Cardiovascular disease (CVD) still remains the leading cause of death in the United States with more than 610,000 people dying annually. Even with the advancements made in preventive cardiology over the past 30 years, there are more than 735,000 heart attacks annually. It is apparent that new approaches to the prevention and management of CVD that would reduce its burden would be an important step forward in decreasing both morbidity and preventable mortality. One approach that is gaining momentum that could accomplish this objective is seen through the prism of, and framed from, the advancements being made in systems biology and functional cardiology. The word “functional” when applied to cardiology a decade ago was mostly associated with psychosomatic and posttraumatic relationships to cardiovascular symptoms.¹ Charles Darwin during most of his adult life was chronically ill and had symptoms of cardiac disease that were attributed to him suffering from posttraumatic stress disorder.² He had experienced a painful, sudden death of his mother when he was 8 years old, seeing operations without anesthetics at a young age and witnessing the death of three of his children. His ill health was attributed at the time to an “irritable heart.” The context of this connection of emotion to cardiovascular symptoms became classified as a member of the conditions termed “functional somatic syndromes” in 1999.³,⁴ In the last 10 years, the use of the term “functional” in cardiovascular medicine, however, has changed considerably. It is recognized that the physiological function of the cardiovascular system can have influence on many other organs including the brain, liver, gastrointestinal, endocrine, and immune systems.⁵ These new discoveries are redefining CVD that results from a complex set of physiological processes that modulate multiorgan systems which, in turn, influence the function of the vascular system.

We are witnessing the application of systems biology to cardiovascular medicine which focuses on the etiology of CVD resulting from the impact of altered physiological function among organ systems.⁶ This systems medicine approach to both research and clinical development has provided the opportunity to better understand the etiology of complex cardiovascular-related disorders.⁷ In this new systems biology application to CVD, the interaction of the functional status of the immune, endocrine, nervous, gastrointestinal microbiome, and hepatic detoxification systems is important in personalizing the treatment plan and making it more precise.⁸ Functional status of the cardiovascular system is a result of the interaction of the organ systems that impact cardiovascular health and disease. The functional status of the cardiovascular system is determined by the unique interaction of the individual’s genome with their lifestyle and environment throughout their lifetime. Functional cardiology then becomes the study of the dynamic factors that influence the plasticity and resilience of the cardiovascular system through the lens of systems biology.

The application of function of the cardiovascular system from this new perspective includes both assessment and intervention. Genomic evaluation coupled with lipid assessment, for example, provides a methodology for looking at CVD from a functional physiological perspective and can guide early intervention.⁹ It is now recognized that several hundred different coronary heart disease (CHD) risk factors have been identified, and many new CHD-associated biomarkers and noninvasive cardiovascular (CV) tests are under evaluation for inclusion in routine practice The CV tests include high-sensitivity C-reactive protein (hsCRP), endothelial function and endothelial dysfunction (ED), arterial elasticity and compliance, pulse waveform analysis (PWA), pulse wave velocity (PWV), augmentation index (AI), central arterial blood pressure (CBP), 24-hour ambulatory blood pressure monitoring (ABPM), carotid artery duplex, micronutrient testing (MNT), cardiovascular toxicology, autonomic function testing (AFT) and heart rate variability, plethysmography, magnetocardiography, gene expression testing, ankle-brachial
index, cardiopulmonary exercise testing (CPET), ECHO and exercise ECHO, computerized tomography angiography (CTA), cardiac magnetic resonance imaging/angiogram (MRI/MRA), positron emission tomography (PET) scans, nuclear medicine scans, and coronary artery calcium (CAC) score. These emergent biomarkers and noninvasive CV tests allow interrogation of the fundamental pathophysiological processes that have been identified to be involved in the understanding of the complex etiology of CVD. Many potential insults to the cardiovascular system have been identified, but only three finite physiological vascular responses to these insults result in disturbance of cardiovascular function that is associated with CVD. These three finite vascular responses are inflammation, oxidative stress, and vascular immune dysfunction.

Functional cardiology assessment has advanced because of multiple discoveries in radiology, bioinformatics, and physiology. Functional assessment using fractional flow reserve (FFR) and quantitative flow reserve has found application in coronary stenosis.¹⁰ It has also been applied to evaluation of microvascular function related to CVD and patients with nonobstructive CHD.¹¹,¹² New developments in the assessment of vascular function provide an accurate determination for the risk of atrial fibrillation and its prevention.¹³ Functional cardiovascular assessment is now applied to evaluating outcomes in patients with transcatheter aortic valve replacement.¹⁴ Evaluation of cardiovascular function has been used to determine the efficacy and safety of new cardiovascular medications as well as performing comparator studies on differing cardiovascular therapies.¹⁵,¹⁶ As a consequence of progress made in functional MRI, better understanding of the unique cardiovascular pathology of the patient has been achieved allowing for greater therapeutic precision.¹⁷,¹⁸,¹⁹,²⁰