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The “New Deadly Quartet” for Cardiovascular Disease in the 21st Century: Obesity, Metabolic Syndrome, Inflammation and Climate Change: How Does Statin Therapy Fit into this Equation?

  • Statin Drugs (MB Clearfield, Section Editor)
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Abstract

Despite population-based improvements in cardiovascular risk factors, such as blood pressure, cholesterol and smoking, cardiovascular disease still remains the number-one cause of mortality in the United States. In 1989, Kaplan coined the term “Deadly Quartet” to represent a combination of risk factors that included upper body obesity, glucose intolerance, hypertriglyceridemia and hypertension [Kaplan in Arch Int Med 7:1514–1520, 1989]. In 2002, the third report of the National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP III) essentially added low HDL-C criteria and renamed this the “metabolic syndrome.” [The National Cholesterol Education Program (NCEP) in JAMA 285:2486–2497, 2001] However, often forgotten was that a pro-inflammatory state and pro-thrombotic state were also considered components of the syndrome, albeit the panel did not find enough evidence at the time to recommend routine screening for these risk factors [The National Cholesterol Education Program (NCEP) in JAMA 285:2486–2497, 2001]. Now over a decade later, it may be time to reconsider this deadly quartet by reevaluating the roles of obesity and subclinical inflammation as they relate to the metabolic syndrome. To complete this new quartet, the addition of increased exposure to elevated levels of particulate matter in the atmosphere may help elucidate why this cardiovascular pandemic continues, despite our concerted efforts. In this article, we will summarize the evidence, focusing on how statin therapy may further impact this new version of the “deadly quartet”.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Kaplan N. The deadly quartet: Upper body obesity, glucose intolerance, hypertriglyceridemia and hypertension. Arch Int Med. 1989;7:1514–20.

    Article  Google Scholar 

  2. The National Cholesterol Education Program (NCEP). Expert Panel of Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (ATP III). JAMA. 2001;285:2486–97.

    Article  Google Scholar 

  3. Young F, Capewell S, Ford E, et al. Coronary mortality declines in the US between 1980 and 2000. Quantifying the contributions from primary and secondary prevention. Am J Prev Med. 2010;39:228–34.

    Article  PubMed  Google Scholar 

  4. Koh HK. A 2020 vision for healthy people. N Engl J Med. 2010;362:1653–6.

    Article  CAS  PubMed  Google Scholar 

  5. Hoyert DL, Xu J. Deaths: Preliminary data for 2011. Natl Vital Stat Rep. 2012;61(6):1–52.

    Google Scholar 

  6. Kones R. Primary prevention of coronary heart disease: integration of new data, evolving views, revised goals and role of rosuvastatin in management. A comprehensive survey. Drug Des Dev Ther. 2011;5:325–80.

    Article  Google Scholar 

  7. Current cigarette smoking among adults –United States 2011. Morbidity and Monthly Weekly Report (MMWR) 2012;61:889–894.

    Google Scholar 

  8. Yoon SS, Burt V, Louis T, et al. Hypertension among adults in United States. National Center Health Statistics Data Brief 2012 http://www.cdc.gov/nchs/data/databriefs/db107.hm

  9. CDC. Vital signs: prevalence, treatment and control of LDL-C. (/mmwr/preview/mmwrhtml/mm6004a5.ht,?s cid = mm6004a5 w) (MMWR) 2011;60Z(4):109–114.\

  10. Goldfine AB. Statins: Is it really time to reassess benefits and risks? N Engl J Med. 2012;366(19):1752–5.

    Article  CAS  PubMed  Google Scholar 

  11. Minder CM, Blaha MJ, Horne A, et al. Evidence based use of statins for primary prevention of cardiovascular disease. Am J Med. 2012;125(5):440–6.

    Article  CAS  PubMed  Google Scholar 

  12. Rehfield P, Kopes-Kerr C, Clearfield M. The evolution or revolution of statin therapy in primary prevention: Where do we go from here? Curr Atheroslcer Rep. 2013;15:298–309.

    Article  Google Scholar 

  13. Lustig RH, Schmidt LA, Brindis CD. The toxic truth about sugar. Nature. 2012;482:27–9.

    Article  CAS  PubMed  Google Scholar 

  14. McLaughlin T, Abbasi F, Cheal A, et al. Use of metabolic markers to identify overweight individuals who are insulin resistant. Ann Intern Med. 2003;139:802–9.

    Article  PubMed  Google Scholar 

  15. Kip KE, Marroquin OC, Kelley DE, et al. Clinical importance of obesity versus metabolic syndrome in cardiovascular risk in women. A report from the Women’s Ischemia Syndrome Evalaution (WISE). Circulation. 2004;109:706–13.

    Article  PubMed  Google Scholar 

  16. Wajchenberg BL. Subcutaneous and visceral adipose their relation to the metabolic syndrome. Endocr Rev. 2000;21:697–708.

    Article  CAS  PubMed  Google Scholar 

  17. Mottillo S, Filion KB, Genest J, et al. The metabolic syndrome.

  18. Alexander CM, Landsman P, Teutsch S, et al. NCEP defined metabolic syndrome, diabetes and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes. 2003;52:1210–4.

    Article  CAS  PubMed  Google Scholar 

  19. Khan U, Wang D, Thurston R, et al. Burden of subclinical cardiovascular disease in “metabolically benign” and “at risk” overweight and obese women. The Study of Women’s Health Across the Nation (SWAN). Atherosclerosis. 2011;217:179–86.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. •• Ortega FB, Lee D, Katzmarzyk PT, et al. The intriguing metabolically healthy but obese phenotype: cardiovascular prognosis and role of fitness. Eur Heart J. 2013;34:389–99. This article showed that once fitness is accounted for, metabolically healthy but obese individuals appear to have a relatively benign condition.

    Article  PubMed  Google Scholar 

  21. Iacobellis G, Ribaudo MC, Zappaterreno A, et al. Small, dense-LDL and CRP in obese subjects with and without other criteria for the metabolic syndrome. J Clin Lipid. 2007;1:599–604.

    Article  Google Scholar 

  22. Miller M, Zhan M, Havas S. High attributable risk of elevated CRP level to conventional coronary heart disease risk factors: The Third National Health and Nutrition Examination Survey. Arch Int Med. 2005;165(18):2063–8.

    Article  CAS  Google Scholar 

  23. Bray G, Fintel DJ, Clearfield MB, et al. Overweight and Obesity: the pathogenesis of cardiometabolic risk. Clin Cornerstone. 2009;9(4):30–42.

    Article  PubMed  Google Scholar 

  24. St-Onge MP, Janssen I, Heymsfield SB. Metabolic syndrome in normal-weight Americans. New definition of the metabolically obese, normal-weight individual. Diabetes Care. 2004;27:2222–8.

    Article  PubMed  Google Scholar 

  25. Cohen JD, Cziraky MJ, Cai Q, et al. 30-year trends in serum lipids among United States adults: results from the National Health and Nutrition Examination Surveys II, III and 1999–2006. Am J Cardiol. 2010;106:969–75.

    Article  CAS  PubMed  Google Scholar 

  26. Ridker PM, Danielson E, Fonseca F, et al. Rosuvastatin to prevent vascular events in men and women with elevated CRP. N Engl J Med. 2008;359:2195–207.

    Article  CAS  PubMed  Google Scholar 

  27. Blaha MJ, Rivera JJ, Budoff MJ, et al. Association between obesity, hsCRP > 2 mg/L, and subclinical atherosclerosis: Implications of JUPITER from the Multi-Ethnic Study of Atherosclerosis (MESA). Arterioscler Thromb Vasc Biol. 2011;31(6):1430–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Cholesterol Treatment Trialists (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomized trials. Lancet. 2010;376:1670–81.

    Article  Google Scholar 

  29. Cholesterol Treatment Trialists (CTT). The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomized trials. Lancet. 2012;380:581–90.

    Article  Google Scholar 

  30. • Kokkinos P, Faselis C, Myers J, et al. Interactive effects of fitness and statin treatment on mortality risk in veterans with dyslipidemia: a cohort study. Lancet. 2013;381:394–9. This analysis demonstrated that statins and fitness were independently associated with lower cardiovascular mortality.

    Article  CAS  PubMed  Google Scholar 

  31. World Health Organization. World Health Report 2002: Reducing risks, promoting healthy life. Geneva Switzerland: World Health Organization 2002.

  32. • Brook RD, Rajagopalan S, Pope CA, et al. Particulate matter air pollution and cardiovascular disease. An update to the scientific statement from the American Heart Association. Circulation. 2010;121:2331–78. Good synopsis of the association between particulate matter and CVD.

    Article  CAS  PubMed  Google Scholar 

  33. Lepeule J, Laden F, Dockery D, et al. Chronic exposure to fine particles and mortality: An extended follow-up of the Harvard six cities study from 1974 to 2009. Environ Health Perspect. 2012;120:965–70.

    Article  PubMed Central  PubMed  Google Scholar 

  34. Bauer M, Mobeus S, Mohlenkamp S, et al. Residential exposure to urban air pollution is associated with coronary atherosclerosis: results from the Heinz Nixdorf Recall Study. J Am Coll Cardiol. 2010;56:1803–8.

    Article  PubMed  Google Scholar 

  35. Kaufman J. Does air pollution accelerate progression of atherosclerosis? J Am Coll Cardiol. 2010;56:1809–11.

    Article  PubMed  Google Scholar 

  36. Hyun Y, Koh S, Chae J, et al. Atherogenicity of LDL and unfavorable adipokine profile in metabolically obese, normal weight women. Obesity. 2008;16:784–9.

    Article  CAS  PubMed  Google Scholar 

  37. Weiss R. Fat distribution and storage: how much, where and how? Eur J Endocrinol. 2007;157:S39–45.

    Article  CAS  PubMed  Google Scholar 

  38. Li Y. Rittenhouse-Olson, Schneider W et al. Effects of particulate matter air pollution on CRP: a review of epidemiologic studies. Rev Environ Health. 2012;27:133–49.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Egger G, Dixon J. Should obesity be the main game? Or do we need an environmental makeover to combat the inflammatory and chronic disease epidemics? Obes Rev. 2009;10:237–49.

    Article  CAS  PubMed  Google Scholar 

  40. •• Gold DR, Mittleman MA. New insights into pollution and the cardiovascular system 2010–2012. Circulation. 2013;127:1903–13. Recent update on the association between particulate matter and CVD.

    Article  PubMed  Google Scholar 

  41. Sacks J, Stanek L, Luben T, et al. Particulate matter induced health effects: who is susceptible? Environ Health Perspect. 2011;119:454–66.

    Google Scholar 

  42. Takano H, Yanagisawa R, Inoue K, et al. Nitrogen dioxide air pollution near ambient levels is an atherogenic risk primarily in obese subjects: a brief communication. Exp Biol Med. 2004;229:361–4.

    CAS  Google Scholar 

  43. Miller J, Siscovick D, Sheppard L, et al. Long term exposure to air pollution and incidence of cardiovascular events in women. N Engl J Med. 2007;356:447–58.

    Article  CAS  PubMed  Google Scholar 

  44. Zeka A, Sullivan J, Vokanos P, et al. Inflammatory markers and particulate air pollution: characterizing the pathway to disease. Int J Epidemiol. 2006;35:13471354.

    Article  Google Scholar 

  45. Diez R, Auchincloss A, Franklin T, et al. Long term exposure to ambient particulate matter and prevalence of subclinical atherosclerosis in the MESA Study. Am J Epidemiol. 2008;167:667–75.

    Article  Google Scholar 

  46. Bennett W, Zeman K. Effect of body size on breathing pattern and fine particulate deposition in children. J Appl Physiol. 2004;97:821–6.

    Article  PubMed  Google Scholar 

  47. Hickling S, Hung J, Knuiman M, et al. Are the associations between diet and CRP independent of obesity? Prev Med. 2008;47:71–6.

    Article  CAS  PubMed  Google Scholar 

  48. Girman C, Rhodes T, Mercuri M, et al. The metabolic syndrome and risk of major coronary events in the Scandinavian Simvastatin Survival Study (4S) and the Air Force Coronary Atherosclerosis Prevention Study. Am J Cardiol. 2004;93:136–41.

    Article  CAS  PubMed  Google Scholar 

  49. Clearfield M, Downs J, Lee M, et al. Implications from the Air Force Coronary Atherosclerosis Prevention Study for the Adult Treatment Panel III guidelines. Am J Cardiol. 2005;96:1674–80.

    Article  PubMed  Google Scholar 

  50. Sever P, Poulter N, Chang C, et al. Evaluation of CRP prior to and on-treatment as a predictor of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Eur Heart J. 2012;33:486–94.

    Article  CAS  PubMed  Google Scholar 

  51. Wald N, Law M. Statins for people at low risk for cardiovascular disease. Lancet. 2012;380:1818.

    Article  PubMed  Google Scholar 

  52. Law M, Wald N, Rudnicka A. Quantifying effects of statins on LDL-C, ischemic heart disease and stroke. Brit Med J. 2003;326:1423–7.

    Article  CAS  PubMed  Google Scholar 

  53. Wong N, Chuang J, Wong K, et al. Residual dyslipidemia among United States adults treated with lipid modifying therapy (Data from National Health and Nutrition Examination Survey 2009–2010). Am J Cardiol. 2013;112:373–9.

    Article  PubMed  Google Scholar 

  54. Onat A, Ceyhan K, Basar O, et al. Metabolic syndrome: major impact on coronary risk in a population with low cholesterol levels-a prospective and cross sectional evaluation. Atherosclerosis. 2002;165:285–92.

    Article  CAS  PubMed  Google Scholar 

  55. Cole T, Contois J, Csako G, et al. Association of apolipoprotein B and nuclear magnetic resonance spectroscopy derived LDL particle number with outcomes in 25 clinical studies: assessment of the AACC lipoprotein and vascular diseases division working group on best practices. Clin Chem. 2013;59:752–70.

    Article  CAS  PubMed  Google Scholar 

  56. Otvos J, Mora S, Shalaurova I, et al. Clinical implications of discordance between LDL-C and particle number. J Clin Lipid. 2011;5:105113.

    Google Scholar 

  57. Cromwell J, Otvos J, Keyes M, et al. LDL particle number and risk of future cardiovascular disease in the Framingham Offspring study-implications for LDL management. J Clin Lipid. 2007;1:583–92.

    Article  Google Scholar 

  58. • Sniderman A, Thanassoulis G, Couture P, et al. Is lower and lower better and better? A re-evaluation of the evidence from the Cholesterol Treatment Trialsists’ Collaboration meta-analysis for LDL-C lowering. J Clin Lipid. 2012;6:303–9. A different perspective, using the large CTT database with apo B to predict CV risk when statins lower LDL-C < 80 mg./dl.

    Article  Google Scholar 

  59. Malave H, Castro M, Burkle J, et al. Evaluation of low density particle number distribution in patients with type 2 diabetes mellitus with LDL-C < 50 mg/dl and Non-HDL-C < 80. Am J Cardiol. 2012;110:662–5.

    Article  CAS  PubMed  Google Scholar 

  60. Faraj M, Lavole ME, Messier L, et al. Reduction in serum apoB is associated with reduced inflammation and insulin resistance in post-menopausal women: a MONET study. Atherosclerosis. 2010;211:682–8.

    Article  CAS  PubMed  Google Scholar 

  61. Kathiresan S, Otvos J, Sullivan L, et al. Increased small LDL particle number: A prominent feature fo the Metabolic syndrome in the Framingham Heart Study. Circulation. 2006;113:20–9.

    Article  CAS  PubMed  Google Scholar 

  62. Sniderman A. Differential response of cholesterol and particle measures of atherogenic lipoproteins to LDL lowering therapy: implications for clinical practice. J Clin Lipid. 2008;2:36–42.

    Article  Google Scholar 

  63. Sniderman A, Willaims K, Contois J, et al. A meta-analysis of LDL-C, non-HDL-C and apolipoprotein B as markers of cardiovascular disease. Circ Cardiovasc Qual Outcome. 2011;5:337–45.

    Article  Google Scholar 

  64. Yang Q, Cogswell M, Flanders D, et al. Trends in cardiovascular health metrics associations with all-cause mortality among US adults. JAMA. 2012;307:1273–83.

    Article  CAS  PubMed  Google Scholar 

  65. O’Keefe J, Cordain L, Harris W, et al. Optimal LDL is 50 to 70 mg/dl: Lower is better and physiologically normal. JACC. 2004;43:2142–6.

    Article  PubMed  Google Scholar 

  66. Jacobson T, Griffiths G, Varas C, et al. Impact of evidence based “clinical judgement” on the number of American adults requiring lipid lowering therapy based on updated NHANES III data. JAMA. 2000;160:1361–9.

    CAS  Google Scholar 

  67. Cohen J, Czuraky N, Cai Q, et al. 30 year trends in serum lipids among United States adults: Results from the National Health and Nutrition Examination Surveys II, III and 1999–2006. AJC. 2010;106:969–75.

    Article  CAS  Google Scholar 

  68. Munter P, Levitan E, Brown T, et al. Trends in the prevalence, awareness, treatment and control of high LDL-C among US Adults from 1999–2000 through 2009–2010. Am J Cardiol 2013.

  69. Goldfine A, Sanjay K, Hiatt W. Fibrates in the treatment of dyslipidemia: time for reassessment. NEJM. 2011;365:481–4.

    Article  CAS  PubMed  Google Scholar 

  70. Onat J, Can G, Kaya H, et al. Atherogenic index of plasma (log10 triglyceride/HDL-C) predicts high blood pressure, diabetes, vascular events. Clin Lipid. 2010;4:89–98.

    Article  Google Scholar 

  71. Carey V, Bishop L, Harshfield B, et al. Contribution of high plasma triglyceride and low HDL-C to residual risk of coronary heart disease after establishment of LDL-C control. Am J Cardiol. 2010;106:757–64.

    Article  CAS  PubMed  Google Scholar 

  72. • Bayturan J, Kapadia S, Nicholls S, et al. Clinical predictors of plaque progression despite very low levels of LDL-C. J Am Coll Cardiol. 2010;55:2736–42. This study suggests increased LDL particle number played a role in the further progression of atherosclerosis despite statin therapy lowering LDL-C < 70 mg/dl.

    Article  PubMed  Google Scholar 

  73. Clearfield M. Another inconvenient truth: Combining the risks from obesity and metabolic syndrome with global warming. Curr Atheroscler Rep. 2008;10:273–6.

    Article  PubMed  Google Scholar 

  74. Quan C, Sun Q, Lippman M, et al. Comparative effects of inhaled diesel exhaust and ambient fine particles on inflammation, atherosclerosis and vascular dysfunction. Inhal Toxicol. 2010;22:738–53.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. James W, Caterson I, Coutinho W, et al. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med. 2010;363:905–17.

    Article  CAS  PubMed  Google Scholar 

  76. Kahn R, Buse J, Ferrannini E, et al. The metabolic syndrome: Time for critical appraisal: the study of Diabetes. Diabet Care. 2005;28:2289–311.

    Article  Google Scholar 

  77. Cromwell W, Otvos J, Keyes M, et al. LDL particle number and risk of future CVD in the Framingham Offspring Study Implications for LDL management. J Clin Lipid. 2007;1:583–92.

    Article  Google Scholar 

  78. Yousef O, Mohanty B, Martin S, et al. High sensitivity CRP and Cardiovascular Disease: a resolute belief or an elusive link? J Am Coll Cardiol. 2013;62:397–408.

    Article  Google Scholar 

  79. Everett BM, Pradham AD, Solomon DH, et al. Rationale and design of the Cardiovascular Inflammation Reduction Trial: A test of the inflammatory hypothesis of atherothrombosis. Am Heart J. 2013;166:199–207.

    Article  PubMed  Google Scholar 

  80. Genest J, McPherson R, Frohlich J, et al. 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and prevention of cardiovascular disease in the adult. Can J Cardiol. 2009;25:567–79.

    Article  CAS  PubMed  Google Scholar 

  81. Reiner Z, Catapano A, De Backer G, et al. ESC/EAS guidelines for the management of dyslipidemis: The task force for the management of dyslipidemias of the European Society of Cardiology and the European Atherosclerosis Society. Eur Heart J. 2011;32:1769–818.

    Article  PubMed  Google Scholar 

  82. Martin S, Metkus T, Horne A, et al. Waiting for the National Cholesterol Education Program Adult Treatment Panel IV Guidelines, and in the meantime, some challenges and recommendations. Am J Cardiol. 2012;110:307–13.

    Article  PubMed  Google Scholar 

  83. Cromwell W, Dayspring T. Lipid and lipoprotein disorders: Current Clinical Solutions. Catonsville: International Guideline Center; 2012.

    Google Scholar 

  84. American Lung Association State of the Air 2011 http//:www.stateoftheair.org http//:www.lungusa.org.

  85. Murray C, Lopez A. Measuring the global burden of disease. N Engl J Med. 2013;369:448–57.

    Article  CAS  PubMed  Google Scholar 

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Michael Clearfield is a consultant to, received honoraria from, and had travel/accommodations expenses covered or reimbursed by Astra Zeneca and Daiichi Sankyo.

Melissa Pearce declares no conflict of interest.

Yasmin Nibbe declares no conflict of interest.

David Crotty declares no conflict of interest.

Alesia Wagner declares no conflict of interest.

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Clearfield, M., Pearce, M., Nibbe, Y. et al. The “New Deadly Quartet” for Cardiovascular Disease in the 21st Century: Obesity, Metabolic Syndrome, Inflammation and Climate Change: How Does Statin Therapy Fit into this Equation?. Curr Atheroscler Rep 16, 380 (2014). https://doi.org/10.1007/s11883-013-0380-2

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