Atherosclerosis: Current Status of Prevention and Treatment

ABSTRACT

The reality of regression of atherosclerotic plaques was established as long ago as 1987 by aggressive cholesterol reduction even before the era of statin therapy. Nevertheless, the most important aspect of patient benefit to prevent cardiovascular (CV) disease events is stabilization of these plaques so they will not rupture. Lowering of low-density lipoproteins is critical to this goal and can be considered the gold standard of preventive CV medicine. The major goal for the high-risk patient and the diabetic patient is lowering these harmful lipoproteins to less than 70 mg/dL. No discussion of CV disease prevention is complete without considering tobacco abuse and its elimination. Even secondhand smoke has been established as harmful. Control of hypertension is another major aspect of CV disease prevention, and a blood pressure less than 120/80 mm Hg is ideal. With obesity a major problem in the developed world, its role in the metabolic syndrome is of major significance as is the high prevalence of this so-called syndrome versus collection of specific risk factors in a population with poor health habits. Control of diabetes mellitus has established benefit from the standpoint of CV disease prevention except that some problems have been reported with extremely tight blood sugar control. Exercise was long considered good but now there are evidence-based reasons to recommend it as essential in CV disease prevention. There are many unforeseen frontiers in CV disease prevention but, for now, everything points to elevation of high-density lipoproteins as the next focus of this prevention.

KEYWORDS

Atherosclerosis - coronary heart disease - peripheral vascular disease - cholesterol - statins

REFERENCES

• 1 The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease.  JAMA. 1984;  251 (3) 351-364
• 2 The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering.  JAMA. 1984;  251 (3) 365-374
• 3 Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).  Lancet. 1994;  344 (8934) 1383-1389
• 4 The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group . Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.  N Engl J Med. 1998;  339 (19) 1349-1357
• 5 Downs J R, Clearfield M, Weis S et al.. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study.  JAMA. 1998;  279 (20) 1615-1622
• 6 Sacks F M, Pfeffer M A, Moye L A et al.. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators.  N Engl J Med. 1996;  335 (14) 1001-1009
• 7 Shepherd J, Cobbe S M, Ford I West of Scotland Coronary Prevention Study Group et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia.  N Engl J Med. 1995;  333 (20) 1301-1307
• 8 Liao J K, Laufs U. Pleiotropic effects of statins.  Annu Rev Pharmacol Toxicol. 2005;  45 89-118
• 9 Libby P. Molecular bases of the acute coronary syndromes.  Circulation. 1995;  91 (11) 2844-2850
• 10 Stoll G, Bendszus M. Inflammation and atherosclerosis: novel insights into plaque formation and destabilization.  Stroke. 2006;  37 (7) 1923-1932
• 11 Nissen S E, Nicholls S J, Sipahi I ASTEROID Investigators et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial.  JAMA. 2006;  295 (13) 1556-1565
• 12 Blankenhorn D H, Johnson R L, Nessim S A, Azen S P, Sanmarco M E, Selzer R H. The Cholesterol Lowering Atherosclerosis Study (CLAS): design, methods, and baseline results.  Control Clin Trials. 1987;  8 (4) 356-387
• 13 Blankenhorn D H, Nessim S A, Johnson R L, Sanmarco M E, Azen S P, Cashin-Hemphill L. Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts.  JAMA. 1987;  257 (23) 3233-3240
• 14 Blankenhorn D H, Selzer R H, Mack W J et al.. Evaluation of colestipol/niacin therapy with computer-derived coronary end point measures. A comparison of different measures of treatment effect.  Circulation. 1992;  86 (6) 1701-1709
• 15 Brown B G, Zhao X Q, Chait A et al.. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.  N Engl J Med. 2001;  345 (22) 1583-1592
• 16 Brown G, Albers J J, Fisher L D et al.. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B.  N Engl J Med. 1990;  323 (19) 1289-1298
• 17 Prasad K, Lee P. Suppression of hypercholesterolemic atherosclerosis by pentoxifylline and its mechanism.  Atherosclerosis. 2007;  192 (2) 313-322
• 18 Falk E, Shah P K, Fuster V. Coronary plaque disruption.  Circulation. 1995;  92 (3) 657-671
• 19 Sacks F M, Svetkey L P, Vollmer W M DASH-Sodium Collaborative Research Group et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet.  N Engl J Med. 2001;  344 (1) 3-10
• 20 Kastorini C M, Milionis H J, Esposito K, Giugliano D, Goudevenos J A, Panagiotakos D B. The effect of Mediterranean diet on metabolic syndrome and its components: a meta-analysis of 50 studies and 534,906 individuals.  J Am Coll Cardiol. 2011;  57 (11) 1299-1313
• 21 Estruch R, Martínez-González M A, Corella D PREDIMED Study Investigators et al. Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial.  Ann Intern Med. 2006;  145 (1) 1-11
• 22 Fitó M, Guxens M, Corella D for the PREDIMED Study Investigators et al. Effect of a traditional Mediterranean diet on lipoprotein oxidation: a randomized controlled trial.  Arch Intern Med. 2007;  167 (11) 1195-1203
• 23 Grundy S M, Cleeman J I, Merz C N National Heart, Lung, and Blood Institute et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.  Circulation. 2004;  110 (2) 227-239
• 24 Wiviott S D, Cannon C P, Morrow D A, Ray K K, Pfeffer M A, Braunwald E. PROVE IT-TIMI 22 Investigators . Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy.  J Am Coll Cardiol. 2005;  46 (8) 1411-1416
• 25 Hsia J, MacFadyen J G, Monyak J, Ridker P M. Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol <50 mg/dl with rosuvastatin. The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin).  J Am Coll Cardiol. 2011;  57 (16) 1666-1675
• 26 Kastelein J J, Akdim F, Stroes E S ENHANCE Investigators et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia.  N Engl J Med. 2008;  358 (14) 1431-1443
• 27 Ridker P M, Danielson E, Fonseca F A JUPITER Study Group et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.  N Engl J Med. 2008;  359 (21) 2195-2207
• 28 Whayne Jr T F, Zielke J C, Dickson L G, Winters J L. State of the art treatment of the most difficult low density lipoprotein (LDL) cholesterol problems: LDL apheresis.  J Ky Med Assoc. 2002;  100 (12) 535-538
• 29 Kajinami K, Takekoshi N, Saito Y. Pitavastatin: efficacy and safety profiles of a novel synthetic HMG-CoA reductase inhibitor.  Cardiovasc Drug Rev. 2003;  21 (3) 199-215
• 30 Smoking and Health: Report of the Advisory Committee to the Surgeon General of the Public Health Service: Superintendent of Documents, U.S. Government Printing Office, Washington, D.C., 20402. 1964: 1-387
• 31 Ambrose J A, Barua R S. The pathophysiology of cigarette smoking and cardiovascular disease: an update.  J Am Coll Cardiol. 2004;  43 (10) 1731-1737
• 32 Benowitz N L. Cigarette smoking and cardiovascular disease: pathophysiology and implications for treatment.  Prog Cardiovasc Dis. 2003;  46 (1) 91-111
• 33 Jha P, Jacob B, Gajalakshmi V RGI-CGHR Investigators et al. A nationally representative case-control study of smoking and death in India.  N Engl J Med. 2008;  358 (11) 1137-1147
• 34 Mulcahy R, Hickey N. Cigarette smoking habits of patients with coronary heart disease.  Br Heart J. 1966;  28 (3) 404-408
• 35 Doyle J T, Kannel W B, McNamara P M, Quickenton P, Gordon T. Factors related to suddenness of death from coronary disease: combined Albany-Framingham studies.  Am J Cardiol. 1976;  37 (7) 1073-1078
• 36 Shaper A G, Wannamethee S G, Walker M. Pipe and cigar smoking and major cardiovascular events, cancer incidence and all-cause mortality in middle-aged British men.  Int J Epidemiol. 2003;  32 (5) 802-808
• 37 Barnoya J, Glantz S A. Cardiovascular effects of secondhand smoke: nearly as large as smoking.  Circulation. 2005;  111 (20) 2684-2698
• 38 Cesaroni G, Forastiere F, Agabiti N, Valente P, Zuccaro P, Perucci C A. Effect of the Italian smoking ban on population rates of acute coronary events.  Circulation. 2008;  117 (9) 1183-1188
• 39 Sargent R P, Shepard R M, Glantz S A. Reduced incidence of admissions for myocardial infarction associated with public smoking ban: before and after study.  BMJ. 2004;  328 (7446) 977-980
• 40 Leng G C, Lee A J, Fowkes F G, Lowe G D, Housley E. The relationship between cigarette smoking and cardiovascular risk factors in peripheral arterial disease compared with ischaemic heart disease. The Edinburgh Artery Study.  Eur Heart J. 1995;  16 (11) 1542-1548
• 41 Critchley J A, Capewell S. Mortality risk reduction associated with smoking cessation in patients with coronary heart disease: a systematic review.  JAMA. 2003;  290 (1) 86-97
• 42 Jonason T, Bergström R. Cessation of smoking in patients with intermittent claudication. Effects on the risk of peripheral vascular complications, myocardial infarction and mortality.  Acta Med Scand. 1987;  221 (3) 253-260
• 43 McRobbie H, Thornley S. [The importance of treating tobacco dependence].  Rev Esp Cardiol. 2008;  61 (6) 620-628
• 44 The Seventh Report of the Joint National Committee on Prevention .Detection, Evaluation, and Treatment of High Blood Pressure: U.S. Department of Health and Human Services. 2004: 1-86
• 45 Wang Y, Wang Q J. The prevalence of prehypertension and hypertension among US adults according to the new joint national committee guidelines: new challenges of the old problem.  Arch Intern Med. 2004;  164 (19) 2126-2134
• 46 Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Prospective Studies Collaboration . Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies.  Lancet. 2002;  360 (9349) 1903-1913
• 47 Levy D, Merz C N, Cody R J et al.. Hypertension detection, treatment and control: a call to action for cardiovascular specialists.  J Am Coll Cardiol. 1999;  34 (4) 1360-1362
• 48 Doumas M, Papademetriou V, Douma S et al.. Benefits from treatment and control of patients with resistant hypertension.  Int J Hypertens. 2011;  2011 318-549
• 49 Perry Jr H M, Davis B R, Price T R et al.. Effect of treating isolated systolic hypertension on the risk of developing various types and subtypes of stroke: the Systolic Hypertension in the Elderly Program (SHEP).  JAMA. 2000;  284 (4) 465-471
• 50 Staessen J A, Thijisq L, Fagard R Systolic Hypertension in Europe (Syst-Eur) Trial Investigators et al. Effects of immediate versus delayed antihypertensive therapy on outcome in the Systolic Hypertension in Europe Trial.  J Hypertens. 2004;  22 (4) 847-857
• 51 Grundy S M, Cleeman J I, Daniels S R American Heart Association et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement.  Circulation. 2005;  112 (17) 2735-2752
• 52 Whayne Jr T F. In defense of the metabolic syndrome.  J Clin Lipidol. 2009;  3 (4) 247-249
• 53 NIH stops clinical trial on combination cholesterol treatment: lack of efficacy in reducing cardiovascular events prompts decision. May 26, 2011 Available at: http://public.nhlbi.nih.gov/newsroom/home/GetPressRelease.aspx?id=2792
• 54 Clofibrate and niacin in coronary heart disease.  JAMA. 1975;  231 (4) 360-381
• 55 Patel A, MacMahon S, Chalmers J ADVANCE Collaborative Group et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.  N Engl J Med. 2008;  358 (24) 2560-2572
• 56 Gerstein H C, Miller M E, Byington R P Action to Control Cardiovascular Risk in Diabetes Study Group et al. Effects of intensive glucose lowering in type 2 diabetes.  N Engl J Med. 2008;  358 (24) 2545-2559
• 57 The Diabetes Control and Complications Trial Research Group . The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.  N Engl J Med. 1993;  329 (14) 977-986
• 58 American Diabetes Association . Implications of the diabetes control and complications trial.  Diabetes Care. 2003;  26(Suppl 1) S25-S27
• 59 Leitzmann M F, Park Y, Blair A et al.. Physical activity recommendations and decreased risk of mortality.  Arch Intern Med. 2007;  167 (22) 2453-2460
• 60 Kujala U M, Kaprio J, Sarna S, Koskenvuo M. Relationship of leisure-time physical activity and mortality: the Finnish twin cohort.  JAMA. 1998;  279 (6) 440-444
• 61 Hakim A A, Curb J D, Petrovitch H et al.. Effects of walking on coronary heart disease in elderly men: the Honolulu Heart Program.  Circulation. 1999;  100 (1) 9-13
• 62 Franco O H, de Laet C, Peeters A, Jonker J, Mackenbach J, Nusselder W. Effects of physical activity on life expectancy with cardiovascular disease.  Arch Intern Med. 2005;  165 (20) 2355-2360
• 63 Bijnen F C, Caspersen C J, Feskens E J, Saris W H, Mosterd W L, Kromhout D. Physical activity and 10-year mortality from cardiovascular diseases and all causes: The Zutphen Elderly Study.  Arch Intern Med. 1998;  158 (14) 1499-1505
• 64 Thompson P D, Buchner D, Pina I L American Heart Association Council on Clinical Cardiology Subcommittee on Exercise, Rehabilitation, and Prevention et al. Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease: a statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity).  Circulation. 2003;  107 (24) 3109-3116
• 65 Lakka T A, Lakka H M, Rankinen T et al.. Effect of exercise training on plasma levels of C-reactive protein in healthy adults: the HERITAGE Family Study.  Eur Heart J. 2005;  26 (19) 2018-2025
• 66 Howard A A, Arnsten J H, Gourevitch M N. Effect of alcohol consumption on diabetes mellitus: a systematic review.  Ann Intern Med. 2004;  140 (3) 211-219
• 67 Wallerath T, Poleo D, Li H, Förstermann U. Red wine increases the expression of human endothelial nitric oxide synthase: a mechanism that may contribute to its beneficial cardiovascular effects.  J Am Coll Cardiol. 2003;  41 (3) 471-478
• 68 Zhang H, Zhang J, Ungvari Z, Zhang C. Resveratrol improves endothelial function: role of TNFalpha and vascular oxidative stress.  Arterioscler Thromb Vasc Biol. 2009;  29 (8) 1164-1171
• 69 Fisher N D, Hughes M, Gerhard-Herman M, Hollenberg N K. Flavanol-rich cocoa induces nitric-oxide-dependent vasodilation in healthy humans.  J Hypertens. 2003;  21 (12) 2281-2286
• 70 Maron D J. Flavonoids for reduction of atherosclerotic risk.  Curr Atheroscler Rep. 2004;  6 (1) 73-78
• 71 Paolini J F, Mitchel Y B, Reyes R et al.. Effects of laropiprant on nicotinic acid-induced flushing in patients with dyslipidemia.  Am J Cardiol. 2008;  101 (5) 625-630
• 72 Barter P J, Caulfield M, Eriksson M ILLUMINATE Investigators et al. Effects of torcetrapib in patients at high risk for coronary events.  N Engl J Med. 2007;  357 (21) 2109-2122
• 73 Yvan-Charvet L, Kling J, Pagler T et al.. Cholesterol efflux potential and antiinflammatory properties of high-density lipoprotein after treatment with niacin or anacetrapib.  Arterioscler Thromb Vasc Biol. 2010;  30 (7) 1430-1438
• 74 Stein E A, Roth E M, Rhyne J M, Burgess T, Kallend D, Robinson J G. Safety and tolerability of dalcetrapib (RO4607381/JTT-705): results from a 48-week trial.  Eur Heart J. 2010;  31 (4) 480-488
• 75 Whayne Jr T F. What should medical practitioners know about the role of alternative medicines in cardiovascular disease management?.  Cardiovasc Ther. 2010;  28 (2) 106-123
• 76 Whayne T F. Vitamin D: popular cardiovascular supplement but benefit must be evaluated.  Int J Angiol. 2011;  20 (2) 63-72