Cardiometabolic Disease

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

Cardiometabolic Medicine

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).

NAFLD

NAFLD is a chronic condition characterized by fat accumulation and/or inflammation in the liver¹⁵ encompassing a spectrum of disease stages from simple hepatic steatosis, also known as nonalcoholic fatty liver (NAFL), to nonalcoholic steatohepatitis (NASH).

The pathogenesis of NAFLD  begins with insulin resistance and excessive fatty acids in the circulation leading to simple hepatic steatosis.³² Insulin resistance promotes progression to NASH, and then other mechanisms such as oxidative stress, lipid peroxidation, and mitochondrial dysfunction promote progression to NAFLD.

Notably, a recent study reported that fasting intact insulin levels were higher in patients with NAFLD, irrespective of diabetes status (T2DM or no T2DM).³³ Obesity, a risk factor for insulin resistance and dyslipidemia, is a major risk factor for the development of NAFLD, and NAFLD is considered a phenotype of cardiometabolic syndrome.¹⁵

NAFLD is associated with

• The development of fibrosis, and eventually progression to cirrhosis, and potentially hepatocellular carcinoma (HCC)²⁹
• T2DM (as the manifestation of hepatic insulin resistance), CVD, and increased cardiovascular and liver-related mortalty³

Lifestyle modification and management of T2DM are the cornerstones of treatment for NAFLD.¹⁵ However, studies are examining the use of medications such as pioglitazone and glucagon-like peptide-1 receptor agonists (GLP-1RAs) for the treatment of NAFLD, which have been shown to reduce the high cardiovascular risk and improve liver histology.³⁴

Cardiometabolic Disease in the Older Person

The prevalence of CVD increases with age, and in the United States the prevalence of CVD is around²⁸

• 54% for persons 40 to 59 years of age
• 78% for persons 60 to 79 years of age
• 90% for persons >80 years old

Unique considerations for the diagnosis and management of cardiometabolic disease in older persons include age-related factors such as increased oxidative stress, inflammation, apoptosis, and overall myocardial deterioration and degeneration.²⁸

Newly recognized age-related cardiovascular risk factors include frailty and sarcopenia.²⁸ Other age-related unhealthy behaviors such as inactivity, malnutrition, and poor sleeping patterns are also factors associated with CVD.²⁸

New predictive tools such as relative hand grip strength have been shown to be significantly associated with factors associated with decreased cardiometabolic risk such as lower blood pressure, favorable lipid profile, and normal fasting glucose.²⁸

How the Laboratory Can Help

Quest offers testing for diagnosis and management of conditions that impact cardiometabolic health so that healthcare professionals can obtain a complete picture of a patient’s cardiometabolic health and institute early interventions that may improve outcomes. Test offerings include assessment of

• Metabolic risk
• Diabetes risk
• Cardiovascular risk
• Liver function
• Kidney function

Additional information is available on the Quest website.

References

1. Schmidt AM. Diabetes mellitus and cardiovascular disease. Arterioscler Thromb Vasc Biol. 2019;39(4):558-568. doi:10.1161/ATVBAHA.119.310961

2. Jankowski J, Floege J, Fliser D, et al. Cardiovascular disease in chronic kidney disease: pathophysiological insights and therapeutic options. Circulation. 2021;143(11):1157-1172. doi:10.1161/CIRCULATIONAHA.120.050686

3. Bedogni G, Gastaldelli A, Foschi FG. Fatty liver, cardiometabolic disease and mortality. Curr Opin Lipidol. 2020;31(1):27-31. doi:10.1097/MOL.0000000000000652

4. Kiapidou S, Liava C, Kalogirou M, et al. Chronic kidney disease in patients with non-alcoholic fatty liver disease: what the hepatologist should know? Ann Hepatol. 2020;19(2):134-144. doi:10.1016/j.aohep.2019.07.013

5. Cardiovascular diseases. World Health Organization. Accessed August 8, 2021. https://www.who.int/health-topics/cardiovascular-diseases#tab=tab_1

6. Mechanick JI, Farkouh ME, Newman JD, et al. Cardiometabolic-based chronic disease, adiposity and dysglycemia drivers: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020;75(5):525-538. doi:10.1016/j.jacc.2019.11.044

7. Mitra S, De A, Chowdhury A. Epidemiology of non-alcoholic and alcoholic fatty liver diseases. Transl Gastroenterol Hepatol. 2020;5:16. doi:10.21037/tgh.2019.09.08

8. Peters SA, Huxley RR, Woodward M. Diabetes as risk factor for incident coronary heart disease in women compared with men: a systematic review and meta-analysis of 64 cohorts including 858,507 individuals and 28,203 coronary events. Diabetologia. 2014;57(8):1542-1551. doi:10.1007/s00125-014-3260-6

9. Portillo-Sanchez P, Bril F, Maximos M, et al. High prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and normal plasma aminotransferase levels. J Clin Endocrinol Metab. 2015;100(6):2231-2238. doi:10.1210/jc.2015-1966

10. Pavkov ME, Collins AJ, Coresh J, et al. Kidney disease in diabetes. In: Cowie CC, Casagrande SS, Menke A, et al, eds. Diabetes in America. 3rd ed. National Institute of Diabetes and Digestive and Kidney Diseases (US); 2018. Accessed July 31, 2021. https://www.ncbi.nlm.nih.gov/books/NBK568002/

11. Johansen KL, Chertow GM, Foley RN, et al. US Renal Data System 2020 annual data report: epidemiology of kidney disease in the United States. Am J Kidney Dis. 2021;77(4) (suppl 1):A7-A8. doi:10.1053/j.ajkd.2021.01.002

12. Mechanick JI, Farkouh ME, Newman JD, et al. Cardiometabolic-based chronic disease, addressing knowledge and clinical practice gaps: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020;75(5):539-555. doi:10.1016/j.jacc.2019.11.046

13. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001;285(19):2486-2497. doi:10.1001/jama.285.19.2486.

14. Alberti KG, Zimmet P, Shaw J, et al. The metabolic syndrome—a new worldwide definition. Lancet. 2005;366(9491):1059-1062. doi:10.1016/S0140-6736(05)67402-8

15. Lim S, Taskinen MR, Borén J. Crosstalk between nonalcoholic fatty liver disease and cardiometabolic syndrome. Obes Rev. 2019;20(4):599-611. doi:10.1111/obr.12820

16. Sattar N, Welsh P, Preiss D. The insulin resistance syndrome. In: International Textbook of Diabetes Mellitus. 4th ed. Wiley-Blackwell; 2015:337-353. doi:10.1002/9781118387658.ch23

17. Priest C, Tontonoz P. Inter-organ cross-talk in metabolic syndrome. Nat Metab. 2019;1(12):1177-1188. doi:10.1038/s42255-019-0145-5

18. Ronco C, Bellasi A, Di Lullo L. Cardiorenal syndrome: an overview. Adv Chronic Kidney Dis. 2018;25(5):382-390. doi:10.1053/j.ackd.2018.08.004

19. Oishi Y, Manabe I. Organ system crosstalk in cardiometabolic disease in the age of multimorbidity. Front Cardiovasc Med. 2020;7:64. doi:10.3389/fcvm.2020.00064

20. Gerdts E, Regitz-Zagrosek V. Sex differences in cardiometabolic disorders. Nat Med. 2019;25(11):1657-1666. doi:10.1038/s41591-019-0643-8

21. Lechner K, von Schacky C, McKenzie AL, et al. Lifestyle factors and high-risk atherosclerosis: pathways and mechanisms beyond traditional risk factors. Eur J Prev Cardiol. 2020;27(4):394-406. doi:10.1177/2047487319869400

22. Wu JHY, Micha R, Mozaffarian D. Dietary fats and cardiometabolic disease: mechanisms and effects on risk factors and outcomes. Nat Rev Cardiol. 2019;16(10):581-601. doi:10.1038/s41569-019-0206-1

23. Attaye I, Pinto-Sietsma SJ, Herrema H, et al. A crucial role for diet in the relationship between gut microbiota and cardiometabolic disease. Annu Rev Med. 2020;71:149-161. doi:10.1146/annurev-med-062218-023720

24. Lee SJ, Oh BK, Sung KC. Uric acid and cardiometabolic diseases. Clin Hypertens. 2020;26:13. doi:10.1186/s40885-020-00146-y

25. Saxon DR, Reiter-Brennan C, Blaha MJ, et al. Cardiometabolic medicine: development of a new subspecialty. J Clin Endocrinol Metab. 2020;105(7):2095-2104. doi:10.1210/clinem/dgaa261

26. Reiter-Brennan C, Cainzos-Achirica M, Soroosh G, et al. Cardiometabolic medicine - the US perspective on a new subspecialty. Cardiovasc Endocrinol Metab. 2020;9(3):70-80. doi:10.1097/XCE.0000000000000224

27. Reiter-Brennan C, Dzaye O, Davis D, et al. Comprehensive care models for cardiometabolic disease. Curr Cardiol Rep. 2021;23(3):22. doi:10.1007/s11886-021-01450-1

28. Sinclair AJ, Abdelhafiz AH. Cardiometabolic disease in the older person: prediction and prevention for the generalist physician. Cardiovasc Endocrinol Metab. 2020;9(3):90-95. doi:10.1097/XCE.0000000000000193

29. Ruissen MM, Mak AL, Beuers U, et al. Non-alcoholic fatty liver disease: a multidisciplinary approach towards a cardiometabolic liver disease. Eur J Endocrinol. 2020;183(3):R57-R73. doi:10.1530/EJE-20-0065

30. Sattar N, Gill JMR, Alazawi W. Improving prevention strategies for cardiometabolic disease. Nat Med. 2020;26(3):320-325. doi:10.1038/s41591-020-0786-7

31. Wong ND. Preventive cardiology or cardiometabolic medicine: a new and emerging subspecialty? Cardiovasc Endocrinol Metab. 2020;9(3):66-69. doi:10.1097/XCE.0000000000000206

32. Kitade H, Chen G, Ni Y, et al. Nonalcoholic fatty liver disease and insulin resistance: new insights and potential new treatments. Nutrients. 2017;9(4):387. doi:10.3390/nu9040387

33. Bril F, McPhaul MJ,  Kalavalapalli S, et al. Intact fasting insulin identifies nonalcoholic fatty liver disease in patients without diabetes. J Clin Endocrinol Metab. 2021:dgab417. doi: 10.1210/clinem/dgab417

34. Budd J, Cusi K. Role of agents for the treatment of diabetes in the management of nonalcoholic fatty liver disease. Curr Diab Rep. 2020;20(11):59. doi:10.1007/s11892-020-01349-1

Models used for illustrative purposes only.

Published date: Sep 2021