Cardiovascular consequences of metabolic syndrome

The metabolic syndrome (MetS) is defined as the concurrence of obesity-associated cardiovascular risk factors including abdominal obesity, impaired glucose tolerance, hypertriglyceridemia, decreased HDL cholesterol, and/or hypertension. Earlier conceptualizations of the MetS focused on insulin resistance as a core feature, and it is clearly coincident with the above list of features. Each component of the MetS is an independent risk factor for cardiovascular disease and the combination of these risk factors elevates rates and severity of cardiovascular disease, related to a spectrum of cardiovascular conditions including microvascular dysfunction, coronary atherosclerosis and calcification, cardiac dysfunction, myocardial infarction, and heart failure. While advances in understanding the etiology and consequences of this complex disorder have been made, the underlying pathophysiological mechanisms remain incompletely understood, and it is unclear how these concurrent risk factors conspire to produce the variety of obesity-associated adverse cardiovascular diseases. In this review, we highlight current knowledge regarding the pathophysiological consequences of obesity and the MetS on cardiovascular function and disease, including considerations of potential physiological and molecular mechanisms that may contribute to these adverse outcomes.

Introduction

The association between visceral obesity, hypertension, and atherosclerosis was recognized as early as 1765 by Joannes Baptista Morgagni in his seminal work entitled “De sedibus et causis morborum per anatomen indagata.”¹ Later studies by Hitzenberger, Richter-Quitner, and Kylin in the early 1920s further documented the coincident relationships between metabolic abnormalities such as hyperglycemia, hypertension, and other maladies such as hyperuricemia.² These pioneering efforts laid the groundwork for what is now commonly referred to as the “Metabolic Syndrome” (MetS), a clustering of interrelated and coincident risk factors which include abdominal obesity, impaired glucose tolerance, hypertriglyceridemia, diminished high-density lipoprotein (HDL) cholesterol, and/or hypertension.³ The original conceptualization of this syndrome focused on a central role of insulin resistance³ and this is clearly a concurrent and associated feature. More recently, the focus has been on the MetS as an epidemiologic tool related to cardiovascular disease risk, and therefore traditional cardiovascular disease risk factors have been adopted as the defining features. Although the precise definition of what clinically constitutes the MetS has generated considerable debate, it is well accepted that these comorbidities represent a pathologic state that substantially augments risk for the development of type 2 diabetes mellitus and atherosclerotic cardiovascular disease.⁴

As of 2014, the Centers for Disease Control and Prevention estimates that ∼70% of adults in the United States are overweight or obese, with ∼40% of these individuals considered obese (defined as body mass index ≥30 kg/m²). The National Health and Nutritional Examination Survey (NHANES) estimates that ∼30% of overweight and ∼60% of obese men and women meet the criteria for a diagnosis of MetS⁵; in other words, most obese people carry the concurrent risk features that identify them as carrying augmented risk of cardiovascular disease. Therefore, in parallel with the obesity epidemic, the MetS is a growing epidemic, affecting ∼20% of adults in the Western world.⁶ Each component of the MetS is an independent risk factor for cardiovascular disease,4, 6 together producing a wide spectrum of vascular and cardiac diseases.7, 8, 9, 10, 11, 12, 13 While some advances in understanding the etiology and consequences of this complex disorder have been made, the underlying mechanisms that translate these obesity-associated risk factors into the full spectrum of observed cardiovascular pathologies remain insufficiently explained. The purpose of this review is to highlight the current knowledge regarding the pathophysiological consequences of obesity and the MetS and to outline the recent advances in potential mechanisms that may contribute to these adverse cardiovascular outcomes. The literature linking type 2 diabetes with cardiovascular outcomes will not be reviewed in detail, because type 2 diabetes exerts effects on cardiovascular disease distinct from those of the underlying obesity and MetS and this would detract from our focus on obesity/MetS. Previous reviews by Abel et al,¹⁴ Poirier et al,¹⁵ Jiamspripong et al,¹⁶ Mottillo et al,¹⁷ Bastien et al,¹⁸ and Grundy et al4, 11, 19 have summarized the current epidemiology or evaluated specific cardiac conditions in the connection between obesity/MetS and cardiovascular disease. Here we focus on physiological and pathophysiological aspects of obesity- and MetS-associated changes in hemodynamics, microvascular dysfunction, myocardial metabolism, atherosclerosis and calcification, and infarction and heart failure.