ACC 2005 ANNUAL SESSION HIGHLIGHT
Cardiac Function and Heart Failure
Daniel F. Pauly, MD, PhD, FACC*
Division of Cardiovascular Medicine, University of Florida College of Medicine, Gainesville, Florida
* Reprint requests and correspondence: Dr. Daniel F. Pauly, P.O. Box 100277, Division of Cardiovascular Medicine, Room M421, University of Florida College of Medicine, 1600 S.W. Archer Road, Gainesville, Florida 32610. (Email: paulydf{at}medicine.ufl.edu).
A total of 811 abstracts were submitted in the area of Cardiac Function and Heart Failure. These are shown by sub-topic in Figure 1. Each abstract was evaluated by 5 to 7 reviewers, 281 were selected for presentation, and 19 are highlighted in the following review. The committee members for Cardiac Function and Heart Failure included C. Noel Bairey Merz, James C. Fang, James A. Hill, Douglas L. Mann, and Christopher M. O’Connor.
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Late-breaking clinical trials
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The late-breaking clinical trials sessions were extraordinarily popular at this year’s meeting. Several of these presentations involved treatment of patients with heart failure (HF).
Myoblasts in HF.
Two reports used skeletal myoblasts for the treatment of ischemic cardiomyopathy. Myoblasts taken from patients’ own thigh muscles were cultured and expanded over four to six weeks. In one report, the myoblasts were implanted through the epicardial surface at the time of coronary bypass surgery. Results of this multicenter study were presented by Dr. Dib, and it was also in the program as a poster (1). Twenty-two patients were studied. All of them had previous myocardial infarction (MI), had ejection fractions (EFs) under 40%, and had been referred for elective coronary bypass surgery. Each patient received 3 to 30 direct injections of skeletal myoblasts (GenVec Inc., Gaithersburg, Maryland) at the time of bypass grafting. The investigators showed evidence of viability of the implanted cellular grafts both by positron emission tomography and magnetic resonance imaging. Twenty-one of the 22 patients are still alive at the three-year follow-up, and the researchers reported significant improvement in EF, from 22.9% to 34.6% in the cohort.
At that same late-breaking clinical trials session, there was a report titled "Myocardial Repair by Percutaneous Cell Transplantation of Autologous Skeletal Myoblasts," but in this case "as a Stand-alone Procedure in post-MI Chronic HF Patients." This was presented by Dr. Serruys and colleagues from the Netherlands and various European sites. The study enrolled 15 patients, who were an average of six years from a previous MI. The patients’ skeletal myoblasts were expanded using the Bioheart Inc. (Sunrise, Florida) method and delivered to the ventricular wall through the endocardial surface using a percutaneous, fluoroscopy-guided, implantation catheter. The results show 13 patients still living at one-year after the procedure. The left ventricular EF in this stand-alone procedure improved from 34.4% to 36.6%, and the wall motion score improved from 3 to 2.7, which was statistically significant. One patient had new episodes of paroxysmal ventricular tachycardia at one week and two other patients developed ventricular tachycardia at two weeks. Following the presentation, the discussant, Dr. Jay Edelberg of New York, raised the possibility that post-procedure arrhythmias might be related to something in the medium used to culture and expand the myoblasts rather than to a direct arrhythmic effect of the implanted cells themselves.
Medications in HF.
Drs. Teerlink and McMurray reported on a trial in the area of novel medications for HF. Because various animal and preclinical studies have indicated that circulating endothelin-1 is a potent vasoconstrictor and that endothelin receptor blockade is beneficial in HF (2), Drs. Teerlink, McMurray, and colleagues evaluated the endothelin receptor blocker tezosentan in acute HF. Their results were combined from two different trials, titled the VERITAS (Value of endothelin receptor inhibition with tezosentan in acute heart failure studies). These were multicenter, double-blind, placebo-controlled, parallel group designs and included a total of 1,449 patients with acute HF, dyspnea at rest, and indication for intravenous treatment. Therapy consisted of a 30-min tezosentan bolus followed by a 24- to 72-h continuous infusion. The composite end point for the study used a dyspnea score and the incidence of death or worsening HF at seven days. Interestingly, the VERITAS studies were negative. The investigators reported no benefit for the group treated with this endothelin receptor blocker, at least for the short-term composite end point that was used.
Another study that was accepted as a late-breaking clinical trial and utilized novel medical therapy was REVIVE II (randomized evaluation of intravenous levosimendan efficacy versus placebo in the short-term treatment of decompensated heart failure). This multicenter, international, double-blind, randomized, placebo-controlled trial was submitted by Dr. Packer and colleagues. Six-hundred subjects were recruited, and the report was selected for mention at the "Meeting Highlights" session. However, data analysis was apparently delayed, so the investigators withdrew it, and the results were not presented. Stay tuned to future meetings.
Device therapies for HF.
In the area of device therapies, Dr. Bourge and colleagues presented the results of the COMPASS-HF (Chronicle offers management to patients with advanced signs and symptoms of heart failure) trial. This was an evaluation of the ability of the Chronicle device (Medtronic Inc., Minneapolis, Minnesota), an implantable hemodynamic monitoring system (3), to guide the management of patients with advanced signs and symptoms of HF. This was a randomized, single-blind trial of the device, which utilizes an indwelling lead in the right heart for measuring filling pressures. The device continuously records an estimate of pulmonary arterial diastolic (ePAD) pressure as a surrogate for the pulmonary capillary wedge pressure. It also records right ventricular systolic and diastolic pressures. The COMPASS-HF study enrolled 274 patients with New York Heart Association (NYHA) functional class III to IV HF symptoms at 28 centers. The study design required patients to transmit data weekly from their devices. The patients were randomized such that the HF physician caring for them either received the data or was blocked from receiving the data. Patients were blinded to their treatment strategy, although their physicians were not. There were 134 and 140 patients, respectively, in the groups, and the efficacy end point used was the composite of hospitalization, emergency room visit, or clinic visit that required intravenous therapy. In the COMPASS-HF study, the primary end point did not reach statistical significance in the study population as a whole. However, when patients with NYHA functional class IV HF were removed from the analysis, there was a 33% reduction in the occurrence of the composite end point when therapy was guided by the Chronicle device versus when data was blocked (p = 0.035).
At the late-breaking clinical trials sessions, Dr. Feldman and colleagues presented the results of the PEECH (Prospective evaluation of EECP in heart failure) trial. This was a prospective evaluation of enhanced external counterpulsation (EECP) in patients with congestive HF. For this trial, 187 subjects were randomized to optimal medical care with or without 35 sessions of EECP. Whereas EECP may have benefit in ischemic heart disease by improving diastolic coronary artery perfusion, it also reduces afterload and may thereby provide benefit in nonischemic disease. For this reason, the PEECH trial included patients with either ischemic or nonischemic HF. At the end of the treatment period, the average exercise time was improved by 25 s in the EECP-treated group, but worsened by 10 s in the non-EECP group (p = 0.013). The Minnesota Living with Heart Failure score was better in the EECP group at one week and three months of treatment, but there was no significant difference in the quality-of-life score at six months.
There was a late-breaking trial using continuous positive airway pressure (CPAP) for the treatment of patients with co-existing HF and central sleep apnea. Dr. Bradley presented the study results, pointing out that "central sleep apnea is very common in HF and is associated with a substantially higher death rate." The study enrolled 258 HF patients from 11 centers, all of whom had central sleep apnea. The average EF in the study group was 24.5%, and patients were randomized to either nocturnal CPAP or no CPAP for the two-year study period. The results showed that patients in the CPAP group had decreases in their apnea-hypopnea indexes and decreases in circulating norepinephrine levels. They also had increases in EF from 24.8% to 27.3%. After two years of CPAP treatments, however, no significant difference was seen between the groups in terms of hospitalization rates for HF, quality-of-life results, exercise test results, or atrial natriuretic peptide levels. The investigators cautioned that the results should not be extrapolated to HF patients with obstructive sleep apnea because the study only enrolled those with central sleep apnea.
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Featured posters
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Various highly scored and very well-received abstracts were presented as featured posters.
Natriuretic peptides.
One presentation used plasma levels of brain natriuretic peptide (BNP) to guide therapy for HF. This was presented by Dr. Jourdain and colleagues from France and involved 220 patients at 21 sites (4). All patients had NYHA functional class II to IV symptoms and systolic dysfunction with left ventricular EFs <45%. Patients were randomized to either standard care or to a strategy that used plasma BNP levels to guide treatment. Patients had monthly visits for three months and then one visit every four months thereafter. The BNP levels were checked, and values >100 pg/ml triggered an increase in HF medical therapy. The median follow-up time was 15 months, and the investigators found fewer total events (hospitalizations and deaths) in the group that had BNP-guided therapy (25 events vs. 57 events; p < 0.001). Improvement in event-free survival is shown graphically in Figure 2.
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Figure 2 Curves showing that event-free survival is better in heart failure patients whose therapy is guided by plasma brain natriuretic peptide (BNP) levels. Reprinted from Jourdain et al. (4) with permission.
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Treatment with BNP was also the subject of a featured poster titled "B-Type Natriuretic Peptide Infusion Improves Systolic Dysfunction and Attenuates Ventricular Remodeling in an Experimental Model of Myocardial Infarction" presented by Dr. Xydas and his group from Columbia University and Scios Inc. (5). For this work, MI was induced by coronary artery ligation in rats. The rats were then treated with continuous infusions of saline, low-dose BNP, or high-dose BNP for seven days after MI. They were then housed for an additional seven weeks, after which time hemodynamic assessments were made. The high-dose BNP infusion was associated with myocardial protection as evidenced by better fractional shortening, better left ventricular end-diastolic pressure, and improved force development at the end of the study (Fig. 3). This suggests a direct effect of intravenous BNP to minimize the adverse ventricular remodeling that occurs in the short term following MI.
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Figure 3 Hemodynamic parameters in post-myocardial infarction (MI) animals are best when the rats are acutely treated with a seven-day continuous infusion of high-dose brain natriuretic peptide (BNP) (cross-hatched bars), as compared to infusion with saline (empty bars) or low-dose BNP (ruled bars). The hemodynamics were measured 8 weeks after the experimental MI and 7 weeks after completion of the infusion. Adapted from Xydas et al. (5) with permission.
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Stem cells.
There were several featured posters in the area of stem cells. One presented by Dr. Na and his group from Seoul, Korea, examined autologous peripheral blood stem cells as treatment for acute MI (6). These investigators used an intravenous infusion of granulocyte colony-stimulating factor (GCSF) to mobilize endogenous stem cells. The study involved 42 patients with acute MI who were undergoing primary percutaneous intervention. The patients were randomized into three groups. The first group received a four-day infusion of GCSF, and then peripheral stem cells were isolated by apheresis and administered to the patient by intracoronary infusion. The second group received only the four-day infusion of GCSF, and the third group received vehicle alone. The investigators showed functional improvement at one year in the group that was treated with intracoronary infusion of autologous peripheral blood stem cells. A significant increase occurred in EF, from 48.9% to 56.7% (p = 0.003). There was also a significant improvement in myocardial perfusion by single-photon emission computed tomography (SPECT) imaging, with an average defect of 12.7% being reduced to 7.4%. No improvement was seen in the groups treated with GCSF infusion alone or vehicle alone. This suggests that peripheral stem cell mobilization (with GCSF) and targeting of the cells to the myocardium via direct coronary artery infusion may both be necessary steps to achieve clinical benefit.
A featured poster in the area of cardiac transplantation also studied peripheral blood stem cells. Dr. Yamani and the group from Cleveland evaluated the effect of peri-transplant ischemic injury on endogenous mobilization of peripheral blood stem cells to the allografted heart (7). These researchers reported on their collection of 114 male patients, all of whom had received heart transplants from female donors. Of the 114 recipients, 26 had ischemic injury on their initial heart biopsy, and they were termed the "ischemic group." Eighty-eight did not, and they were called the "control group." At one week from cardiac transplant, Y-chromosome-containing nuclei were significantly increased in the 26-patient ischemic group at a level of 0.68%, versus Y-chromosome-containing nuclei in the control group at only 0.04%. The investigators performed follow-up studies at one year and found that Y-chromosome-containing nuclei were increased to 1.25% in the ischemic group as compared to 0.08% in the control group. These results suggest that circulating peripheral blood stem cells are being mobilized to the myocardium at a much greater rate in hearts that are insulted by ischemia. The research team also demonstrated that these mobilized stem cells persist in the heart muscle for at least one year.
Inherited cardiomyopathies.
A featured poster in the area of hypertrophic cardiomyopathy was presented by Dr. Valgimigli and colleagues from Leiden, the Netherlands (8). These investigators used conductance catheters to record pressure-volume loops at the time of percutaneous alcohol septal ablation. Eleven consecutive patients with hypertrophic obstructive cardiomyopathy were treated with alcohol septal ablation, and the hemodynamics were followed in real time. The researchers found that the alcohol septal ablation procedure acutely improved the end-systolic volume (35 ml  49 ml), acutely reduced the EF (74% 59%), acutely improved the minimum dP/dt (–1,681 mm Hg/s –1,346 mm Hg/s), reduced the end-systolic pressure (163 mm Hg 124 mm Hg), reduced the end-diastolic pressure (24 mm Hg 16 mm Hg), and improved the pressure half-time (43 ms 34 ms). These changes occurred rapidly once the alcohol was infused.
A featured poster was presented in the area of arrhythmogenic right ventricular dysplasia (or arrhythmogenic right ventricular cardiomyopathy [ARVC]). It was presented by Dr. Rampazzo and her colleagues from Padua, Italy, and Houston, Texas (9). These investigators performed mutational screening in a 4-generation, 38-member family that carried the diagnosis of ARVC. The team then extended the study to 30 other unrelated patients who carried the diagnosis. The analyses identified two different mutations in the gene for transforming growth factor ß3. In the large pedigree the defect was identified in the 5' upstream region of the gene, and in one of the 30 unrelated patients a defect in the 3' untranslated region of the gene was found. These mutations may cause aberrant regulation of the transforming growth factor ß3 gene. Aberrant regulation of this gene may be directly disease-causing, because transforming growth factor ß3 is known to be involved in the regulation of cardiac fibrosis and cell-to-cell adhesion.
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Oral sessions
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Various abstracts presented at the oral sessions received substantial interest both in their sessions and from the graders of the abstracts.
Animal models.
One oral presentation on "Experimental Models of Heart Failure" evaluated messenger ribonucleic acid (mRNA) expression and protein levels for GCSF in dogs with HF. These results were reported by Dr. Huang and colleagues from Detroit, Michigan (10). Heart failure was produced by intracoronary microembolization, and these dogs were compared against normal dogs. In the myocardium of the HF dogs, the mRNA for GCSF was increased from 24 to 37 arbitrary units, and the protein expression was increased as well (p < 0.05). The investigators postulate that the increase in GCSF production may represent an intrinsic adaptive mechanism that stimulates movement of primitive bone marrow cells to the injured myocardium.
A presentation that was made in the session on "Novel Mechanisms of Cardiomyopathy" related to doxorubicin cardiotoxicity. Panjrath et al. (11) showed that rats fed carbonyl iron, in addition to receiving intraperitoneal or intravenous doxorubicin, had much worse survival than rats receiving doxorubicin alone. The rats receiving dietary iron and doxorubicin had a death rate of 45%, whereas the death rate with doxorubicin alone was 12% and no deaths occurred with dietary iron alone. Characteristic findings of myocyte injury on electron microscopy paralleled the mortality data, and the researchers concluded that dietary iron loading increases the cardiotoxicity produced by doxorubicin, probably through a free radical injury mechanism.
Human HF studies.
In the oral session on "Revascularization and Heart Failure," there was a presentation by Dr. Buszman and his group from Poland that focused on percutaneous revascularization versus surgical revascularization in patients with depressed left ventricular EF (12). Titled "Revascularization in Ischemic Heart Failure Trial" (REHEAT), this was a prospective case-control study, with 52 patients in the percutaneous coronary intervention (PCI) group and 51 patients in the bypass surgery group. Investigators evaluated the 12-month survival and found it to be 100% in the PCI group and 94% in the bypass group, with major adverse events occurring at 21% and 11% in the two groups, respectively. The EF improved from 32% to 39% in the PCI group, with a similar improvement in the bypass group. The team concluded, relevant to the ongoing, somewhat similar trial in the U.S. called STICH (Surgical Treatment of Ischemic Heart Failure), that treating ischemic heart failure using a PCI strategy versus a bypass surgery strategy leads to similar outcomes at 12 months.
There was an oral session on "Heart Failure and the Kidney." An abstract presented in this session involved continuous recording of hemodynamic responses in dialysis patients with impaired left ventricular function. This was presented by a group from Sweden and involved nine patients with end-stage kidney disease who were on chronic intermittent hemodialysis (13). The patients had EFs of 20% to 50%, and all received implantable hemodynamic monitoring (Chronicle) devices. The investigators showed that gradual increases occurred in the right ventricular pressure and ePAD pressure as the time since hemodialysis treatment increased (Fig. 4).
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Figure 4 Gradual rise in filling pressures as assessed by implanted hemodynamic monitoring device in patients with chronic, end-stage kidney disease on hemodialysis. Values were recorded the first, second, and third nights after hemodialysis therapy. Adapted from Linde et al. (13) with permission. PA = pulmonary arterial; RV = right ventricular.
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In the oral session on "Heart Failure and Statins" there was a report titled "Statins Improve Survival in Patients With Congestive Heart Failure: A Study of U.S. Veterans." This was submitted by Jaganmohan and Khurana (14) from Shreveport, Louisiana, and was a retrospective, case-control study of over 30,000 veterans from Louisiana, Mississippi, Texas, and Arkansas who carried the diagnosis of congestive HF. The mean age of the cohort was 62.7 years, and 61% were on statins. Thirty-one percent of the patients had ischemic heart disease. A Cox proportional hazards model was used to adjust for the covariates of age, gender, smoking, ischemic heart disease, diabetes, and beta-blocker use. The researchers showed improved survival in the cohort who received statin therapy, with an adjusted hazard ratio (HR) for statin use of 0.90 (95% confidence interval [CI] of 0.88 to 0.92). The unadjusted HR favored statin use even more. Mean survival was 22.8 ± 0.2 months in the statin group and 17.2 ± 0.2 months in the non-statin group. The investigators concluded that the beneficial effect of statin therapy is independent of traditional coronary risk factors and is independent of whether the HF is ischemic in origin. This suggests a direct beneficial effect of statin therapy in HF, perhaps via an anti-inflammatory mechanism.
Exercise and cardiac rehabilitation.
In the area of exercise physiology, an oral presentation studied improvement in functional capacity and heart rate recovery after clinically indicated phase II cardiac rehabilitation (15). These investigators from Cleveland, Ohio, studied 692 consecutive patients referred for cardiac rehabilitation. Patients were classified as either having good functional capacity at entry (group 1), low functional capacity that improved to good functional capacity after completing phase II cardiac rehabilitation (group 2), or low functional capacity that remained low despite the cardiac rehabilitation program (group 3). Patients were then followed over several years, and survival curves were generated (Fig. 5). The patients who had good functional capacity at enrollment had the best survival. Those who had low functional capacity that improved with cardiac rehabilitation had intermediate survival, and those who had persistently low functional capacity despite completing the cardiac rehabilitation program had the worst survival.
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Figure 5 Survival curves for patients with good functional capacity at study entry (group 1), good functional capacity only after completing phase II cardiac rehabilitation (group 2), and poor functional capacity despite completing phase II cardiac rehabilitation (group 3). Reprinted from Pothier et al. (15) with permission.
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Summary
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The ACC 2005 Scientific Sessions showed many new and exciting developments in the area of Cardiac Function and Heart Failure. This is a credit to the many invited speakers who presented symposia and special sessions in this area, the 811 groups who submitted abstracts of their original research, the 71 reviewers who evaluated the submissions, and the 281 presenters who prepared their research for oral and poster presentations. Cardiac Function and Heart Failure continues to be one of the larger sections within the ACC Scientific Sessions. Similar to a positive feedback loop, it is the enthusiasm for this topic that drives the novel research that is presented, and the research that is presented in turn drives ongoing enthusiasm for this topic.
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References
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1. Dib N, Kereiakes D, McCarthy P, et al. Three year follow-up of the feasibility and safety of autologous myoblast transplantation for ischemic cardiomyopathy in patients undergoing coronary artery bypass grafting(abstr) J Am Coll Cardiol 2005;45(Suppl A):4A.[CrossRef]2. Cowburn PJ, Cleland JG, McDonagh TA, et al. Comparison of selective ET(A) and ET(B) receptor antagonists in patients with chronic heart failure Eur J Heart Fail 2005;7:37-42.[Abstract/Free Full Text] 3. Adamson PB, Magalski A, Braunschweig F, et al. Ongoing right ventricular hemodynamics in heart failureclinical value of measurements derived from an implantable monitoring system. J Am Coll Cardiol 2003;41:565-571.[Abstract/Free Full Text] 4. Jourdain P, Funck F, Gueffet P, et al. French Working Group on Heart Failure Benefit of BNP plasma levels for optimizing therapythe systolic heart failure treatment supported by BNP multicenter randomised trial (STARS-BNP). (abstr) J Am Coll Cardiol 2005;45(Suppl A):3A. 5. Xydas S, Klotz S, Hay I, et al. B-Type natriuretic peptide infusion improves systolic dysfunction and attenuates ventricular remodeling in an experimental model of myocardial infarction(abstr) J Am Coll Cardiol 2005;45(Suppl A):16A. 6. Na S-H, Cho H-J, Chung J-W, et al. Comparison of two methods of peripheral blood stem cell transplantation in patients with myocardial infarction: intracoronary infusion of mobilized peripheral blood stem cell vs. mobilization only (MAGIC: myocardial regeneration and angiogenesis with G-CSF mobilization and intracoronary infusion of stem cell)(abstr) J Am Coll Cardiol 2005;45(Suppl A):4A. 7. Yamani MH, Cook DJ, Yu Y, et al. Peritransplant ischemic injury triggers mobilization of stem cells top allograft following heart transplantation(abstr) J Am Coll Cardiol 2005;45(Suppl A):16A. 8. Valgimigli M, Steendijk P, Biagini E, et al. Acute changes in left ventricular function induced by percutaneous transluminal septal alcohol ablation in patients with hypertrophic cardiomyopathy assessed by pressure-volume loops(abstr) J Am Coll Cardiol 2005;45(Suppl A):10A. 9. Rampazzo A, Beffagna G, Occhi G, et al. Regulatory mutations in transforming growth factor-ß3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1(abstr) J Am Coll Cardiol 2005;45(Suppl A):10A. 10. Huang M, Rastogi S, Sharov VG, et al. mRNA gene expression and protein levels for granulocyte colony stimulating factor are increased in left ventricular myocardium of dogs with heart failure(abstr) J Am Coll Cardiol 2005;45(Suppl A):151A. 11. Panjrath GS, Patel V, Narula N, et al. Potentiation of doxorubicin cardiotoxicity by iron loading in a rodent model(abstr) J Am Coll Cardiol 2005;45(Suppl A):182A. 12. Buszman PE, Szkrobka I, Tendera Z, et al. Percutaneous versus surgical revascularization in patients with low left ventricle ejection fractionthe results of revascularization in ischemic heart failure trial (REHEAT). (abstr) J Am Coll Cardiol 2005;45(Suppl A):162A. 13. Linde C, Braunschweig F, Soderhall M, et al. Continuous recording of the hemodynamic response to dialysis in patients with impaired left ventricular function(abstr) J Am Coll Cardiol 2005;45(Suppl A):172A. 14. Jaganmohan S, Khurana V. Statins improve survival in patients with congestive heart failure: a study on 32,000 U.S. veterans(abstr) J Am Coll Cardiol 2005;45(Suppl A):183A. 15. Pothier C, Blackburn G, Lauer M. Do improvements in functional capacity and heart rate recovery after phase II cardiac rehabilitation predict better long-term survival?(abstr) J Am Coll Cardiol 2005;45(Suppl A):187A.
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Late-breaking clinical trials
Featured posters