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2 decades of molecular cardiology and genetics
A Cardiology Today Editorial Board Member discusses the impact of molecular biology and genetics research on cardiology.
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Editor’s Note: Cardiology Today is celebrating its 20th anniversary in 2017. We are reaching out to experts in cardiology for their take on changes in CV medicine since the publication launched in 1997. In this issue, Robert Roberts, MD, FRCPC, MACC, FRSC, LLD (Hon.), focuses on molecular cardiology and genetics.
The modern era of the application of molecular biology and recombinant DNA techniques is claimed to be initiated in the early 1970s due to four discoveries.
No. 1, specific restriction endonucleases were discovered, making it possible to cut DNA at desirable sites. No. 2, discovery of the enzyme reverse transcriptase made it possible to develop a complementary DNA from messenger RNA. No. 3, the birth of cloning. No. 4, the rapid sequencing of DNA. Nobel prizes were awarded for each of these discoveries.
These discoveries made it possible to pursue the molecular basis underling human growth and replication. The cardiologists were mostly unaware of these techniques, let alone their utility and application. The American Heart Association recognized the need to train cardiologists that would apply these techniques in CV research. This led to the establishment of three centers (AHA-Bugher Foundation Centers for Molecular Biology in the Cardiovascular System at Harvard Medical School, University of Texas Southwestern Medical School and Baylor College of Medicine) in 1986 for the training of cardiologists in the techniques of molecular biology and recombinant DNA. The AHA and those of us who were directors of the Bugher Training Centers were excited, but concerned as to whether we could recruit cardiac fellows willing to extend their training an extra 2 years in a basic laboratory. There were other barriers, namely, the heart, being terminally differentiated, does not generate new cardiomyocytes after the first month of life. The skeptics, including some of the funding agencies, while recognizing the necessity of these techniques for research in growth-related diseases such as cancer, did not consider them appropriate to advance the field of CV research.
The three original AHA Bugher Centers were funded for 5 years, and the NHLBI and others provided funding to sustain training in this discipline. It was soon appreciated that CV research in our pursuit to understand normal physiology and pathophysiology would be enhanced by these techniques. After all, the heart replaces itself every 3 to 4 weeks (eg, myosin, the main contractile element of the heart, has a half-life of 3 to 5 days and accounts for 36% of the weight of the heart). The heart harbors many genetic abnormalities due to inherited DNA mutations. Cardiac hypertrophy is the normal compensatory growth response of the heart to most forms of stress, such as hypertension or MI. Genetics and all forms of growth, whether maintenance or compensatory, are initiated and directed by DNA, hence a prerequisite to their understanding is the application of these techniques.
Early discoveries
The recombinant DNA techniques initiated the genetic engineering of the first genetic recombinant cardiac drug, tissue plasminogen activator (tPA). This drug revolutionized the treatment of MI, reducing its acute mortality to 4% to 5%. The second low-lying fruit was genetics, which led to the discovery of the first gene responsible for familial hypertrophic cardiomyopathy in 1990. This was quickly followed by the discovery of genes responsible for multiple cardiac disorders.
The 1990s were a golden age for single-gene disorders. Most of these single-gene disorders are autosomal dominant, which means only one-half of the offspring will have the gene. The clinical application is almost self-evident; genetic screening would immediately exclude half of the offspring from the need for periodic cardiac follow-up, and would also assure these individuals that they could not pass on the gene for this disease to their children. Individuals with the gene and the potential to develop the disease are better managed. Identification of a family with a mutation in PCSK9 led to the development and approval by FDA of a potent and novel therapy to decrease plasma LDL, which markedly reduces cardiac morbidity and mortality. Other therapies for specific inherited disorders are in the pipeline.
In 2007, these techniques enabled the discovery of the first genetic risk variant (9p21) for a CV polygenic disorder, CAD. Currently, over 60 genetic risk variants have been discovered that predispose to CAD.
These studies provided several important observations. No. 1, genetic risk for CAD is directly related to the number of risk variants rather than the intensity of any one risk variant. No. 2, only one-third of these genetic risk variants mediate their risk for CAD through known conventional risk factors such as cholesterol or hypertension, indicating there are other mechanisms contributing to the pathogenesis of CAD. No. 3, stratifying for risk for CAD based on a genetic risk score is mostly independent of conventional risk factors and more discriminatory than conventional risk factors. No. 4, genetic risk score is independent of age and because one’s DNA does not change in one’s lifetime, risk stratification for CAD can be determined at any time throughout one’s lifetime. The latter feature could induce a paradigm shift in primary prevention based on genetic risk stratification of asymptomatic individuals.
Mendelian randomization crucial
Discovery of genetic variants mediating risk for CAD makes possible the widespread use of the power of Mendelian randomization. Utilizing this technique, it is possible to assess the safety, causality and to some extent efficacy of a lifetime exposure to a particular genetic variant without confounding factors. Application of Mendelian randomization has already made significant contributions.
Utilizing Mendelian randomization, one can determine a priori whether the target for which a drug is developed is indeed causal of the disease. An example of the application of Mendelian randomization in determining a drug target was recently illustrated for the drugs varespladib (Anthera Pharmaceuticals) and darapladib (GlaxoSmithKline), inhibitors of secretory phospholipase A2 (sPLA2) and lipoprotein-associated PL A2 (Lp-PLA2). It was observed that sPLA2 and Lp-PLA2 are consistently present in coronary atheromatous plaques, and hence their inhibition would potentially be beneficial. Three clinical trials, costing millions of dollars, were performed, and all were negative. A Mendelian randomization study performed prior to the completion of the third clinical trial showed that phospholipase A2 is only a marker and not causative of coronary plaques. The Mendelian randomization study predicted the clinical trial should show no benefit. It is expected that the routine use of Mendelian randomization studies will decrease the time required from bench to bedside, as well as be cost-effective.
A major research and therapeutic thrust of the 21st century is the administration of pluripotent stem cells to regenerate the human myocardium — regenerative medicine. A decade of clinical trials has led to the successful delivery of human stem cells to the heart, proving that cell therapy is feasible and safe. However, incorporation and regeneration of these cells into the myocardium has not been achieved, and remains a future goal. The success or failure to regenerate the human heart is likely to be a distinguishing feature of the 21st century. As we conquer more diseases such as CAD, regenerating organs such as the heart will become an even greater barrier to improving the quality of life and prolonging one’s life span.
In just 2 decades, the techniques of molecular biology have become routine in CV research laboratories throughout the world. The impact of their application on the management of cardiac patients is particularly evident in inherited disorders. The future application of genetic risk stratification for CAD and utilizing them as targets for development of novel therapy is likely to markedly attenuate the pandemic of CAD.
– Robert Roberts, MD, FRCPC, MACC, FRSC, LLD (Hon.)
Cardiology Today Editorial Board Member
University of Arizona College of Medicine
Disclosure: Roberts reports consulting for Cumberland Pharmaceuticals and having no conflicts relevant to the present article. He acknowledges Arlene Guadalupe Campillo, MPH, for her support in the preparation of the manuscript.