New cardiovascular treatment approaches

In an era of increasing death and illness from heart and blood vessel disease - which also can impair kidney function - Mayo Clinic researchers have designed two promising new cardiovascular treatment approaches.

In the process, they have overcome a key technological hurdle that has stymied researchers around the world in the development of new therapies based on clusters of amino acids called peptides. The Mayo Clinic researchers presented their findings at the American College of Cardiology's 56th Annual Scientific Sessions.

The first advance supports the feasibility of developing a peptide-based drug that can be given in pill form to lower high blood pressure, and that is based on a hormone originating in the heart, called B-type natriuretic peptide (BNP).

"Our formulation of an oral peptide is a technological accomplishment that really can advance the field," says John Burnett, Jr., M.D., director of Mayo Clinic's Cardiorenal Research Lab who led both studies. "Prior to this, it was unheard of that a peptide could be given orally, because it is so rapidly degraded by stomach enzymes. Yet we overcame this significant constraint. This is the first report demonstrating that a peptide -- in this case, BNP -- can be developed by innovative technology to be absorbed orally."

The second advance is the development of a therapeutic hybrid molecule that helps improve both heart and kidney function. Addressing kidney blood vessel disease in addition to heart vessel disease is an increasingly important clinical focus for therapies as kidney failure becomes epidemic in the 21st century, and diseases of both heart and kidney link the health of the two organ systems.

Heart disease continues to be a leading cause of death and disability in Western countries, and kidney disease is a fast-growing threat to public health. These two disease processes are linked by the fact that they both are often the result of high blood pressure. "New treatment strategies are therefore urgently needed," Dr. Burnett says. In tackling heart disease, Mayo Clinic researchers considered the heart from a different perspective -- not merely a mechanical pump, as it is traditionally regarded, but as a hormone-secreting endocrine organ.

"To view the heart this way is a distinct innovation that presents new opportunities for cures that we've made good progress toward exploring," Dr. Burnett says. The researchers were the first to harness the natural properties of the heart hormone BNP, working in partnership with scientists from the biotechnology firm, Biocon, and to formulate it so it can be taken orally, in pill form. BNP's therapeutic properties include its ability to dilate blood vessels, promote salt discharge in urine, and prevent both excessive cell growth and growth of fibrous tissues. The researchers tested the oral BNP by inducing high blood pressure in laboratory animals, and then giving them the experimental drug. Results showed that the experimental oral drug reduced the mean arterial pressure steadily over time, beginning at 30 minutes after the oral treatment was given, and continuing to reduce blood pressure for two hours, the study's endpoint.

"Clearly, this novel oral form of BNP significantly reduces mean arterial pressure in an experimental model of high blood pressure," says Dr. Burnett. "Our findings are both exciting and important because they advance an innovative strategy of orally administering BNP therapy for cardiovascular diseases such as high blood pressure."

In heart failure, the kidneys also can become impaired and salt and water retention can occur, resulting in congestion. Reduced kidney function leads to buildup of toxins in the blood that can disable a person -- and progress to kidney failure that requires lifelong dialysis, or an organ transplant.

Mayo Clinic researchers created a hybrid molecule they describe as safe and efficient -- called a chimera -- that may provide the basis for a new treatment which could be infused into a patient to treat both heart and kidney impairment in the setting of acute heart failure. The Mayo Clinic team started with a cluster of amino acids called C-type natriuretic peptide (CNP). CNP has properties important for heart health, such as resisting cell proliferation and promoting dilation of blood vessels without causing low blood pressure. However, CNP had no effect on increasing kidney filtration. But another peptide, called D-type natriuretic peptide (DNP), did. The Mayo Clinic solution was to synthesize a hybrid between CNP and DNP that preserved DNP's capacity to promote kidney filtration. In this way, the team designed a novel chimeric peptide and defined its heart-kidney action by testing it in laboratory animals. Results showed that Mayo's chimeric peptide had the desirable attributes of increasing salt excretion in the urine, as well as increasing urine production.

Says Dr. Burnett, "This finding is important because our chimera has minimal negative side effects, while promoting beneficial kidney actions such as increased filtration rate. This is a high clinical priority because it may suggest a highly safe and efficacious base for creating new therapies for heart and kidney diseases."