Abstract and Case Studies
Abstract
Cardiometabolic syndrome (CMS) is a clustering of interrelated risk factors that promote the development of atherosclerotic vascular disease and type 2 diabetes mellitus. These interrelated risk factors have a direct effect on atherogenic dyslipidemia, elevated blood pressure, and elevated plasma glucose, and promote proinflammatory and prothrombic states. Mechanisms of the major underlying forces of CMS—abdominal obesity and insulin resistance—are discussed and include review of obesity-induced inflammation with the development of abdominal obesity. Two clinical case studies are presented for primary and secondary cardiovascular disease patients with discussion of clinical management based on guideline recommendations.
Case Studies
Case Study 1. A 52-year-old female with dyslipidemia and a family history of premature coronary artery disease (CAD) and type 2 diabetes mellitus (DM; mother is diabetic with CABG at 56 and PCI/stent at 70). She denies cigarette smoking, exercises only occasionally, and does not pay attention to her diet. She does not take prescription medications. Her blood pressure is 142/78 mmHg, body mass index 27, and waist circumference 38 inches. The fasting glucose level is 98 mg/dL. The total cholesterol level is 220 mg/dL, the low-density lipoprotein cholesterol (LDL-C) level is 168 mg/dL, the high-density lipoprotein cholesterol (HDL-C) level is 38 mg/dL, and the triglyceride level is 68 mg/dL.
Case Study 2. A 65-year-old male with dyslipidemia, hypertension, and a history of PCI/stent 4 years previously. There is no known family history of coronary heart disease or type 2 DM. He was a former smoker (1 pack/day; quit after PCI). He follows a low saturated fat diet but never exercises. Medications include a statin, a beta-blocker, an angiotensin-converting–enzyme inhibitor, and aspirin. His blood pressure is 146/86 mmHg, body mass index is 29, and waist circumference is 43 inches. The fasting glucose level is 99 mg/dL. The total cholesterol level is 191 mg/dL, the LDL-C level is 125 mg/d, the HDL-C level is 32 mg/dL, and the triglyceride level is 170 mg/dL.
Case study 1 represents a primary cardiovascular disease (CVD) prevention patient classified as low risk by the Framingham Risk Score (FRS),[1] with 4% risk of myocardial infarction (MI) in 10 years. By ATP III guidelines for LDL-C management,[2] her goal LDL-C is <>[2] Both patients have been identified with cardiometabolic syndrome (CMS). What strategies will reduce their risk for atherosclerotic cardiovascular disease (ASCVD) and type 2 DM?
Clinical Problem
Cardiometabolic syndrome (CMS), also known as "metabolic syndrome," "Syndrome X," and "pre-diabetes," is a clustering of interrelated risk factors that promote the development of ASCVD[3,4] and type 2 DM.[4,5,6,7] While some reports indicate that CMS is associated with a greater risk for ASCVD,[8] once type 2 DM emerges, the risk of ASCVD may further increase.[9] CMS is also a risk factor for cardiovascular events. A recent meta-analysis of almost 175,000 patients with metabolic syndrome indicates a relative risk of 2.2 and 1.9 for cardiovascular events and death, respectively.[10] Over one quarter of the U.S. population has CMS,[11,12] with abdominal obesity[13,14] and insulin resistance[15,16] as the driving forces.
Etiology of CMS
Interrelated Risk Factors
The interrelated risk factors for CMS, with a direct effect on atherosclerotic vascular disease, include atherogenic dyslipidemia, elevated blood pressure, elevated plasma glucose, and the proinflammatory and prothrombic states.[7] The lipoprotein abnormalities underlying ASCVD consist of elevated triglyceride and small, dense LDL-C particles and reduction in HDL-C. Both triglyceride-rich lipoproteins and small, dense LDL-C particles carry the greatest risk for atherosclerosis.[3,17] HDL-C plays a protective role in atherogenesis via cytokine production, lipid oxidation, cholesterol efflux, and reverse cholesterol transport, with low levels of HDL-C identified as independently atherogenic.[3,18] Increased renin-angiotensin-aldosterone system resulting in elevated blood pressure is a metabolic abnormality associated with CMS.[19] Elevated blood pressure, a well-known risk factor for ASCVD,[20] together with atherogenic dyslipidemia, as described above, can increase risk for ASCDV, even with only mild abnormality of each component.[7] Elevated plasma glucose can result in glycosylated proteins that can induce oxidative stress and stimulate proinflammatory responses.[21]
CMS has also been associated with the presence of inflammatory markers. Finally, high circulating levels of prothrombic factors may play an important role in predisposing to prothrombic episodes, which underlie ASCVD events. Hypofibrinolysis, due to elevated plasminogen activator inhibitor-1 (PAI-1) levels, has been implicated in CMS.[22]
Abdominal Obesity and Insulin Resistance
Abdominal obesity and insulin resistance are major underlying forces in CMS. Eckel et al[23] define the link between abdominal obesity and insulin resistance (Figure 1A). Briefly, in expanded adipose tissue, free fatty acids (FFA) stimulate increased production of glucose, triglycerides, LDL-C, and VLDL-C from the liver, along with reductions in HDL-C. FFA also induce insulin resistance of skeletal muscle, inhibiting insulin-mediated glucose uptake and storage as glycogen. The resulting increase in circulating glucose and FFA stimulate pancreatic insulin secretion, which enhances sodium reabsorption and sympathetic nervous system drive, resulting in high blood pressure.
 | Figure 1. The metabolic syndrome. Eckel et al. Lancet 2005;365:1415. Used by permission. |
Figure 1.
Superimposed on this insulin resistance scheme are the proinflammatory and prothrombic states (Figure 1B). Adipose tissue adipocytes and monocyte-derived macrophages produce cytokines, including interleukin-6 (IL-6) and tumor necrosis factor (TNF) among others, which further stimulate insulin resistance as well as lypolysis of adipose tissue triglycerides. Cytokines also increase glucose and VLDL-C production by the liver and insulin resistance in the skeletal muscle. PAI-1 and plasminogen are also produced by the liver in response to cytokines and FFA, resulting in a prothrombic state. Finally, adiponectin, which plays a role as an anti-inflammatory molecule and an insulin-sensitizing agent, is reduced in expanded adipose tissue.
In reviewing the link between adipose tissue and insulin resistance, it is clear that adipose tissue plays an important role in CMS. A more in-depth view of adipose tissue in CMS (Figure 2) reveals obesity-induced infiltration by macrophages and inflammation as obesity develops.[24] With expansion of adipose tissue, adipocytes begin to secrete TNF (which stimulates production of monocyte chemoattractant protein-1[MCP-1]), and leptin (and/or decreases production of adiponectin), which contribute to macrophage accumulation in adipose tissue. The presence of macrophages in adipose tissue then perpetuates more recruitment of macrophages and inflammation. Inflammation is characterized by the overproduction of proinflammatory cytokines (IL-6, resistin TNF, and C-reactive protein [CRP]) and the deficiency of antinflammatory cytokines (adiponectin). Of the multiple substances that play a role in obesity and insulin resistance, CRP, Il-6, MCP-1, PAI-1, and TNF also play a role in atherosclerosis, also considered an inflammatory disease.[25]
 | Figure 2. Inflammation in obese adipose tissue. Wellen and Hotamisligil. J Clin Investig. 2003;112:1785-1788. Used by permission. |
Figure 2.
Genes and Environment
There is evidence for a genetic contribution to CMS from observations in twins and families.[26] In addition, single-gene human models and genetic association studies have identified multiple genes associated with the phenotypic expression of CMS. However, no genomic DNA markers have been identified and no genetic test is currently available in the diagnosis or treatment of CMS. The influence of ethnicity and sex and the interaction of genes with environmental factors (calorie excess, physical inactivity) will likely influence the phenotypic expression of CMS and complicate the genetic associations that can be made.
Clinical Diagnosis
Multiple clinical definitions for CMS have been established in an attempt to provide a list of clinical markers that can be used to identify individuals with CMS.[26] Three of these definitions include those proposed by the World Health Organization (WHO), the US National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), and the International Diabetes Foundation (IDF) (Figure 3).[1,27,28] Guidelines for all 3 include glucose/insulin abnormality, obesity/central adiposity, dyslipidemia, and hypertension. Only the WHO guideline includes microalbuminuria, while the IDF prioritizes abdominal obesity, making only individuals with increased waist circumference eligible for assessment.
 | Figure 3. Clinical definitions for CMS. |
Minimum criteria for diagnosis by the WHO is glucose intolerance/insulin resistance plus 2 other features, by NCEP ATPIII is any 3 features, and by IDF is central adiposity plus 2 other features. Of the 3, the NCEP ATPIII definition has empirical clinical value because it is more predictive in lower risk subjects and more strongly associated with incidence of DM.[6,29] However, regardless of the definition used, a diagnosis of CMS can be predictive of increased lifetime risk of cardiovascular disease.
Clinical Management of CMS in Primary and Secondary CVD Prevention Patients
Using the NCEP ATP III guidelines, both patients have CMS. In case study 1, the 52-year-old primary prevention patient with a history of dyslipidemia has 3 risk factors for CMS, including low HDL-C, hypertension, and abdominal obesity. In case study 2, the 65-year-old secondary prevention patient with dyslipidemia, hypertension, and coronary artery disease status post PCI/stent has 4 risk factors for CMS including low HDL-C, elevated triglycerides, hypertension, and abdominal obesity. In both cases, they do not have fasting blood glucose levels above 100 mg/dL, although the levels are in the upper range of normal (60-99 mg/dL).
The identification of CMS places both patients at increased risk for the development of type 2 DM, particularly in the case of the 52-year-old patient who has a family history of type 2 DM. This is important in that the identification of CMS identifies a dysmetabolic state that is predictive of diabetes.[30]
With regard to ASCVD, the identification of CMS also places the 65-year-old male with CAD at increased risk for progression of atherosclerotic vascular disease and subsequent myocardial infarction as CMS risk factors collectively accentuate progression of ASCVD and increase end points such as stroke, congestive heart failure, chronic kidney disease, and overall mortality.[31] The 52-year-old female with dyslipidemia and no known ASCVD, but a family history of ASCVD, is considered low risk by FRS. However, the FRS, which provides a short-term 10-year assessment of risk, frequently classifies women as low risk even in the presence of significant coronary artery calcium (CAC).[32] Because the addition of CMS to the FRS adds little to this 10-year risk prediction, it is prudent to apply further measures for risk stratification for this primary prevention patient.
Further Risk Stratification
There are 2 additional tests that may be useful in further assessing the ASCVD risk of the 52-year-old female with dyslipidemia and no known ASCVD, but a family history of premature ASCVD: a CAC scan and measurement of high-sensitivity (hs) CRP. CMS predicts the presence of CAC and thus, atherosclerotic vascular disease, in asymptomatic low-risk patients.[33] In addition, there is evidence that increasing CAC improves prediction of events in asymptomatic adults.[34] While guidelines from the ACC/AHA and NCEP endorse the measurement of CAC in intermediate risk patients (6%-10% FRS), it may be prudent to measure CAC in this low-risk patient (4% FRS) because of her family history of premature CAD. In addition, in a situation where the use of aspirin and statin therapy are unclear, as in this patient, a CAC scan may be helpful in reclassifying her as intermediate or high risk and thus move toward applying these therapeutic options.
In CMS, obesity-induced infiltration by macrophages and inflammation with expanded adipose tissue (obesity) results in overproduction of proinflammatory cytokines, including CRP. CRP is also a sensitive measure of subclinical atherosclerosis[35] and a simple way to identify a proinflammatory state in clinical practice. While guidelines from the AHA/CDC support measurement of hs-CRP in intermediate-risk patients, it may also be prudent to measure hs-CRP in this patient as a further means of risk stratification for ASCVD.
Clinical Management
Many patients at risk for, or with ASCVD, present with CMS. The clustering of risk factors that define CMS promotes the development of ASCVD[3,4] and type 2 DM.[4,5,6,7] Aggressive risk reduction management in both primary and secondary CVD prevention patients cannot only reduce the risk for type 2 DM but minimize progression to ASCVD or worsening of disease and increased risk of cardiac event. In reviewing the mechanisms that underlie CMS, it is clear that management of obesity (adipose tissue expansion) to minimize insulin resistance and inflammation is of importance. Thus, the primary therapy of CMS involves lifestyle modifications that focus on weight reduction through increased physical activity, with increased calories expended, and a non-atherogenic diet, with reduced calorie intake. The therapeutic goal for weight reduction[7] is defined as reduction in body weight by 7% to 10% during one year of therapy, with an ultimate goal of a body mass index (BMI) <>2 and waist circumference <>
Physical activity contributes to cardiorespiratory fitness, which is associated with increased insulin sensitivity[36] and decreased risk for CMS.[37] The therapeutic goal for exercise[7] is defined as regular moderate-intensity physical activity at least 30 minutes 5 days/week, preferably daily. An increase in daily activity is also recommended, such as gardening and housework. Resistance training 2 days/week is also encouraged.
Diets rich in fruits, vegetables, fiber, whole grains, omega 3 fatty acids, and other unsaturated fats have been shown to reduce pro-inflammatory cytokines and increase anti-inflammatory cytokines.[38] The Mediterranean diet, shown to reduce insulin resistance and proinflammatory cytokines,[39] and a low glycemic index diet, shown to optimize HDL-C and triglycerides and reduce weight,[40] have shown to be beneficial in patients with CMS. The recommended therapeutic, non-atherogenic diet[7] includes saturated fat <>
Changes in physical activity and diet to affect weight loss and reduction in waist circumference and thus, abdominal obesity, require behavioral change that is often difficult for many patients to initiate and maintain. It is important that health care providers not only define goals for patients in these areas but discuss strategies to attain those goals. Setting specific, attainable, and forgiving goals is a first step in this process. Keeping a journal, rewarding short-term goals, and learning social or environmental cues that result in set backs are also important.[41]
Drug therapy is also used to target individual risk factors for CMS.[7] Drug therapy includes lipid-lowering drugs, antihypertensive agents, hypoglycemic drugs, antiplatelet drugs, and weight loss agents. It is recommended that the use of these drugs follow current treatment guidelines.[1,3,20,42,43,44,45] With the exception of antiplatelet drugs, the combination of drug therapy and lifestyle modifications is important in affecting change in lipids, blood pressure, glucose, and weight.
Specific Management Guidelines for Case Studies
Primary Prevention Patient
In the 52-year-old primary prevention patient identified as low risk for a cardiac event in 10 years, further risk stratification is recommended in light of her family history of premature CAD and personal history of dyslipidemia (elevated LDL-C and low HDL-C), new onset hypertension, and increased BMI/waist circumference. A coronary calcium scan and measurement of hs-CRP are recommended. Lifestyle modifications and possibly drug therapy will be initiated to minimize risk of CAD and progression to type 2 DM.
Lifestyle Modifications. Aggressive risk factor modification through lifestyle changes is the primary goal of therapy. She should be encouraged to develop a regular aerobic exercise program consisting of brisk activity for 30 minutes 5 days/week. She should also be counseled on dietary choices to maintain a low saturated fat, low cholesterol diet high in fruits, vegetables, whole grains, and fiber with reduced serving size. The combination of increased calorie expenditure and reduction in caloric intake will drive weight loss and reduction in waist circumference.
Drug Therapy. Even though patients with CMS are at increased risk of thrombosis as a result of decreased fibrinolysis via increased PAI-1, the benefits of aspirin must be weighed against the risk of bleeding, which are greater in women less than 65 years old.[46] The use of aspirin as an antiplatelet agent would be recommended if above-average levels of coronary calcium were observed and/or hs-CRP was > 3 mg/dL, moving her to a high risk category. The ACC/AHA guidelines have outlined a class Ib recommendation (Benefit ≥ Risk; additional studies/registry data would be helpful; procedure or Rx may be considered) for intermediate risk women <>[47] Thus, unless her risk status is elevated through further risk stratification, aspirin would not be prescribed for this patient.
Several studies support the use of angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARB) in the prevention of diabetes[48,49,50] and are recommended as the first choice for treating patients with CMS. The addition of an ACE-I or ARB, in addition to lifestyle modifications, would be recommended in this patient to optimize blood pressure to the JNC7 target of, 140/90.[7,20]
This patient exhibits an LDL-C above the ATPIII guidelines (130 mg/dL) for individuals with 21 risk factors.[2] While the use of a low-dose statin would be beneficial in lowering her LDL-C to goal, without further risk stratification, lifestyle modifications would be the initial focus to optimize her LDL-C. However, if upon further risk stratification, she is reclassified as intermediate or high risk, a low-dose statin, in addition to lifestyle modifications, would be recommended, given her family history of premature CAD and personal history of dyslipidemia and new-onset hypertension.
Secondary Prevention Patient
In the 65-year-old secondary prevention patient identified as high risk with known CAD and a history of dyslipidemia and hypertension, aggressive risk factor modification through lifestyle changes and optimization of drug therapy is required for minimizing progression of atherosclerotic vascular disease and progression toward type 2 DM.
Lifestyle Modifications. As with the primary prevention patient, lifestyle changes are an important part of therapy. He will also be encouraged to develop a regular aerobic exercise program and counseled on incorporating unsaturated fats, fiber, whole grains, and fruits and vegetables into his low saturated fat diet. As with the primary prevention patient, the combination of increased calorie expenditure and reduction in caloric intake will drive weight loss and reduction in waist circumference.
Drug Therapy. It is recommended that he remain on aspirin, based on the ACC/AHA class I recommendation (Benefit >>> Risk; procedure or Rx should be performed or administered) for secondary prevention patients with known CHD/ASVD. He is currently on an ACE-I and a statin, as recommended by JNC7 and NCEP ATPIII guidelines. However, his blood pressure and LDL-C are suboptimal. Modification of his antihypertensive therapy, following JNC7 guidelines, to reach optimal blood pressure, as well as titration of the statin to reach the optimal LDL-C goal of <>
Summary
Primary and secondary CVD prevention patients often present with clustering of interrelated risk factors known as CMS. These interrelated risk factors promote the development and/or progression of ASCVD as well as the development of type 2 DM. In preventive cardiovascular medicine, it is important to identify patients with CMS as a means to reduce the risk for progression of atherosclerotic disease and development of type 2 DM. While neither of the patients presented have plasma glucose levels above 100 mg/dL, failure to offset poor lifestyle habits, resulting in further weight gain, will promote CMS.
Both primary and secondary CVD patients can benefit from the development of a regular aerobic exercise program, dietary modifications, and weight loss, which are the primary therapeutic goals of CMS. In CMS, expansion of adipose tissue (abdominal obesity) drives dyslipidemia, elevated blood pressure, elevated plasma glucose, inflammation, insulin resistance, and the prothrombic state. Modifications in lifestyle that result in weight loss and reduction in waist circumference are important in minimizing this drive. Working with patients to identify CMS and optimize their lifestyle, with the possible optimization of drug therapy, can minimize disease in those individuals without ASCVD or diabetes and minimize progression of ASCVD and development of type 2 DM in those with ASCVD.
Source : http://www.medscape.com/viewarticle/583529
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