Cardiometabolic disease describes the interplay between risk factors for interrelated disorders that affect cardiovascular and metabolic health. For example, atherosclerosis, type 2 diabetes mellitus (T2DM), nonalchoholic fatty liver disease (NAFLD), and chronic kidney disease (CKD) are not distinct; they share common triggers and risk factors driving their progression.1-4 Patients presenting with 1 of these disorders may be at risk for, or already have, 1 or more of the other interrelated disorders.
This article will discuss how the interplay of various bodily systems affects the risk and development of cardiometabolic diseases. It will also discuss new paradigms of management and how the laboratory can help identify patients with, or at risk of, one or more cardiometabolic disorders.
Cardiometabolic Disease and Metabolic Syndrome
Cardiovascular disease (CVD; eg, coronary heart disease, cerebrovascular disease, peripheral arterial disease) is the leading cause of death globally.5 Decreases in overall CVD mortality rates have been associated with effective primary prevention strategies, such as lifestyle modification and the use of cholesterol-lowering drugs, such as statins.6 Subsequent increases in CVD-related deaths reflect population growth, aging, and most importantly marked increases in the rates of obesity and T2DM.6 CVD is the leading cause of death for individuals who have T2DM,1 stage 4-5 CKD,2 and NAFLD.7 These cardiometabolic conditions are strongly associated. For example
- Persons with T2DM have a risk of fatal coronary heart disease: relative risk 2.04 (95% confidence interval [CI], 1.72-2.43) for men, 2.93 (95% CI, 2.25-3.54) for women.8
- More than 75% of persons with T2DM have NAFLD.9
- Nearly 40% of persons who have diabetes and more than 30% of those who have hypertension also have CKD.10
- The leading causes of end-stage renal disease (ESRD) are diabetes and hypertension.11
Because of the strong associations of cardiometabolic disorders, detection of these conditions in their early stages provides the opportunity for stage-targeted intervention and the potential for improved clinical outcomes.6,12
A common factor that persons with cardiometabolic disorders may share is the presence of metabolic syndrome.
- The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III) (NCEP ATP III) defined metabolic syndrome as the presence of 3 or more of the following 5 criteria: waist circumference over 40 inches (men) or 35 inches (women), blood pressure >130/85 mm Hg, fasting triglyceride (TG) level >150 mg/dL, fasting high-density lipoprotein (HDL) cholesterol level <40 mg/dL (men) or 50 mg/dL (women), and fasting blood glucose >100 mg/dL.13
- International Diabetes Foundation (IDF) criteria for metabolic syndrome, published in 2005, and includes the same general criteria as above; these criteria require the presence of obesity, but not necessarily insulin resistance.14
- Because of the close relation between cardiometabolic disorders and metabolic syndrome, metabolic syndrome has been described as “cardiometabolic syndrome.”15
Notably, the keystone of metabolic syndrome in the majority of individuals is insulin resistance.16 The combination of insulin resistance and compensatory hyperinsulinemia can result in a syndrome defined by a cluster of abnormalities including obesity, hypertension, dyslipidemia, T2DM, and CVD such as atherosclerotic heart disease.16
Organ Crosstalk and Multimorbidity
In the context of cardiometabolic disease, organ crosstalk is a bodily response to changes, such as increased or decreased metabolic demand.17 However, dysregulation of crosstalk and communication between different bodily systems contributes cardiometabolic disorders.17 Examples are presented below.
Liver Crosstalk With Multiple Organ Systems
- The liver metabolizes fatty acids released by adipose tissue during fasting and those consumed during a meal.3
- Accumulation of excess lipids in the liver triggers the production and release of hepatokines (eg, small molecules, peptides, lipids, and hormones).17
- Hepatokines have diverse effects on target organs such as the gut, muscle, pancreas, and the central nervous system (CNS), as well as adipose tissue. They can help maintain energy homeostasis, but their dysregulation is associated with conditions such as T2DM.17
- Altered levels of hepatokines in fatty livers (see Sidebar) affect metabolism in the whole body and is a mechanism linking liver disease such as NAFLD with metabolic syndrome and CVD.17
Kidney Crosstalk With Multiple Organ Systems
- Cardiorenal syndrome can generally be defined as a pathophysiological disorder of the heart and kidneys, in which acute or chronic dysfunction of 1 organ may induce acute or chronic dysfunction to the other.18
- Heart failure broadly impacts various organs and systems, including the kidney, liver, lung, and nervous system.19
- Conversely, systemic dysregulation of metabolism, immunity, and nervous system activity greatly affects heart failure development and prognosis.19
Organ crosstalk is particularly important for patients with multimorbidity; the coexistence of 2 or more chronic conditions such as CVD and renal disease, as well as mental health conditions such as dementia or mood disorder.19 Notably, approximately 75% of persons 65 years of age and older have multimorbidity (see Sidebar).19 Components of metabolic syndrome (eg, insulin resistance, dyslipidemia, central obesity, hypertension) synergistically increase the risks for multimorbidity including coronary artery disease, T2DM, heart failure, and some cancers.19
Nontraditional Determinants of Cardiometabolic Health
Some nontraditional and emerging risk factors that reflect organ crosstalk are shown below:
- Sex hormones, sex-specific molecular mechanisms, and sex have a marked influence on glucose and lipid metabolism and cardiac energy metabolism and function, suggesting that methods to determine cardiometabolic health may need to be specific for males and females.20 Differences are reflected in the prevalence of cardiometabolic disorders such as heart failure and ischemic heart disease, which vary between sexes.20
- Chronic exposure to environmental stressors such as poor diet quality, a sedentary lifestyle, ambient air pollution and noise, sleep deprivation, and psychosocial stress affect a large number of traditional and nontraditional factors related to atherosclerotic cardiovascular disease (ASCVD).21 These include body composition, cardiorespiratory fitness, muscle strength and functionality, and the intestinal microbiome.21-23
- Hyperuricemia, a cause of gout and nephrolithiasis, may be an independent predictor of hypertension, coronary heart disease, heart failure, insulin resistance, and NAFLD.24 Mechanisms by which uric acid causes cardiometabolic disease are not clear but may include oxidative stress, reduced nitric oxide bioavailability, inflammation, and endothelial dysfunction.24
Notably, a low-risk lifestyle may impact plaque vulnerability and alter adipose tissue and skeletal muscle phenotype.24 Low-risk lifestyle factors cause a set of phenotypic adaptations that shift crosstalk from a pro-inflammatory state associated with high-risk for atherosclerosis to a relative anti-inflammatory state associated with low-risk for atherosclerosis.21
Cardiometabolic Disease Model
In one approach to address cardiometabolic disease, a model was developed to promote cardiometabolic health and mitigate the development of CVD by providing a basis for early, sustainable, evidence-based therapeutic targeting.6
Included in the model are the interactions and common pathologies of insulin resistance, T2DM, obesity, and CVD.6 The model is based on genetic, environmental, and behavioral factors, and adiposity and dysglycemia associated with insulin resistance.6 Interventions target these complex interactions and metabolic pathways associated with cardiometabolic disease in order to prevent later stage disease.6,12
Role of Testing
A comprehensive assessment of risk factors associated with cardiometabolic disease is crucial for establishing disease risk, diagnosis, and management. Evidence suggests that identification of disease risk, early diagnosis, and intervention can delay or prevent disease progression.25-29 Laboratory testing is the keystone for the screening, diagnosis, and management of cardiometabolic disease. Many experts are suggesting that broader laboratory screening and testing is needed to identify cardiometabolic disorders earlier and potentially improve outcomes (see next section).12,25,27,30
The increasing prevalence of cardiometabolic disease has placed stress on healthcare systems. The current “siloed care model” may complicate care coordination for patients with cardiometabolic disease who are receiving care from multiple specialists, resulting in overall insufficient treatment, higher costs, and poorer outcomes.25
Cardiometabolic patients require the care of specialists in a wide range of specialties such as cardiology, endocrinology, primary care, nutrition, podiatry, neurology, nephrology, hepatology, pediatrics, and family medicine. Dedicated cardiometabolic clinics, with health professionals trained across relevant disciplines, have been proposed as one approach to provide prevention-focused treatment to patients at risk for, or with established, cardiometabolic disease.27
Greater resources are required from the healthcare sector to support this multidisciplinary training and establish centers of excellence in cardiometabolic medicine.31 However, screening tools, based in part on test results,12,25,27,30 are already in place to help patients and their healthcare providers assess cardiometabolic health (see Sidebar for information about Quest Diagnostics test offerings that use these tools).