Thirty-one years ago, it was not known that the heart produces hormones. That changed in 1981 when Adolfo de Bold, PhD, discovered that muscle cells in the atria of the heart secrete atrial natriuretic factor (ANF), an essential hormone that regulates fluid volume, blood pressure and sodium. Since that watershed discovery, thousands of scientific papers have been published on cardiovascular endocrinology, and related diagnostic and therapeutic tools have been developed.
On September 23 and 24, the University of Ottawa Heart Institute hosted “The Endocrine Heart: 30 Years Later,” an international symposium to celebrate de Bold’s achievement and look at the past, present and future of cardiovascular endocrinology. Held in association with the International Society of Hypertension, the event brought together leading scientists from as far away as Brazil, Japan and New Zealand.
Prior to the discovery of cardiac endocrine function, the heart was considered what amounts to a passive pump, simply pushing blood through the body as directed by the brain stem. It was not thought to exert hormonal control over the cardiovascular or other body systems.
In that intellectual climate, de Bold’s chosen area of research was considered unfashionable, and funding did not flow easily. The discovery of ANF was the culmination of 12 years of painstaking bench work with a laboratory staff that consisted primarily of de Bold himself; his wife, Mercedes; and a technician.
ANF turned out to be the first in an entirely new family of hormones, the cardiac natriuretic peptides, which also includes brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). These cardiac hormones play an important role in blood pressure regulation and the growth of heart tissue, and they have been shown to impact most known biological functions. Their relationship to heart failure and inflammation makes them attractive targets for research into the treatment of heart disease.
As one speaker at the “Endocrine Heart” symposium made clear, de Bold’s tenacity was inspirational. Benoit Bruneau pursues questions of cardiac development at the Gladstone Institute and the University of California, San Francisco. He received his PhD under de Bold and lauded him as a mentor. De Bold, he said, provided a good model of what it is to be a scientist, by encouraging his students to think critically, to ask the right questions and, importantly, to pursue them.
The core of the symposium focused on what we have come to know about the genetics and molecular pathways involved in the function of cardiac natriuretic peptides, as well as their impacts on the cardiovascular system.
The Heart Institute’s own Dr. Michael Gollob and Dr. Haissam Haddad discussed the broad relevance of ANF to the clinical setting. Dr. Gollob, Director of the Inherited Arrhythmia Clinic and the Genetics of Cardiac Arrhythmias Research Laboratory, spoke on the connection between ANF and atrial fibrillation, the most common cardiac arrhythmia.
“De Bold provided a good model of what it is to be a scientist, by encouraging his students to think critically, to ask the right questions and, importantly, to pursue them.”
– Benoit Bruneau, PhD, Gladstone Institute and the University of California, San Francisco
Like atrial fibrillation, heart failure is a growing problem in an aging population. Associated health care costs are $4 billion annually in Canada. Dr. Haddad, Director of the Heart Failure Program and Medical Director of Transplantation, discussed the role of ANF and BNP in the clinical management of heart failure. Measurement of circulating BNP is a common diagnostic tool for the condition. As Dr. Haddad reported, ANF and BNP are independent markers of heart failure, they are strongly predictive of death and, used alone, they are as good or better than physical exam of the patient for diagnostic purposes.
Many presenters focused on potential diagnostic and therapeutic applications of the natriuretic peptides. Dr. John Burnett of the Mayo Clinic described his work on the use of ANF and BNP in treating heart failure. No new drugs for heart failure have come through the development pipeline in more than 10 years, even as the elderly population continues to grow. ANP and BNP are currently used to treat acute heart failure, since they have significant protective (anti-cell death) and regenerative properties. However, the natural hormones have a very short half-life—a matter of minutes—within the body.
Dr. Burnett is working on developing synthetic versions that would not promote the unwanted side effect of excessively low blood pressure and would have longer-lasting positive effects. Since these synthetic compounds mimic natural peptides, they should be safe and effective, he told the audience. Currently, his research group has one synthetic peptide in human studies and is conducting other research into using ANP therapy after a heart attack to prevent heart failure. They are also looking at CNP to prevent fibrosis in cardiac tissue. “None of this would be possible,” he said, “without Adolfo’s work.”
The de Bold lab is also actively pursuing synthetic therapeutic analogs of ANF to create compounds that could stimulate regeneration of the heart tissue for days instead of minutes. Such compounds could have clinical applications for the treatment of acute heart failure and heart-tissue repair after a heart attack. To date, they have filed one patent application for a promising compound that genetically fuses ANF to human serum albumin, which extends its time in the bloodstream by more than 70-fold.
De Bold and his colleagues are also working to understand the factors that control BNP gene expression, since the hormone appears to play an important role in remodelling heart muscle under chronically stressful conditions, such as high blood pressure or inflammation. They are also examining how the biophysical forces that expand and contract the heart muscle affect the secretion of ANF and BNP.
Even after more than 40 years at the bench, de Bold remains enthusiastic about the opportunities to continue harnessing the endocrine function of the heart to improve the treatment of cardiac disease. He thanked the symposium participants for their dedication to a field of research that only emerged three decades ago.
“Probably the greatest honour in life is to have your achievements recognized by your friends and colleagues. It is quite a privilege to have this event organized in recognition of the work we have done,” he told the audience.
In scientific terms, the importance of the ANF discovery is reflected in the nearly 27,000 articles indexed in PubMed on the subject. By extension, tens of thousands of researchers have found ANF and related hormones a subject worth investigating. Clinically, the anticipated availability of synthetic natriuretic peptides in coming years will greatly increase the therapeutic value of these hormones and has the potential to impact millions of people suffering from chronic heart failure and hypertension.