The annual scientific sessions of the American Heart Association (AHA; Dallas) primarily feature broad platforms for new product rollouts, an avalanche of clinical trials and even, occasionally, some interesting debate. And this year's edition produced at least one issue for the controversy-prone general media to bite into. Garnering major press coverage was the announcement of the positive effects of BiDil, a new drug from NitroMed (Bedford, Massachusetts), showing an ability to treat heart disease among African-Americans.
The benefit of such a drug was the major emphasis of these stories, but it was often expressed with various degrees of concern. USA Today highlighted the report in a front-page story, emphasizing the benefits to blacks, but also suggesting that this kind of patient targeted might indicate a sort of drug/racial "profiling." A local radio talk show in New Orleans – the city hosting this year's AHA meeting – also expressed concern along these lines, suggesting something amiss for a pharmaceutical company to target, especially with a profit motive, a particular racial or ethnic group. And even The New York Times, in an editorial, expressed considerable uneasiness about using race as a targeting strategy for drug development. "Race," it said, "is too superficial and subjective a concept, mostly based on skin color, to match up well with any underlying genetic or physiological differences that may affect how an individual responds to a disease or a drug treatment."
But such concerns may seem somewhat beside the point – or points. In terms of drug development, pharmaceutical companies frequently look at various distinct populations as part of their strategy for drug development. They do so with the primary motive of making money, lots of money, and no one suggests that these efforts are in any way unsavory or represent some sort of profiling.
The Times' editorial concern has more substance. But its contention that race and genetics can't be matched up well seems to fall outside the realities of disease and the obvious frequent occurrence of certain illnesses in specific racial groups. Sickle cell anemia is just one very large case in point, and there are certainly many other examples of racial and ethnic groups being more susceptible than others to certain illnesses (and even less distinctly defined by skin color). And the determinants of race are hardly superficial to those who define themselves ethnically or racially and are aware that they are susceptible to certain health risks. Here also, it should be noted that the use of BiDil was for those who enrolled in the study as "self-identified" African-Americans.
But perhaps most importantly, the development of race-targeting points to the broad current trend toward "personalized medicine," designed to enable the effective matching of genetic disease predisposition with the best targeted therapies for them – and more generally, "theranostics," a term suggesting the predicting of best therapies for disease risks, via genetic analysis.
Even more generally, targeting specific populations as one method for guiding the search for new therapies highlights continuing research in the cardiovascular arena as demonstrated by the studies presented at the AHA meeting. Interestingly, an increasing number of these focus on women as a "minority" group.
- Researchers affiliated with Northwestern University (Evanston, Illinois) reported that women, "as well as men, may benefit from implantable cardioverter-defibrillators (ICDs) as a treatment for arrhythmias." Early results form the DEFINITE, 458-patient trial, indicated that women had higher rates of death from all causes after ICD placement, but later analysis showed that this was due to "an increase in non-cardiovascular causes of death."
- Researchers from Greece and the Netherlands reported higher in-hospital complications, both morbidity and mortality, for women than men following percutaneous and surgical coronary interventions.
- A combination of sex/age interaction was explored by French researchers, concluding that the worst prognosis for women after acute myocardial infarction (AMI) is found among younger women during hospitalization. The findings indicate the need for "specific pathophysiologic studies and appropriate care in younger women during the early phase of AMI."
- Several studies examined racial differences. As examples:
- Researchers from various California institutions reported that 10% of African-Americans over age 60 with congestive heart failure carry an allele responsible for a genetically determined autosomal dominant form of heart disease, and an overlooked factor in dealing with this population.
- Researchers at the Wake Forest University School of Medicine (Winston-Salem, North Carolina) found that, compared with non-Hispanic whites, non-Hispanic blacks and Hispanics who qualify for cholesterol-lowering drug treatment are less likely to have their "bad" LDL cholesterol controlled to recommended levels compared with non-Hispanic whites.
- University of Kansas Medical Center (Kansas City, Kansas) researchers reported an increased risk for childhood obesity as a cardiac risk factor among Hispanic and African-American children as a product of "fetal overnutrition in utero, as characterized by a high birth weight."
- Another large group of studies examined various age groups, with increasing emphasis on children and young adults with heart disease. For instance:
- German researchers reported that microvascular graft vessel disease is the most life-threatening long-term complication for children after heart transplantation, accounting for one-third of cardiac deaths.
- Researchers representing institutions in Iowa and Minnesota reported that tricuspid valve replacement in children is associated with a high mortality rate, especially in infants less than one-year-old, indicating the need for a closer look at surgical options.
- Various studies highlighted the physical/psychological associations in young people with heart disease, one highlighting a greater level of hostility among teens with cardiac problems than in adults and the value of exercise rehabilitation in this group.
Overall, the 2004 sessions of the AHA also produced an increased emphasis on heart disease in obese populations, especially those showing not just one, but a combination of risk factors.
Valve repair and replacement: an overview
Heart valve disease is reaching epidemic proportions as worldwide populations age and mankind continues to fail to contain rheumatic heart disease in developing countries. Worldwide, 850,000 patients will need replacement valves in 2050. To deal with this problem, transcatheter heart valve replacement is still in its infancy – but not for long. The latest minimally invasive transcatheter approaches for the repair of heart valves were discussed during a November webcast sponsored by Medtronic (Minneapolis), with Phillip Bonhoeffer, MD, of the Great Ormond Street Hospital for Children (London), moderating the presentations. Other speakers included Carlos Ruiz, MD, of the University of Illinois at Chicago (Chicago) and Sir Magdi Yacoub, MD, of the National Heart and Lung Institute (London).
Ruiz, a leading interventional cardiologist, specializes in structural cardiovascular disease. His presentation, "Transcatheter Valve Technology ... It's not as Easy as You Think," reviewed the many different devices being developed for transcatheter repair of valves. Ruiz sees these new percutaneous valve interventions as the future for interventional cardiology. "What is the rationale for percutaneous valve repair or replacement?" he asked. "Patients always opt for lesser invasive techniques as long as we can assure them that the safety and efficacy of the MIS [minimally invasive surgery] approach is equal to standard therapy." Ruiz went on to describe some of the latest developments for transcatheter valve repair, both mechanical and biological, many still in animal model stages.
An exciting new mechanical valve involves nanotechnology. Using vacuum deposition, Steve Bailey, MD, of San Antonio can produce 4 micron-thin nitinol to make the Nitinol Membrane PercValve. This device has been used in a small series of animal models.
On the biological side, there are a number of entries. Edwards Life Sciences (Irvine, California) has, according to Ruiz, made a major leap with the PVT valve. There is an ongoing human trial. "This valve is constructed from equine pericardium on a very strong stent and results have been spectacular," said Ruiz. The CoreValve, from CoreValve (Irvine, California), is being developed with a self-expandable, high-radial force nitinol stent. This valve has been used in two patients with excellent results, according to the company. Other biological valves include the Numed Valve from NuMED (Hopkinton, New York) and the Cook SIS valve from Cook Biotech (West Lafayette, Indiana). Using submucosa from pig intestine, the SIS collagen base material includes growth factors. Pig studies show a remodeling process that occurs long-term.
Ruiz said the ideal transcatheter valve is not yet available. He said the requirements for the ideal valve include issues of delivery, scaffold, material and design. For delivery, the valve needs to be low profile, reliable for orientation and easily placed. "The scaffold of the valve must be flexible, and stentless is better," he said. As to material for the valve, it must be non-thrombogenic, non-inflammatory and would be best if it could sustain somatic growth. It should also be readily available off the shelf, with no preparation needed.
Mitral valve regurgitation is another valvular problem. This occurs when the mitral valve doesn't hold a good seal. Interventional cardiologists have invented a number of potential devices to treat this problem with transcatheter approaches. Edwards Lifesciences has the Milano II LifeStitch, a device using stitches that are applied to the valve, and a nitinol anchor used to tighten the knots. Cardiac Dimensions (Seattle) is developing an implant using the superior vena cava as its entry point. Guided by echocardiogram, traction is placed on the valve leaflets. A device from Viacor (Wilmington, Massachusetts) uses nitinol covered with surgical-grade Teflon.
Ruiz noted that, "No one single device will fix all the varieties of valvular disease and I wonder how the regulatory agencies will compare the products to traditional surgery."
Tissue engineering has captured the imagination of patients, venture capitalists, corporations and scientists. Yacoub reviewed the current status for tissue-engineered valves (TEVs). "Valve replacements do save lives, but patients do not have the survival rate of the general population," Yacoub said. "This is due to the imperfections in the valve substitutes available today." He said that living valves would translate into better survival and quality of life. They could restore survival to a normal level. He defined a TEV as "capable of reproducing all or most of the sophisticated functions of a normal valve. Those functions depend on the geometry and dynamic features of the valve. They are able to change shape and size during different parts of the cardiac cycle." This involves sophisticated cellular fluctuation, gene expression, cell-to-cell interaction and cell-to-matrix communications. "Valve function is extremely sophisticated using complex biological systems," Yacoub said. "Considerable progress has been made in understanding the requirements for a TEV, but there is much more to be done."
Sirolimus seen as heart transplant aid
A study published recently in Circulation demonstrates that sirolimus – getting most frequent publicity these days as a drug coating for stents – provides sustained protection against coronary allograft vasculopathy, used from the time of heart transplantation, while also halving acute organ rejection in these patients. Cardiac allograft vasculopathy, an aggressive form of coronary artery disease, involves the narrowing and blocking of the coronary arteries. The disease occurs in 50% or more of heart transplant patients in the first five years after transplant and is the most common cause of death in these patients, its importance growing with time after the transplant. Acute rejection is responsible for early deaths in the first year, post heart transplant, whereas cardiac allograft vasculopathy causes 17% of all deaths beyond three years.
Associate professor Anne Keogh of St Vincent's Hospital (Sydney, Australia) said, "Cardiac allograft vasculopathy is the major challenge in heart transplant patients. Treatment for this relentlessly progressive complication has to date been disappointing. Cholesterol-lowering agents and calcium channel blockers have some protective effect but they do not eliminate the problem. This exciting drug – the mTOR inhibitor sirolimus – actually substantially prevents its development in heart transplant patients. This is well in line with its effects in regular coronary artery disease to stop in-stent retenosis, a fact known now for several years."
Five cardiac transplant centers from Australia and New Zealand enrolled 136 heart recipients in this open-label study. Following heart transplantation, patients were randomized to receive sirolimus or azathioprine in combination with cyclosporine and steroids. Intracoronary ultrasound and coronary angiography were performed at six weeks, six months and two years and compared between the two groups. At two years, all parameters of cardiac allograft vasculopathy had progressed markedly in those patients on azathioprine. In contrast, the development of vasculopathy was not observed in patients receiving sirolimus.