CD&D National Editor

TORONTO – The Heart Failure Society of America (HFSA; Minneapolis) gathered here in September to consider the growing number of tools in its warehouse of weaponry against a disease that is progressive and progressively debilitating. These tools include a first-line range of pharmaceuticals for early-stage heart failure, followed by – as the patient retreats from compromised activity and quality of life to being severely compromised, unable to perform even the simplest activities – a combination of drugs and device therapies. Adding to this effort is the increasing emphasis on the development of early diagnostics to identify those at risk for heart disease and the frequent deaths that may be largely asymptomatic.

In the face of this weapon-packed armamentarium, heart failure is an increasing threat to individual health, to the families of those suffering from the disease, and to whole societies attempting to rein in healthcare costs. The HFSA reports 5 million Americans with heart failure, saying it is the only major cardiovascular disorder increasing in frequency. It says that 400,000 to 700,000 new cases of heart failure are diagnosed each year, with about 250,000 deaths annually, more than doubling the number of deaths reported in 1979.

The growth of this disease is seen not only in America and other developed countries, but also in rapidly developing and under-developed countries around the world.

Moving to the city

A key fact in this fight is that the opposing sides are obviously uneven, because of broad cultural trends worldwide, according to Salim Yusuf, MD, who argued at the HFASA meeting that these trends are overwhelming human biology.

Yusuf, director of the division of cardiology and director of the Population Health Research Institute at McMaster University (Hamilton, Ontario), was the keynote speaker at a session titled "Aerobiology, the Environment and Cardiovascular Health." That opened the HFSA gathering at the sprawling Metro Toronto Convention Center – though might have been better and more simply titled "The Environment and Cardiovascular Health," since that was the primary emphasis.

The environment that Yusuf identified as detrimental to cardiovascular health is urban sprawl, with more and more of the planet's citizens moving to cities, doing less physical labor, getting less exercise, and adding pounds that destroy the efficiency of the cardiovascular pump and its plumbing.

As background, Yusuf noted the development of two contradictory healthcare trends: on the one hand, medical science's victories against infectious diseases that used to take the most lives; on the other, increasing urbanization –from one-third of the world's populations living in cities in 1970 to an expected 60% in 2025, he said.

Yusuf emphasized that these urbanizing factors aren't taking place only in the most developed "rich countries," or mostly among white people. From 80% to 90% of this burden "is in lower- and middle-income countries," he said, so that targeting cardiovascular disease among "a minority of rich people will not solve the problem. We need a global perspective rather than a North American perspective." Focusing on "less than 2 billion white Caucasians … is not the basis for action," Yusuf said.

The core issue is not "ethnicity," but rather "where you live and how you live –as people in India and China start to live like people in Europe and America, they will start to die like people in Europe and America."

Building further on Yusuf's analysis, Richard Jackson, MD, of the School of Public Health at the University of California (Berkeley), described the typical pre-heart failure patient produced by the urban environment and seen by the cardiologist: a middle-aged man working at a sedentary job, complaining of being tired all the time. Though advised to exercise, he can't find the time or opportunity, and he looks and feels depressed, his inaction leading to further complications.

"The environment," Jackson said, "is rigged against your patient and against you," he told the clinician attendees. And he argued that one of the major weapons against heart failure is urban planning, encouraging one of the more interesting (and, realistically, less workable) recommendations made at the conference: that a medical person be part of the planning team to encourage the development of walking paths and park systems.

Air pollution a big unknown

While "aerobiology" got the first word in the title of the initial presentation and may have produced large attendee expectations concerning revelations about the impact of air pollution on heart disease, none were forthcoming. Joel Kaufman, MD, professor of medicine and director of the Occupational and Environmental Medicine Program at the University of Washington (Seattle), noted that while air pollution obviously impacts breathing, but said its role in heart disease is not well understood.

He described a variety of dangerous pollutants but said a key issue remains: how to link these to impact on the heart and that it is too early to make specific recommendations concerning pollution and heart health improvement. Most of the research in this area is looking at "particulate matter [PM], commonly referred to as soot," he said, and the possibility that this is related to "premature" death. "Very fine soot particles may be causing cardiovascular disease," and "a lot of work is going on trying to understand this."

Kaufman said some studies indicate that people living close to major highways have higher risk for left ventricular myocardial infarction. And after adjustments for factors such as blood pressure, the use of medications and other factors, it is clear, he said, that "something is going on."

Micro-particles may result in inflammation, oxidative stress and basil construction, Kaufman said, but the way in which these small particles move from the lungs to the cardiac epithelium is still "an open question."

"Lumped together, cardiopulmonary mortality and the mechanisms underlying these observations are obscured, not well worked out," he said. But he expressed certainty that short-term PM exposure is linked to hospitalizations for heart failure and represents a "substantial public health burden."

Many therapies – which to use, and when?

Conference presentations made it clear that another difficulty in the treatment of heart failure is what might be termed a "perfect storm" of complexities: the complex nature of the disease, the specific, often complex circumstances of the patient, and the difficulties inherent in knowing which therapies to use – this latter despite a wealth of guidelines based on a growing mass of evidence concerning their use.

At a session titled "Improving the Quality of Care and Outcomes in Heart Failure: a Call to Action," Gregg Fonarow, MD, professor of medicine at the University of California at Los Angeles and the Eliot Corday Chair in Cardiovascular Medicine and Science, described various studies that have shown a failure to use drug and device therapies based on evidence-based guidelines. "Life-prolonging drug and device therapies have been developed and are now widely available for managing patients with heart failure," Fonarow said. But he went on to assert that, "despite overwhelming clinical trial evidence," they are not being used consistently.

Perhaps even more disturbing, he cited studies showing that those "at higher risk for dying are less likely to be treated," and, as well, that "Those deriving greatest benefit [from drug and device therapies] are less likely to be treated." And he cited drug studies demonstrating a failure to provide beneficial dosages or to up-titrate dosages when necessary to patients.

Fonarow cited the IMPROVE HF trial – the results published in July in the New England Journal of Medicine – showing some improvements in guidelines-based therapies delivered in out-patient settings, but also the continuing existence of significant gaps, especially in educational programs and the use of appropriate documentation necessary to determine and quantify the match between patient and appropriate therapy.

Fonarow noted the inconsistent use of available drugs but that that gaps in the use of devices – primarily implantable cardioverter devices (ICDs) and cardiac resynchronization (CRT) devices – are even larger.

The IMPROVE HF study says that the decision to use a device therapy "often requires in-depth and multiple discussions with patients but may not always be documented in the medical record, especially when the decision is to forego use of an otherwise indicated device."

Underlining another disparity in the treatment of heart failure, Fonarow cited a study in Circulation, "Use of Cardiac Resynchronization Therapy in Patients Hospitalized with Heart Failure," finding less use of CRT devices in black patients (though no disparity for use in women less than men, found in other studies).

Study authors say the conclusion about this disparity "is particularly concerning because black patients have a higher incidence of non-ischemic cardiomyopathy, which has been shown to be associated with greater rates of clinical response to CRT."

The "call to action" part of the session came in presenters' recommendations to develop rigorous hospital programs to systematize the use of evidence-based guidelines and provide improved documentation.

What guidance by evidence-based guidelines?

But another session at the HFSA gathering – "Device Therapy for Heart Failure: Debating the Guidelines–Which Should We Really Follow?" – questioned the unquestioned precision of evidence-based guidelines.

Session moderator Clyde Yancy, MD, of Dallas, noted significant reductions in the use of ICD therapies for blacks, as well as for women, suggesting that this could be the result of discriminatory biases in the practice of using the use the guidelines recommending these therapies.

But he then indicated an alternative interpretation: that there may be significant difficulties in interpreting and applying the guidelines.

This interpretation received the primary emphasis by three physician presenters and the subsequent case study debates concerning whether to use these therapies on specific patients underlined the point. And a great many reservations were expressed concerning the evidence on which medical guidelines are based, how they are developed and the ability of physicians to understand and interpret them.

Mariell Jessup, MD, of Philadelphia, suggested, for instance, the inconclusive nature of the initial version of American College of Cardiology/American Heart Association guidelines for ICD use, developed in 2005, based on the MADIT trial, and then the updated guidelines based on MADIT II. Given the increased confidence concerning ICD use, and the resultant detailed guidelines, the initial, two-paragraph guidelines might have looked as providing little help to clinicians.

Likewise, the other presenters noted how often guidelines tend to lag behind new evidence.

JoAnn Lindenfeld, MD, of Denver, underlined the frequent tentative nature of the evidence-based guidelines by describing the evolution of HFSA's comprehensive guidelines for ICD use in 2006. She said that these initial guidelines were developed by writers who first reviewed the basic literature, "wrote what we thought, submitted it to the executive committee, and then to the society at large" – then adding that this was "not a very systematic process."

Lindenfeld went on to note the subsequent controversies and a variety of issues raised concerning the validity and usefulness of some sets of guidelines.

Included among those issues:

• That guidelines are too often "cumbersome" and thus difficult to use.
• The presence of multiple, and differing, sets of guidelines for the same disease.
• "Variable" rather than consistent guideline formats.
• Frequent writer bias (Lindenfeld citing a set of pharmacologic guidelines for the use of statins, written by those with interests in this drug type).
• Not making "explicit" the expected outcomes, such as a realistic look at mortality, exercise capacity and quality of life.

Lindenfeld said that while evidence-based guidelines may aid the cardiologist, they leave many questions unanswered for the patient, or for how the cardiologist communicates with the patient. They don't provide much direction, she said, for helping the patient understand the "absolute risk and benefit" of a therapy. "The benefit may be greater, but how much greater? … We need to tell our consumers what the timing of the benefit is – right away or take some time."

On the risk side, she noted that while ICDs have been shown to save lives – from seven to eight people out of 1,000 implanted – patients also should be told that "30 patients will die anyway with an ICD." So, guidelines could be improved, she said, by helping "all of us individualize" what they mean for patients – "how to apply them to my individual patient."

Leslie Saxon, MD, of Los Angeles – following a detailed review of a combined set of guidelines by the ACC/AHA and European Society of Cardiology – suggested that evidence-based guidelines aren't likely to be structured as patient-friendly statements. She excused her drill-down detailing of the combined guidelines by saying, "Every time I put an ICD in, I fill out a three-page form about why I did it and what my thinking was. We're not going to get paid unless this thing is filled out." That, she said, "is the benefit of these guidelines and the detail is pretty clear to us."

Debate … and disagreement

This session was wrapped up with the presentation of case studies, with the discussion casting further doubt on the definitive ease of use in a disease with so many variables (dyssynchrony exactly in which ventricle? And other questions) and when dealing with human beings with lives and circumstances lying outside clinical parameters.

Considerable debate ensued concerning the case of a 56-year-old male hospitalized for "increasing dyspnea," after a year of heart failure symptoms, but responding "well" in the hospital to diuretics and characterized as "treated for a week, had something for a year." So, put in an ICD or not?

While the three presenters opted to treat him pharmacologically and hope for improvement, session moderator Yancy said he would implant, because "for this patient to get better he would have to [show] reverse modeling; he would have to have improvement in EF [ejection fraction] greater than 10."

But Jessup threw in a real-world variable from the experience of one of her own patients similar to the hypothetical case: Her patient worked on a tugboat, at a strenuous job. "With an ICD, he would lose his job – and probably his insurance."

CD&D's conclusions from this debate: Evidence-based guidelines aren't exact. And they had better be complemented by superior physician judgment and excellent communication with the patient.

First drugs for AF … then drug/device combos

But there is no debate about the types of treatments used first in dealing with heart failures: drugs come before devices

In a satellite session titled "The Impact of Atrial Fibrillation [AF] on Heart Failure Patients," the presentations underlined the initial use of drugs, and new drug therapy developments, for this increasingly common heart arrhythmia, rather than the increasing emphasis on the primary device therapy to treat AF, catheter ablation.

But this symposium (supported by Sanofi-aventis [Paris]) clearly indicated that both drug and device therapies for AF – and their frequent use in combination – will be a necessary and ever-increasing therapies, for two reasons: the growing awareness of AF as associated with heart failure; and the increase of both problems, described as ballooning to epidemic proportions, given the double conundrum of aging demographics and lengthening life spans.

Opening the session was Barry Massie, MD, of San Francisco, an ex officio member of the HFSA's executive council (and a participant in a trial studying the use of irbesartan, an angiotensin receptor blocker, with disclosed ties to two drug firms). He said that the "intersection between heart failure and atrial fibrillation makes our life miserable on both [patient and physician] sides."

Further expanding on this was Lynn Stevenson, MD (disclosing a consultant role with Medtronic [Minneapolis]), who highlighted the frequency of AF in heart failure patients, saying "the more sick [heart failure patients] are, the more likely they are to have atrial fibrillation." And among heart failure patients who die of cardiac causes, "half of those patients have AF before death."

Once AF is "present," she said, "the more worried we are in terms of outcomes, even with no symptoms of heart failure. AF contributes to the risk of asymptomatic heart failure."

Despite the use of the word "contributes" in the above quote, Stevenson went on to acknowledge a key unsolved question concerning AF and heart failure: Is AF something that works to cause heart failure or one of its key effects and symptoms? "There's nothing to demonstrate either possibility, but both are in play," she said.

Products in posters and presentations

Among key presentations and posters at the meeting:

• Reports were presented on the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) trial and PARTNERS HF (Multi-site Program to Access and Review Trending Information and Evaluate Correlation to Symptoms in Patients with Heart Failure, both sponsored by Medtronic (Minneapolis).

The studies showed that cardiac resynchronization therapy (CRT) reduced time to first heart failure hospitalization or death by nearly half, in patients with mild heart failure, and that devices equipped with Medtronic's OptiVol Fluid Status Monitoring identified patients who were at a significantly higher risk (3.5 times) of having a heart failure event in the near future.

REVERSE was billed as the first large-scale, global, randomized, double blind trial to demonstrate the benefits of CRT in mild heart failure patients or asymptomatic patients who previously had heart failure symptoms. Currently, CRT is indicated for patients with moderate or severe heart failure. Optimal medical therapy is considered to be beta blockers and ACE inhibitors or aldosterone receptor blockers.

At 18 months, 15.7% of study patients without CRT were hospitalized for heart failure or died, vs. 7.5% of heart failure patients studied with CRT, a roughly 50% reduction. Additionally, CRT was shown to help improve the heart's pumping efficiency and reduce its size.

REVERSE data for 12 months has been presented at previous scientific sessions. The results presented at the 2008 HFSA are findings at 18 months for a European cohort,to will be followed for 24 months.

Despite the trial not meeting statistical significance for its primary endpoint (percent of patients worsened at 12 months using a heart failure Clinical Composite Score), more patients in the trial improved with CRT; this trend continues at 18 months.

PARTNERS HF data demonstrated that monitoring fluid trends in the chest cavity using OptiVol identified patients more likely to have subsequent heart failure events, such as shortness of breath, fatigue, tissue swelling due to fluid build up, and decompensation or deterioration of the heart.

• The Rheos System from CVRx (Minneapolis) significantly improves heart structure and function in treating early-stage heart failure patients, according to data presented in a poster session by John Bisognano, MD, PhD, associate professor of medicine at the University of Rochester School of Medicine and Dentistry (Rochester, New York).

Rheos is a pulse generator implanted under the collar bone and connected at the left and right carotid arteries with two lead wires.

The clinical data showed that continuous use of the Rheos in early-stage heart failure patients remodels cardiac structure and improves heart function. The system was implanted in 18 patients, at Europe and U.S. medical centers, who had early-stage heart failure and high blood pressure and were on optimal medication levels. After one year of Rheos therapy, left ventricular mass and left atrial dimension were reduced toward normal levels. In addition, blood pressure was lowered.

According to CVRx, the Rheos is designed to activate the carotid baroreceptors, components of the body's natural cardiovascular regulation system. When the baroreceptors are activated, signals are sent through neural pathways to the brain and interpreted as a rise in blood pressure. The brain works to counteract this perceived rise in blood pressure by sending signals to other parts of the body that relax the blood vessels and inhibit the production of stress-related hormones. These changes enable the heart to increase blood output, while maintaining or reducing its workload.

The company also reported that the first study evaluating the Rheos in diastolic heart failure patients has been launched in Europe.

• Palatin Technologies (Cranbury, New Jersey) presented results from a Phase I clinical study with PL-3994, a novel, long-acting natriuretic peptide receptor A (NPRA) agonist under development for treatment of the chronic treatment of heart failure. The Phase I trial was a randomized, double-blind, placebo-controlled, single ascending dose study in 26 healthy volunteers who received the medication or placebo subcutaneously. The objective of the trial was to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of subcutaneously administered PL-3994 in healthy male subjects.

Dosing concluded with achievement of the primary endpoint of the study, a pre-specified reduction in systemic blood pressure. PL-3994 produced dose-related decreases in blood pressure, increases in plasma cGMP, and increases in urine volume and sodium excretion. There were no serious or severe adverse events.

Palatin reported completing a positive Phase IIa clinical study with PL-3994 in August in 21 volunteers with controlled hypertension who received the medication or placebo subcutaneously. The results of the study demonstrated that PL-3994 can be given safely to patients taking anti-hypertensive medications commonly administered to heart failure and hypertension patients.

• Cytokinetics (South San Francisco, California) presented oral and poster presentations of the trials evaluating CK-1827452 in stable heart failure patients at the 2008 annual scientific. The interim analysis, presented in the oral presentation, demonstrated statistically significant correlations between CK-1827452 polama concentration and measures of cardiac systolic function. The poster presentation outlined the design of a Phase IIa trial intended to evaluate CK-1827452 in patients with heart failure undergoing cardiac catheterization.

Stem cell and tissue therapies

The HFSA sessions featured a sprinkling of presentations concerning stem cell and tissue engineering for heart disease, all of this research much closer to "basic" than developmental, and still from broad clinical application. But the work in these areas is always both enticing and tantalizing.

In a session titled "Approaches to Cardiac Repair: Protein Delivery and Biomaterials," Doris Taylor, PhD, director of the Center for Cardiovascular Repair at the University of Minnesota (Minneapolis), issued a sharp challenge to a large proportion of current efforts in this field, saying that stem cell and tissue engineering "may not suffice for end-stage heart failure and that such interventions are only effective with the use of allografts or transplants."

She characterized work in this area as "moderately positive, negative and mixed," and described her own team's research as an attempt to "intervene early and work backwards" and that it had made progress beyond proof of concept.

Rather than attempting to build three dimensional tissues and whole organs, this research is focused on "recellularization," or repopulating an organ with cells.

To do this, Taylor's team first figured out how to remove the cells from an organ – "decelullarization" – and then put the cells back – "recellularzation." As she said, the team felt it would be "cool to remove cells and put cells back in."

Taylor said that this strategy works to get around the major difficulties of regeneration or repair vs. cell therapy, the requirement to have a matrix on which to place and build the cells into a whole organ, and a method of perfusing, or "feeding" the cells so that they live and grow.

"To build a new heart, we need cells and a framework for the cells and a way to feed the cells and keep them alive in the new organ via perfusion."

Nature definitely smarter

She added, "We're not smart enough" to do this, "but nature is." So Taylor's team developed a method for decellularizing not only individual organs but a whole animal, leaving a matrix primarily of the basic collagen superstructure of the organ or animal, demonstrating this approach with the rather ghostly image of a rat with all its cells removed, leaving simply a mostly collagen animal.

The matrix thus provides the necessary scaffolding to build on, along with available conduits. And Taylor said this approach fulfilled one of her two mantras, "Give Nature the tools and get out of the way" (the other being, "Trust your crazy ideas").

For the initial decellularization, the researchers developed "a detergent process" that they used to isolate rat and pig cells – "smooth muscle cells and endothelial cells" – and then they did this in a "human-sized organ," the heart of a pig.

In another phase of the research, the team injected what she called "neo-cardiac cells" into the wall of a "bioreactor," simulating the effect of repopulating a heart. The result was a recellularized left ventricle that matured and beat synchronously at "day eight,"

This beating "generates force, but only 25% of fetal heart force," Taylor said. By advancing its "learning curve," she said, the reseachers hope to develop a beating tissue "that gets stronger over time."

Another step in the research, she said, will be to test the tissue's responsiveness to drugs and whether different drugs will result in the beating speeding up or slowing down.

"We're pretty excited about the ability to recellularize these hearts," Taylor said, with future possibilities of translating this same process to other organs; but added that there is still "a huge amount to do."

From modular repair to micro-improvement

In other presentations on cellular repair of the heart:

• Richard Lee, founder of Provasculature, reported on his company's development of peptides that "self-asemble into scaffolds" to provide a three-dimensional matrix for cell culture development. He described the resultant product "sort of like Jell-O – an expensive form of Jell-O – but designed with intelligent modifications."

He further called the design of this material "like Legos for cells" and able to create "a modular system to deliver many types of growth factors." He said that the use of atomic force microscopy had shown these materials "stable for three to four months inside the myocardium

• Randall Lee of UCLA described what he described as a type of fibrin glue injected into the left ventricle of the heart of a rat following infarct, in the attempt to increase the thickness of the wall of the ventricle, change its "geometry" in order to prevent "negative dilatation."

Echocardiography showed that the "animals did improve."

• Hani Sabbah, director, Henry Ford Health System and on the faculty at Wayne State University (both Detroit), described the use of a polymer and alginate to increase the pumping function of the heart.

He said the goal was to "influence the micro-environment" of the heart to create an extracellular matrix which restores the geometry of the left ventricle. "We're not only influencing the microenvironment, but trying to alter the shape and hope to maintain the shape, recruit enough cells in or recruit more cells in there."