The Cardiometabolic Syndrome and Cardiovascular Disease
Linda R. Peterson, MD, Washington University School of Medicine, Campus Box 8086, 660 South Euclid Avenue, St. Louis, MO 63110
The cardiometabolic syndrome is a prevalent metabolic disorder. Epidemiologic studies correlate the cardiometabolic syndrome with an increased risk of coronary heart disease, ischemic stroke, cardiovascular mortality, and total mortality. There is also evidence that the cardiometabolic syndrome is a risk factor for abnormalities in myocardial metabolism, cardiac dysfunction, and arrhythmias such as atrial fibrillation. Multiple imaging modalities, both invasive and noninvasive, may help physicians better define the presence or risk of cardiovascular disease in their patients with the cardiometabolic syndrome.
The cardiometabolic syndrome (CMS) has been defined in slightly different ways by various consensus panels.1 While there is controversy over the exact definition of CMS, for the purposes of this article the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines for the definition of the metabolic syndrome will be used. CMS is thus defined as having three or more of the following conditions: low levels of high-density lipoprotein, high blood pressure, increased waist circumference, high triglyceride levels, and elevated fasting glucose.2
The prevalence of CMS varies depending on the population, gender, age, and race studied, as well as the definition of CMS used. Most experts point to a recent increase in obesity worldwide, which has likely contributed to the global epidemic of CMS.3 Prevalence figures among adults range from 7% in France and 9% in China to 24% in the United States and 43% in Iranian women.4–6 Moreover, the number of cases of CMS is expected to rise along with the rise in the number of patients with obesity and/or type 2 diabetes.3
Data from large epidemiologic trials suggest that patients with CMS have a 1.5 to 3-fold risk of cardiovascular disease (CVD) morbidity compared with normal controls.7,8 CVD mortality and total mortality are also increased in people with CMS, according to a 2004 study from the Second National Health and Nutrition Examination Survey (NHANES II) in the United States, in which 6225 subjects were followed over an average of 13.3 years.9 The age-, gender-, and risk factor-adjusted hazard ratios in patients with CMS (but without preexisting CVD) for coronary heart disease mortality, CVD mortality, and total mortality were 2.02, 1.82, and 1.4, respectively. In those with CMS and preexisting CVD, the hazard ratios were even higher: 4.19, 3.14, and 1.87, respectively.9 Studies from other countries have also demonstrated greater risks for total mortality and mortality from either coronary heart disease or CVD in patients with CMS.5,10
The relative contribution of the individual components of CMS to coronary and CVD mortality has also been examined. There are data showing that patients with just one or two components of the CMS had a higher risk of coronary heart and CVD mortality than normal controls.9 The same study showed that patients with diabetes and CMS had a higher risk of coronary, CVD, and total mortality than those with CMS but without diabetes.9 In the NHANES III study, the rare patients with diabetes but without CMS had a risk of CVD like that of subjects without either condition.8 Furthermore, the San Antonio Heart Study showed that presence of CMS was more predictive of CVD mortality in women than in men.11
CMS and Stroke
In one study of more than 14,000 patients, a significant relationship between CMS and acute ischemic stroke or transient ischemic attack (TIA) was established; patients with CMS (but not diabetes) exhibited a 1.49-fold increased risk compared with patients without CMS.12 Diabetes, by itself, was associated with an even higher risk of stroke or TIA (2.29 times normal controls). As is the case with CMS and CVD, CMS in women was associated with a much higher risk of acute ischemic stroke and TIA compared with men.12 Moreover, the difference in risk of acute ischemic stroke or TIA between men and women appeared greater with each additional component of CMS that a patient had. For example, men with all five components of CMS had an age-adjusted rate of approximately 10 per 100 person-years, but the rate for women was approximately 20 per 100 person-years.
CMS and Vascular Imaging
Angiography and Ultrasound. The results of vascular imaging studies regarding the association between CMS and the progression of vascular disease have been somewhat mixed, but the majority of studies appear to show a detrimental effect from CMS.
In the secondary prevention Estrogen Replacement and Atherosclerosis trial,13 women with diabetes had significant progression of atherosclerosis, quantified using angiography, compared with women without diabetes. The presence of CMS without diabetes, however, was not associated with an increased risk of atherosclerosis progression. In contrast, in another angiographic study, CMS was associated with a detrimental effect on the patency of saphenous vein grafts early in the postbypass period.14 There are also several recent studies that demonstrate that CMS is associated with increased carotid intimal-medial thickness.15,16 As in coronary artery disease, CMS appears to be a stronger risk factor for carotid atherosclerosis in women than it is in men.15 In another study, CMS appeared to have an independent detrimental effect on carotid intimal-medial thickness and stiffness, even after accounting for the individual components of CMS; thus, it appeared that CMS CVD risk factors had a synergistic, deleterious effect on the vasculature.17
Electron Beam Computed Tomography. Studies using a newer form of noninvasive vascular imaging, electron beam computed tomography, have also shown an association between CMS and coronary artery calcification score. Of the 1000 patients in one such study, 24.7% of those with CMS had a positive coronary artery calcification score (scans with at least four contiguous pixels with ≥130 Hounsfield units were considered positive), compared with only 16.5% of those without CMS.18 In another study of patients with diabetes, a multivariate analysis showed that there were independent relationships among systolic blood pressure, male gender, and statin use and coronary calcium score, supporting the link between CMS and atherosclerosis.
Endothelial Function Studies. As with electron beam computed tomography, endothelial function imaging studies demonstrate the detrimental effects of CMS on the vascular tree, which may be detected before clinical evidence of vascular disease is found. In endothelial function imaging studies, a stimulus (e.g., shear stress from hyperemic flow, or acetylcholine infusion) is made upon the endothelium, and it responds by producing NO, a known vasodilator. The amount of vasodilation is then measured through direct imaging, usually by angiographic or ultrasound techniques, or by measuring blood flow amounts using strain-rate plethysmography. Many of the individual components of CMS—hypertension, diabetes, hyperlipidemia, and obesity—have been associated with endothelial dysfunction, and CMS itself has also been associated with endothelial dysfunction.19–21 However, one study of 60-year-old men did not demonstrate a significant relationship between endothelial dysfunction and CMS. The relatively low endothelial function in the normal controls at this increased age, and the low number of patients with CMS, may have contributed to the lack of a statistical difference in this study.22
CMS and Heart Failure
Many of the components of the CMS are known risk factors for the development of nonischemic heart failure. Diabetes, insulin resistance, obesity, and hypertension, in particular, are known to be risk factors for the development of increased left ventricular mass and diastolic and systolic dysfunction.23–28 It is thought that insulin resistance can precede and contribute to heart failure.29,30 Excessive calorie intake, one of the most important features leading to CMS, may contribute to insulin resistance and cardiac dysfunction through a variety of mechanisms, including a process that has been demonstrated in animal models known as “lipotoxicity.” In lipotoxicity, excessive fatty acid accumulation in the heart and other nonadipose tissues over time leads to apoptosis, or programmed cell death.31 Free radical production also may contribute to insulin resistance-related cardiac dysfunction.32 Conversely, heart failure may precede and contribute to insulin resistance due to increased sympathetic output, loss of skeletal muscle mass, and/or increased cytokine production.33
Regardless of whether insulin resistance is an antecedent or consequence of heart failure, its presence has important implications for the metabolism of substrates and, hence, for the generation of energy for contractile function of the heart. For example, in young women with abdominal obesity, insulin resistance was an independent predictor of increased myocardial fatty acid uptake, utilization, and oxidation as quantified using positron emission tomography.34 Myocardial oxygen consumption increased and efficiency decreased (a hallmark of heart failure) as obesity increased.34 Other evidence from humans that supports the theory that insulin resistance and its attendant increase in free fatty acids are detrimental to the heart include magnetic resonance spectroscopy data correlating increasing obesity with triglyceride accumulation in human myocardium; this increased triglyceride was related to impaired cardiac contractility.35 In addition, patients with type 2 diabetes, who often have CMS, also appear to have detrimentally altered energy production, manifested by decreased adenosine triphosphate production.36 These data all fit with the hypothesis that excessive fatty acid delivery to the myocardium may contribute to decreased function exclusive of coronary artery disease. There are other studies in humans that do not support this hypothesis, possibly due to differences in patient population, study numbers, radiolabeled tracers, and kinetic modeling.37,38 Nevertheless, the general notion that altered myocardial metabolism may contribute to cardiac dysfunction in patients with heart failure and CMS (or one or more of its components) is gaining wider acceptance, and provides a novel paradigm for designing new metabolic treatments for cardiac failure associated with CMS.29,39–41
CMS and Electrophysiology
Atrial Flutter and Fibrillation. Although CMS itself has not been extensively linked to cardiac arrhythmias, many of its components have been linked to supraventricular arrhythmias. Atrial fibrillation or flutter, in particular, has been associated with obesity in two recent, large trials.42,43 In the Danish Diet, Cancer, and Health Study,42 the adjusted hazard ratio for atrial fibrillation or flutter increased 1.08 in men and 1.06 in women per unit of increase in body mass index. Interestingly, in one study, patients with the risk factors hypertension and diabetes had a significantly higher age- and body mass index-adjusted risk of atrial fibrillation, but each risk factor was not independently associated with a higher risk.44
Sudden Cardiac Death. Although there is limited information linking CMS with ventricular arrhythmias, they are a known cause of sudden death, and some components of CMS—hypertension (with related left ventricular hypertrophy) and obesity—have been associated with sudden cardiac death.45 There are also biomarkers of sudden cardiac death that are common among patients with CMS. Among the best markers of increased sudden death risk in hypertension is left ventricular hypertrophy, which can be measured using standard two-dimensional echocardiographic imaging.46 Concentric remodeling and frank hypertrophy are also common complications of obesity, diabetes, and CMS.25,47 Another biomarker that has been correlated with an increased risk of sudden death and that is common in patients with diabetes, hypertension, and CMS is low heart rate variability.48–51 Heart rate variability is a noninvasive parameter for studying the autonomic function of the heart. Small changes in the interval between normal heartbeats are mediated by both the parasympathetic and sympathetic systems. A low heart rate variability, suggesting decreased autonomic control of the heart, may contribute to the increased risk of sudden death. Given the associations between CMS or its components and known markers of sudden cardiac death, it follows that CMS may also be linked with an increased risk of sudden death.
There is no universally agreed upon treatment regimen for the prevention of CVD in patients with CMS, and the vast array of possible therapeutic options is beyond the scope of this review; however, most experts generally recommend diet and exercise for patients with CMS who are overweight (body mass index >25 kg/m2) or obese (body mass index >30 kg/m2). Also, treatment aimed at tight control of the individual CMS components, which are accepted CVD risk factors (hypertension, diabetes, and low levels of high-density lipoprotein) for the prevention of CVD is generally accepted.
CMS is a prevalent metabolic disorder that is associated with an increased risk of coronary, CVD, and all-cause mortality. Vascular imaging techniques may be used to highlight the diverse and adverse impact of CMS on the cardiovascular tree. Cardiac imaging may also be used to demonstrate the detrimental effect of CMS on myocardial metabolism, structure, and function. CMS is also associated with arrhythmias such as atrial fibrillation. Given the current epidemic of CMS and its attendant CVD morbidity and mortality, it is imperative that we improve our understanding of the mechanisms involved in the development of CVD complications of CMS to combat this global problem.
Acknowledgments: We thank Kristin O'Callaghan and Sharon Cresci, MD, for their expert editorial assistance.