Precision Medicine for Heart Failure: using "omics" technologies to find the road to personalized care

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 information^2-4. Furthermore, it is increasingly evident that responses to medical therapies for heart failure vary based on age where pediatric patients derive significantly less benefit^5,6. 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 cardiomyopathy^{8, 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.