (U.S. Food and Drug Administration [FDA], Rockville, Maryland), and Abraham M. Karkowsky (FDA, Silver Spring, Maryland).
Dr. Elkayam explained that management of ADHF often involves a prolonged hospital stay. Treatment of volume overload is ineffective, and many patients are still symptomatic at discharge, with the result that readmissions and mortality continue to be high after discharge. Three recent studies of therapies for ADHF, including 2 drugs and one device, all used different criteria to define efficacy. The challenge is how to assess the effect of new treatment on symptoms in patients with ADHF and how to design a study to assess the effect on length of hospital stay. He posed the question of whether a therapy for ADHF need also improve long-term survival.
Dr. Cohn addressed questions about the measurement of symptoms in clinical trials. He noted that patients presenting with ADHF present with a number of hemodynamic abnormalities as well as associated signs and symptoms. Symptoms are very difficult to objectively quantify and have been misused during in-hospital assessment as a guide to long-term efficacy and as a substitute for quality of life. However, he noted that symptoms and hemodynamics are correlated and suggested monitoring hemodynamic changes in ADHF as well as their effect on long-term outcomes.
Dr. Yancy argued that the use of hospital length of stay as an outcome measure for treatment of ADHF was not a good metric. Up to one-fifth of the variation in hospital length of stay is due to nonmodifiable components, such as variation in the baseline characteristics of patients and variables in hospital processes and procedures. Policies on hospital length of stay vary substantially between the U.S. and Europe. The presence or absence of cardiogenic shock can also have a big impact on length-of-stay measurements. He suggested freedom from rehospitalization as a more clinically meaningful target, although a large sample size may be required for assessment.
Drs. Califf and Young presented opposing viewpoints on the question of whether therapy for ADHF should also improve long-term survival. Dr. Califf stated that the treatments for other diseases, including acute coronary syndromes, must demonstrate improvement in long-term prognosis and, therefore, so should treatment for ADHF. Dr. Young argued that the ADHF patient who presents at the hospital with chronic congestion or acute pulmonary edema is asking for immediate help to feel better and not whether they will be alive in 5 years. Preventing death is not unimportant, but we have to look at whether we have reduced pain and suffering and improved quality of life.
Dr. Zuckerman discussed the challenges for the FDA in determining an acceptable trial design for heart failure devices. A randomized controlled trial is the gold standard, but in some cases a nonrandomized trial may be appropriate. He said there is substantial flexibility in trial design. However, he also underscored the need for prospective data. The FDA receives a lot of retrospective data and does not know how to deal with it. Data from trials conducted outside of the U.S. should be collected using the same protocol used in the U.S. trial.
Dr. Karkowsky concluded the session with a discussion of issues involved in designing clinical studies of drugs for ADHF. To show a mortality benefit, generally on top of standard care, to fulfill approval criteria, a large sample size is needed, owing to low in-hospital mortality. Symptom-based outcomes pose difficulties, partly because standard care is so good that it is difficult to show that the drug being studied provides superior benefit. Citing the example of nesiritide, Dr. Karkowsky said the dose response for significant dose-related adverse events should be known for all such therapies for ADHF.
So Why, and If Not, Why Not?
Four controversies regarding the management of heart failure were addressed in a session that touched on blood pressure-lowering limits, anticoagulation, coronary angiography, and anemia treatment. Jonathan G. Howlett (Dalhousie University, Halifax, Canada) discussed whether blood pressure should be lowered as far as tolerated in patients with heart failure. There are a lot of reasons why lowering blood pressure makes sense. However, lowering blood pressure too far may cause symptoms or syncope and cause hypotension with resulting reduction in coronary blood flow and increased mortality. The clinical rationale for lower blood pressure differs for systolic and diastolic heart failure, and the scientific literature suggests differing targets. Dr. Howlett recommended, for patients with systolic heart failure, lowering systolic blood pressure to <120 mm Hg and adding spironolactone, an angiotensin-receptor blocker, or hydralazine nitrate for patients who are above the target while on standard therapy. He added that managing blood pressure in patients with diastolic heart failure was more difficult, because they are similar to high-risk vascular patients. In either case, there must be careful surveillance for side effects.
Ronald S. Freudenberger (Lehigh Valley Hospital, Allentown, Pennsylvania) examined the routine use of anticoagulation in heart failure. We do not know enough about thromboembolism in heart failure to recommend the routine use of anticoagulation, because the true risk of thromboembolism in the absence of atrial fibrillation is unknown. However, there is evidence that heart failure is likely a prothrombotic state. Results of the ATLAS (Assessment of Treatment with Lisinopril and Survival) trial have demonstrated that coronary thrombosis is a frequent mechanism of death, thus providing a strong rationale for the use of antithrombotic drugs in patients with heart failure. The question of what to do in clinical practice is difficult, given the lack of evidence. A number of trials have studied the use of antithrombotic treatments in heart failure but were not powered to provide definitive results. Dr. Freudenberger concluded that the ongoing WARCEF (Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction) trial is our last hope.
Mihai Gheorghiade (Northwestern University, Chicago, Illinois) addressed recommendations regarding the use of coronary angiography. In North America and Europe, heart failure is often a manifestation of coronary artery disease (CAD). Therapies to prevent the progression of CAD can also affect outcomes in patients with heart failure. Unfortunately, the importance of CAD as a continuing contributor to the progression of heart failure has been ignored. Instead, the focus has been on left ventricular remodeling and dysfunction. Coronary artery disease is a major contributor to the prognosis of heart failure patients with diastolic dysfunction and to sudden cardiac death in patients with heart failure. Certain heart failure therapies may result in further damage in patients with CAD. Cardiac catheterization is not only important in prognostication but is also related to the implementation of life-saving therapies in patients with CAD and heart failure. Therefore, Dr. Gheorghiade advocated the routine use of coronary angiography in patients with heart failure.
Stefan Anker (Center for Cardiovascular Research, Berlin, Germany) concluded the session with a discussion of a controversial issue, the treatment of anemia in heart failure. He framed the talk by first explaining that what is considered to be anemia in heart failure does not follow the classical definition of the term. A hemoglobin level of ≤12 g/dl is considered to be anemia in large ongoing heart failure studies, whereas anemia has traditionally been defined at a lower hemoglobin cutoff point. Treatment of anemia in heart failure patients may be beneficial in improving quality of life, functional capacity, or symptoms and may reduce morbidity or mortality. Therapeutic options include blood transfusions, iron, and erythropoietic agents alone or in combination with intravenous iron therapy. Although approximately 10% to 15% of heart failure patients have anemia, Dr. Anker cautioned against treating these patients with the therapies that he discussed until safety and efficacy is shown in randomized, controlled clinical trials, which to this date have remained evasive.
Excellence in Basic Science
A highlight of the scientific meeting was the Special Sunday Scientific Session centered on the theme “Excellence in Basic Science.” This session began with a Distinguished Lecture in Basic Science by Robert J. Lefkowitz (James B. Duke Professor of Medicine, Duke University, Durham, North Carolina) entitled “A Brief History of Seven Transmembrane Receptors: New Approaches to Drug Therapy.” In his lecture, Dr. Lefkowitz chronicled the major discoveries in his laboratory that have led to our current understanding of how G protein-coupled receptors are activated, turn off, and initiate cellular signaling. In recognition of the tremendous contribution to advancing our understanding of the fundamental mechanisms in heart failure, Dr. Lefkowitz was presented with the first annual HFSA Award in Basic Science for his passion, achievement, and integrity in discovery science while in the pursuit of the fundamental mechanisms that underlie heart disease.
Dr. Lefkowitz’s lecture was followed by 4 outstanding presentations by scientific leaders in other areas of basic science related to heart failure: Dr. Andrew R. Marks (Columbia University, New York, New York) discussed the role of ryanodine receptor function and its importance in the development of heart failure and the potential therapeutic implications. Dr. Christine E. Seidman (Harvard Medical School, Boston, Massachusetts) presented data on novel inherited diseases of the heart and their progression to heart failure. Dr. Jonathan Epstein (University of Pennsylvania, Philadelphia, Pennsylvania) presented a marvelous overview of our current understanding of the molecular mechanisms of congenital heart disease, and the final presentation in the session was delivered by Dr. Jonathan S. Stamler (Duke University, Durham, North Carolina), who presented exciting data from his laboratory showing the novel and diverse function for S-nitrosylation in the heart. Overall, the session was a tremendous success and set the tone for the entire meeting.
From basic science to clinical care, the 11th Annual Scientific Meeting of the HFSA brought together health care experts from various disciplines to examine one syndrome: heart failure. This interaction, designed to promulgate rapid translation of bench research to the bedside, should serve to prevent the development of heart failure and improve outcomes for those suffering from this clinical syndrome.
The authors thank Harriet Guthertz for help with the composition of the manuscript and Cheryl Yano and Bart Galle for their assistance with editing of the paper as well for organization of the 11th Annual Scientific Meeting of the HFSA.
↵1 Dr. Mehra has received research grants from the National Institutes of Health, Industrial Partnerships Agency, State of Maryland Other Tobacco Related Diseases Fund, and Orqis. He has served as a consultant to Orqis, Roche, Astellas, Celladon, Geron, Debio Pharma, Solvay, GlaxoSmithKline, Novartis, Medtronic, Scios, Boston Scientific, and St. Jude Medical.
↵2 Dr. Greenberg has served as a consultant to AstraZeneca, Celladon, GlaxoSmithKline, NitroMed, Otsuka and has received honoraria from AstraZeneca, GlaxoSmithKline, Medtronic, Merck, NitroMed, Novartis, and Scios.
- Received November 2, 2007.
- Accepted November 8, 2007.
- American College of Cardiology Foundation
- Opening Session: Empowering Innovation in Research
- Recent and Late-Breaking Trials
- Progress in the HFSA Practice Guidelines
- “Common” Rare Causes of Heart Failure
- Gender, Hormones, and Heart Failure
- Evaluating Drugs and Devices for Acute Decompensated Heart Failure (ADHF)
- So Why, and If Not, Why Not?
- Excellence in Basic Science