Pub Date: Thursday, Sep 12, 2019
Author: 1. Kory J. Lavine MD, PhD and 2. Charles E. Canter, MD
Affiliation: 1. Departments of Medicine, Developmental Biology, Immunology and Pathology, Washington University School of Medicine 2. Departments Pediatrics, Washington University School of Medicine
Precision and personalized approaches to health care hold incredible promise to improve patient outcomes across the spectrum of health care disciplines. The overarching vision of precision medicine is to employ diagnostic and tailored therapeutic strategies to identify and treat disease at the individual patient level targeting specific mechanisms and/or pathways that govern the pathogenesis of each person’s disease. Today, precision medicine paradigms are routinely integrated into the care of cancer patients and have provided substantial increases in cancer free survival. These advancements were fueled by translational studies investigating genetic, epigenetic, transcriptional, proteomic, and metabolomic signatures within the tumor that drive disease progression and predict individual responses to standard and targeted chemotherapy regimens1.
Over the past several decades, the cardiovascular and heart failure fields have embarked on a very different path. The prevailing focus has centered on identifying common factors that contribute to the progression of prevalent syndromes, including heart failure. These initiatives have formed the basis of our current approach to patient care, which is generally agnostic to the underlying cause of an individual’s disease. For example, patients diagnosed with heart failure are offered essentially identical treatments regardless of whether their disease was caused by coronary artery disease, genetic mutations, or autoinflammatory processes. While this “one-size-fits-all’ approach has led to improvements in clinical outcomes when large populations are examined, individual response rates vary tremendously, and it is often difficult to distinguish patients who will achieve a favorable response from those who will experience disease progression and ultimately succumb to their illness. Consequently, many individuals are left inadequately treated and substantial room for improvement exists.
The above observations highlight the need to rethink our approach to treating heart failure. Among many possible strategies, precision medicine has attracted tremendous interest and excitement. Key studies demonstrating selective efficacy of β-blockers and hydralazine/nitrate combination therapy in patients harboring specific genetic variants have provided fundamental insights that treatment responses can be predicted using genetic information2-4. Furthermore, it is increasingly evident that responses to medical therapies for heart failure vary based on age where pediatric patients derive significantly less benefit5,6. In fact, children with dilated cardiomyopathy display minimal evidence of myocardial remodeling (target of heart failure medications) at the pathological and gene expression level7. Finally, recent studies have questioned whether we fully appreciate the diversity of heart failure phenotypes and etiologies. For example, patients with Lamin A mutations display a molecular phenotype that is dramatically distinct from other forms of dilated cardiomyopathy8, 9. This finding raises the possibility that individual dilated cardiomyopathy mutations may actually give rise to distinct diseases. Thus, despite the common surface phenotype of left ventricular dilation and reduced ejection fraction, many forms of dilated cardiomyopathy may exist with differing natural histories and responses to currently available medical and device based therapies.
“Omics” technologies including genomics, transcriptomics, epigenetics, proteomics, and metabolomics represent robust unbiased technologies that have revolutionized the study of patient derived biospecimens. Such analyses are now possible at single cell resolution and hold the potential to allow us to better define heart failure etiologies, identify prognostically relevant biomarkers, and discover the molecular mechanisms responsible for the initiation and progression of an individual patient’s disease. Currently, translational studies of this nature are generally limited to small patient cohorts due to specimen availability and cost. Institutional investment and establishment of large integrated heart failure registries and biospecimen repositories containing blood and myocardial tissue samples paired with detailed clinical, imaging, and outcome data constitutes an essential step to truly realize the potential of precision medicine. Given recent cost reductions, it is now feasible to perform routine exome sequencing to identify genetic variants that predict heart failure prognosis and response to medical and device based therapies. Such information will be immediately clinically actionable and provide critical insights into new disease mechanisms. It is not immediately clear whether integration of genetic information with the electronic medical record will suffice to achieve these goals as precise and accurate clinical information is necessary to make rigorous conclusions. It is likely that data adjudication will continue to be an important component of maintaining clinical registries and biorepositories. Moreover, while the exact role of artificial intelligence and other deep learning technologies remains unclear, it is certainly likely that these informatics strategies will ultimately be employed in some capacity to develop testable hypotheses from large datasets.
The AHA scientific statement on precision medicine in heart failure is a timely and comprehensive review of the current state of this field. The statement provides a detailed overview of how omics technologies have rapidly improved our understanding of heart failure pathogenesis and demonstrated surprising heterogeneity in pathologies and responses to optimal medical therapy. These observations lay the foundation for the development and future applications of precision medicine paradigms in heart failure. The future of precision medicine for heart failure is indeed bright and today represent an exciting time in this emerging field.
Cresci S, Pereira NL, Ahmad F, Byku M, de las Fuentes L, Lanfear DE, Reilly CM, Owens AT, Wolf MJ, on behalf of the American Heart Association Council on Genomic and Precision Medicine, Council on Cardiovascular and Stroke Nursing, and Council on Quality of Care and Outcomes Research. Heart failure in the era of precision medicine: a scientific statement from the American Heart Association [published online ahead of issue September 12, 2019]. Circ Genom Precis Med. 2019,12:e000058. doi: 10.1161/HCG.0000000000000058.
- Prasad V, Fojo T and Brada M. Precision oncology: origins, optimism, and potential. Lancet Oncol. 2016,17:e81-e86.
- McNamara DM, Taylor AL, Tam SW, Worcel M, Yancy CW, Hanley-Yanez K, Cohn JN and Feldman AM. G-protein beta-3 subunit genotype predicts enhanced benefit of fixed-dose isosorbide dinitrate and hydralazine: results of A-HeFT. JACC Heart Fail. 2014,2:551-7.
- Cresci S, Kelly RJ, Cappola TP, Diwan A, Dries D, Kardia SL and Dorn GW, 2nd. Clinical and genetic modifiers of long-term survival in heart failure. J Am Coll Cardiol. 2009,54:432-44.
- Liggett SB, Mialet-Perez J, Thaneemit-Chen S, Weber SA, Greene SM, Hodne D, Nelson B, Morrison J, Domanski MJ, Wagoner LE, Abraham WT, Anderson JL, Carlquist JF, Krause-Steinrauf HJ, Lazzeroni LC, Port JD, Lavori PW and Bristow MR. A polymorphism within a conserved beta(1)-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure. Proc Natl Acad Sci U S A. 2006,103:11288-93.
- Shaddy RE, Boucek MM, Hsu DT, Boucek RJ, Canter CE, Mahony L, Ross RD, Pahl E, Blume ED, Dodd DA, Rosenthal DN, Burr J, LaSalle B, Holubkov R, Lukas MA, Tani LY and Pediatric Carvedilol Study G. Carvedilol for children and adolescents with heart failure: a randomized controlled trial. JAMA. 2007,298:1171-9.
- Kantor PF, Abraham JR, Dipchand AI, Benson LN and Redington AN. The impact of changing medical therapy on transplantation-free survival in pediatric dilated cardiomyopathy. J Am Coll Cardiol. 2010,55:1377-84.
- Patel MD, Mohan J, Schneider C, Bajpai G, Purevjav E, Canter CE, Towbin J, Bredemeyer A and Lavine KJ. Pediatric and adult dilated cardiomyopathy represent distinct pathological entities. JCI Insight. 2017,2.
- Cheedipudi SM, Matkovich SJ, Coarfa C, Hu X, Robertson MJ, Sweet M, Taylor M, Mestroni L, Cleveland J, Willerson JT, Gurha P and Marian AJ. Genomic Reorganization of Lamin-Associated Domains in Cardiac Myocytes Is Associated With Differential Gene Expression and DNA Methylation in Human Dilated Cardiomyopathy. Circ Res. 2019,124:1198-1213.
- Chen SN, Lombardi R, Karmouch J, Tsai JY, Czernuszewicz G, Taylor MRG, Mestroni L, Coarfa C, Gurha P and Marian AJ. DNA Damage Response/TP53 Pathway Is Activated and Contributes to the Pathogenesis of Dilated Cardiomyopathy Associated With LMNA (Lamin A/C) Mutations. Circ Res. 2019,124:856-873.
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-- The opinions expressed in this commentary are not necessarily those of the editors or of the American Heart Association --