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Coronary Artery Disease: Pathways and Subtypes

Key findings

  • Gene-association studies of heart disease causality raise the question: do current treatment paradigms optimally address genetic heterogeneity?
  • Precision medicine, a genetics-informed approach to discovering the nature and course of disease, can help answer this question
  • As of 2017, a landmark CAD precision medicine study called the All of Us Research Program is enrolling patients

Does coronary atherosclerosis manifest as one disease – or many?

Is it the product of rare genetic variants with large effect—or of a mix of common variants with modest effect?

These questions about the pathological identity of coronary artery disease (CAD) take on new and urgent meaning in the rapidly emerging era of precision medicine. It is a genetics-informed approach to discovering the nature and course of disease with the goal of devising individually tailored treatments based on that information.

The questions also are the subject of an editorial in the journal Circulation by Sekar Kathiresan, MD and Amit Khera, MD of Massachusetts General Hospital. The authors strive to ensure that expectations for this new field are realistic, particularly since as of 2017, a landmark CAD precision medicine study called the All of Us Research Program is now enrolling.

Given that significant variation exists among CAD patients in terms of physiology, risk factors and response to therapy, the authors consider: Perhaps CAD patients now managed by a single set of guidelines actually manifest just one of a multiplicity of disease subtypes. If so, each subtype might produce CAD through a distinct “driving pathway,” as the authors term routes of causality. If so, each subtype might be optimally treated by a distinct therapeutic approach targeting a pathway.

Alternatively, perhaps CAD arises as the result of what the authors call “a quantitative blend” of causal risk pathways. If so, this would require different management approaches from those used in CAD treatment informed by the distinct driving pathway concept.

The alluring potential of the precision medicine approach holds its evidence infrastructure, based as it is in analyzing the human genetics of disease. According to the authors, the All of Us Research Program—and the evolution of the precision medicine field itself—will be most productive by identifying causal-risk pathways that contribute to CAD and the development of new tailored, individualized treatments based on these pathways, rather than teasing out new subtypes of disease.

1980
 Year of publication confirming a pathway approach to CAD treatment, citing statins as leading to a 25% decrease in circulating cholesterol

60
 genetic variants robustly associated with CAD, and the vast majority are common in the general population

1938
 Year of first publication on a CAD subtype approach to managing disease, documenting a familial subpattern of hypercholesterolemia by Carl Müller

Refer a patient to the Massachusetts General Hospital Corrigan Minehan Heart Center

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Precision medicine can help answer whether or not current heart disease treatment paradigms optimally address genetic heterogeneity.