LDL Debate - Role in CVD / Exercise, Diet Inflammation, Mortality
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low Level activity vs moderate vs vigorous activity: "a lack of leisure time physical activity when combined with obesity is associated with markedly diminished life expectancy.....a lack of activity and a high BMI (obese class II+) were associated with 7.2 y of life lost relative to meeting recommended activity levels and being normal weight. For comparison, long-term cigarette smoking reduces life expectancy by approximately 10 y.....More leisure time physical activity was associated with longer life expectancy across a range of activity levels and BMI groups......A high level of moderate to vigorous leisure time physical activity was associated with a lower risk of mortality during follow-up and a longer life expectancy after age 40....Compared to no leisure time physical activity (0 MET-h/wk), low levels of leisure time physical activity, i.e., 0.1-3.74 MET-h/wk and 3.75-7.4 MET-h/wk, had multivariable-adjusted HRs of 0.81 (95% CI: 0.79-0.83) and 0.76 (0.74-0.78), and life expectancies that were higher by 1.8 (1.6-2.0) and 2.5 (2.2-2.7) y, respectively. Levels at or just above the minimum level recommended by guidelines (7.5-14.9 MET-h/wk) were associated with even lower risks of mortality (HR = 0.68; 95% CI: 0.66-0.69) and higher life expectancies (3.4 y higher; 95% CI: 3.2-3.6). Finally, levels at two times (15.0-22.4 MET-h/wk) and three or more times (22.5+ MET-h/wk) the minimum recommended level were associated with further, albeit diminishing, reductions in risk of mortality. The respective HRs were 0.61 (0.59-0.63) and 0.59 (0.57-0.61), and life expectancies were higher by 4.2 (4.0-4.5) and 4.5 (4.3-4.7) y."
Debate on LDL Role in Heart Disease Reignited Out of the Blue
May 09, 2017 http://www.medscape.com/viewarticle/879731
"There is a dose-dependent, log-linear association between absolute LDL cholesterol and cardiovascular risk, and this association is independent of other cardiovascular risk factors and is consistent across the multiple lines of evidence," EAS consensus panel cochair Prof M John Chapman (Pitie-Salpetriere University Hospital, Paris, France) said during a late-breaking session at the European Atherosclerosis Society 2017 Annual Congress. http://www.medscape.com/viewarticle/879063
Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel Published: 24 April 2017
To appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD).
We assessed whether the association between LDL and ASCVD fulfils the criteria for causality by evaluating the totality of evidence from genetic studies, prospective epidemiologic cohort studies, Mendelian randomization studies, and randomized trials of LDL-lowering therapies. In clinical studies, plasma LDL burden is usually estimated by determination of plasma LDL cholesterol level (LDL-C). Rare genetic mutations that cause reduced LDL receptor function lead to markedly higher LDL-C and a dose-dependent increase in the risk of ASCVD, whereas rare variants leading to lower LDL-C are associated with a correspondingly lower risk of ASCVD.Separate meta-analyses of over 200 prospective cohort studies, Mendelian randomization studies, and randomized trials including more than 2 million participants with over 20 million person-years of follow-up and over 150 000 cardiovascular events demonstrate a remarkably consistent dose-dependent log-linear association between the absolute magnitude of exposure of the vasculature to LDL-C and the risk of ASCVD; and this effect appears to increase with increasing duration of exposure to LDL-C. Both the naturally randomized genetic studies and the randomized intervention trials consistently demonstrate that any mechanism of lowering plasma LDL particle concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C, provided that the achieved reduction in LDL-C is concordant with the reduction in LDL particle number and that there are no competing deleterious off-target effects.
Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD.
Considered together, the strong and consistent evidence from the genetic studies, prospective epidemiologic cohort studies, Mendelian randomization studies, and randomized intervention trials discussed here, supported by mechanistic evidence to be presented in the second Consensus Statement on LDL causality, establishes that LDL is not merely a biomarker of increased risk but a causal factor in the pathophysiology of ASCVD. The key implications for this conclusion are presented in Box 1.
Low-density lipoprotein (LDL) as a causal factor for atherosclerotic cardiovascular disease: key implications
⋅Cumulative LDL arterial burden is a central determinant for the initiation and progression of atherosclerotic cardiovascular disease.
⋅The lower the LDL cholesterol (LDL-C) level attained by agents that primarily target LDL receptors, the greater the clinical benefit accrued.
⋅Both proportional (relative) risk reduction and absolute risk reduction relate to the magnitude of LDL-C reduction.
⋅Lowering LDL-C in individuals at high cardiovascular risk earlier rather than later appears advisable, especially in those with familial hypercholesterolaemia.
LONDON, UK - A recent editorial asserting that coronary artery disease is a chronic inflammatory condition best reduced by simple lifestyle choices rather than focusing on LDL cholesterol continues to reverberate among cardiologists.
The opening salvo is that the conceptual model of coronary arteries as kitchen pipes clogged with dietary saturated fat is "just plain wrong."
The argument, however, is hardly new. Editorial coauthor Dr Aseem Malhotra (Lister Hospital, Stevenage, UK) took the clogged-pipe analogy to task in a 2013 editorial, as did Dr Michael Rothberg (Cleveland Clinic, OH) in a second editorial published that year.
So why pen yet another editorial?
There is sufficient evidence now against lowering LDL cholesterol and consumption of dietary saturated fat as the primary means to prevent heart disease, Malhotra told heartwire from Medscape.
"It's important that the mainstream narrative changes. This is an inflammatory condition, a chronic inflammatory disease," he said.
The provocative editorial has kept the Twittersphere buzzing since it hit just as the European Atherosclerosis Society released its consensus statement declaring that LDL cholesterol causes atherosclerotic CVD.
Lead author of that document, Dr Brian Ference (Wayne State University School of Medicine, Detroit, MI), told heartwire that a systematic review in elderly patients cited by the editorialists was "neither systematic nor quantitatively literate, but instead was based on a highly selected group of studies with no quantitative synthesis of the presented evidence."
The editorial, published April 25, 2017 in the British Journal of Sports Medicine, contains no new data, but Malhotra and coauthors Dr Rita Redberg (University of California, San Francisco) and Dr Pascal Meier (University College London, UK) highlight several studies to support their position. They include:
⋅The 2014 PREDIMED study, in which a Mediterranean-style diet high in fat from sources such as extra virgin oil and nuts reduced the risk of CVD by 30% in high-risk patients compared with following a low-fat diet.
⋅A 2015 systematic review/meta-analysis by De Souza et al finding no association between saturated-fat consumption and all-cause mortality, CHD, CHD mortality, ischemic stroke, or type 2 diabetes in healthy adults.
⋅A 2016 systematic review by Ravnskov et al concluding that LDL cholesterol is not associated with CVD and is inversely associated with all-cause mortality in the elderly.
The editorialists suggest "selective reporting" may partly explain this misconception and cite a reanalysis of unpublished data from the Minnesota Coronary Experiment reporting that replacing saturated fat with vegetable oils rich in linoleic acid increased the risk of death, despite significant reductions in LDL and total cholesterol.
Ference argues that the new EAS consensus statement on LDL causality was designed specifically to avoid the type of "selective reporting of the evidence" contained in the review by Ravnskov et al by focusing on the "totality of the evidence" from more than 200 studies with more than 2 million participants and over 200 million person-years of follow-up.
"These studies demonstrate a remarkably consistent dose-dependent log-linear association between the absolute magnitude of exposure of the vasculature to LDL-C and the risk of atherosclerotic cardiovascular disease," Ference said.
Conflating Dietary Fat with LDL-C
Furthermore, Ference said the editorialists "appear to conflate dietary fat with plasma LDL-cholesterol levels" and that the EAS consensus statement clearly points out that the efficacy of any intervention that attempts to reduce the risk of atherosclerotic CVD by lowering plasma LDL-C, such as a low-fat diet, will depend on both the absolute magnitude and achieved LDL-C reduction and the total duration of exposure to lower LDL-C.
He added, "The interpretation of the dietary trials has been limited by the fact that data on the effect of low-fat diets on circulating plasma LDL-C over the 3 to 5 years of follow-up that would be needed to demonstrate a clinical benefit are not sufficient to make quantitatively reliable inferences of the potential efficacy of low-fat diets to reduce the risk of cardiovascular events by lowering LDL-C."
In statement to heartwire , prepared for the American Heart Association and reported elsewhere, Dr Frank Sacks (Harvard School of Public Health, Boston, MA) assails the De Souza paper for using "obsolete methodology" that didn't take into account the replacement of macronutrients for saturated fat.
Sacks adds, "The editorial is misleading, ignoring a large database of highest-quality evidence that saturated fat does cause atherosclerosis and does so in large part because it increases LDL cholesterol."
Cone of Silence
Of special note, heartwire contacted at least a dozen cardiologists regarding the editorial, alternately called "worthy of coverage" and "deplorable." One cardiologist laughed it off, another noted its appearance in a "low-impact sports-medicine journal," and still others punted the request to their colleagues.
Malhotra said accusations of cherry-picking the data or being extremists are nothing new and reflect a larger issue in healthcare of stifling debate that contradicts the status quo or powerful competing interests.
"Science doesn't progress when you try to stifle debate and there are legitimate questions being asked," he said. "It's a system failure."
Mutually Exclusive Approaches to Prevention?
The editorialists conclude that the way to combat heart disease is to decrease insulin resistance and inflammation through stress reduction, brisk walking for 22 minutes a day, and eating real food.
"There's no business model or market to help spread this simple yet powerful intervention," they write.
Sacks remarked, "This 'real-food' recommendation is not a scientific approach."
Dr Neil J Stone (Northwestern Memorial Hospital, Chicago, IL) told heartwire in an email that the key point to the editorial "is that the two approaches are not mutually exclusive. Lowering LDL and inflammation (cutting down on sugar especially) are both important."
It's unlikely the debate will die down any time soon, with The Telegraph just reporting that a coalition of physicians, which includes Malhotra, is calling for patients to be warned that the "hugely expensive" PCSK9-inhibitor evolocumab (Repatha, Amgen) does not provide a cardiovascular or all-cause survival benefit, despite lowering LDL cholesterol by some 59%.
Malhotra reports being the coproducer of the documentary The Big Fat Fix. Redberg reports having served as a consultant for one day in 2015 for Amgen. Meier reports no relevant financial relationships. Ference reports consulting for or serving on advisory boards of Merck, Ionis, the American College of Cardiology, Amgen, and Esperion Therapeutics; speaker honoraria and fellowship/travel grants from Merck; and research grants from Merck, Esperion Therapeutics, and Amgen. Sacks reports being a coinventor of a patent held by Harvard University for the measurement of HDL subspecies by apoC-III. Stone reports being the lead author for the 2013 American College of Cardiology/American Heart Association cholesterol guidelines.
Saturated fat does not clog the arteries: coronary heart disease is a chronic inflammatory condition, the risk of which can be effectively reduced from healthy lifestyle interventions
BJSM Online First, published on April 25, 2017
Aseem Malhotra,1 Rita F Redberg,2,3 Pascal Meier4,5
1Lister Hospital, Academy of Medical Royal Colleges, Stevenage, UK2Philip R Lee Institute for Health Policy Studies, San Francisco, California, USA3Department of Medicine, UCSF School of Medicine, San Francisco, California, USA4Department of Cardiology, University Hospital Geneva, Geneva, Switzerland5Department of Cardiology, University College London, London, UK
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Coronary artery disease pathogenesis and treatment urgently requires a paradigm shift. Despite popular belief among doctors and the public, the conceptual model of dietary saturated fat clogging a pipe is just plain wrong. A landmark systematic review and meta-analysis of observational studies showed no association between saturated fat consumption and (1) all-cause mortality, (2) coronary heart disease (CHD), (3) CHD mortality, (4) ischaemic stroke or (5) type 2 diabetes in healthy adults.1 Similarly in the secondary prevention of CHD there is no benefit from reduced fat, including saturated fat, on myocardial infarction, cardiovascular or all-cause mortality.2 It is instructive to note that in an angiographic study of postmenopausal women with CHD, greater intake of saturated fat was associated with less progression of atherosclerosis whereas carbohydrate and polyunsaturated fat intake were associated with greater progression.3
(1) de Souza RJ, Mente A, Maroleanu A, et al. Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 diabetes: systematic review and meta-analysis of observational studies. BMJ 2015;351:h3978
Conclusions Saturated fats are not associated with all cause mortality, CVD, CHD, ischemic stroke, or type 2 diabetes, but the evidence is heterogeneous with methodological limitations. Trans fats are associated with all cause mortality, total CHD, and CHD mortality, probably because of higher levels of intake of industrial trans fats than ruminant trans fats. Dietary guidelines must carefully consider the health effects of recommendations for alternative macronutrients to replace trans fats and saturated fats.....Trans fats contribute about 1-2% of energy in the North American diet9 10 11 and are produced industrially through partial hydrogenation of liquid plant oils in the presence of a metal catalyst, vacuum, and high heat or can occur naturally in meat and dairy products, where ruminant animals biohydrogenate unsaturated fatty acids via bacterial enzymes.
In this synthesis of observational evidence we found no clear association between higher intake of saturated fats and all cause mortality, CHD, CHD mortality, ischemic stroke, or type 2 diabetes among apparently healthy adults. Consumption of trans unsaturated fatty acids, however, was associated with a 34% increase in all cause mortality, a 28% increased risk of CHD mortality, and a 21% increase in the risk of CHD. Further, these data suggest that industrial trans fats confer a 30% increase in the risk of CHD events and an 18% increase in the risk of CHD mortality. No associations were observed for ruminant trans fat. Because of inconsistency in the included studies, we could not confirm an association between trans fats and type 2 diabetes and found no clear association between trans fats and ischemic stroke. This is the first meta-analysis of prospective observational studies examining associations of saturated and trans fats with all cause mortality and confirms the findings of five previous systematic reviews of saturated and trans fats and CHD.1 3 91 92 93
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Preventing the development of atherosclerosis is important but it is atherothrombosis that is the real killer
The inflammatory processes that contribute to cholesterol deposition within the artery wall and subsequent plaque formation (atherosclerosis), more closely resembles a 'pimple' (figure 1). Most cardiac events occur at sites with <70% coronary artery obstruction and these do not generate ischaemia on stress testing.4 When plaques rupture (analogous to a pimple bursting), coronary thrombosis and myocardial infarction can occur within minutes. The limitation of the current plumbing approach ('unclogging a pipe') to the management of coronary disease is revealed by a series of randomised controlled trials (RCTs) which prove that stenting significantly obstructive stable lesions fail to prevent myocardial infarction or to reduce mortality.5
Dietary RCTs with outcome benefit in primary and secondary prevention
In comparison with advice to follow a 'low fat' diet (37% fat), an energy-unrestricted Mediterranean diet (41% fat) supplemented with at least four tablespoons of extra virgin olive oil or a handful of nuts (PREDIMED) achieved a significant 30% (number needed to treat (NNT)=61) reduction in cardiovascular events in over 7500 high-risk patients. Furthermore, the Lyon Heart study showed that adopting a Mediterranean diet in secondary prevention improved hard outcomes for both recurrent myocardial infarction (NNT=18) and all-cause mortality (NNT=30), despite there being no significant difference in plasma low-density lipoprotein (LDL) cholesterol between the two groups. It is the alpha linoleic acid, polyphenols and omega-3 fatty acids present in nuts, extra virgin olive oil, vegetables and oily fish that rapidly attenuate inflammation and coronary thrombosis.6 Both control diets in these studies were relatively healthy, which make it highly likely that even larger benefits would be observed if the Mediterranean diets discussed above were compared with a typical western diet.
LDL cholesterol risk has been exaggerated
Decades of emphasis on the primacy of lowering plasma cholesterol, as if this was an end in itself and driving a market of 'proven to lower cholesterol' and 'low-fat' foods and medications, has been misguided. Selective reporting may partly explain this misconception. Reanalysis of unpublished data from the Sydney Diet Heart Study and the Minnesota coronary experiment reveal replacing saturated fat with linoleic acid containing vegetable oils increased mortality risk despite significant reductions in LDL and total cholesterol (TC).7
A high TC to high-density lipoprotein (HDL) ratio is the best predictor of cardiovascular risk (hence this calculation, not LDL, is used in recognised cardiovascular risk calculators such as that from Framingham). A high TC to HDL ratio is also a surrogate marker for insulin resistance (ie, chronically elevated serum insulin at the root of heart disease, type 2 diabetes and obesity). And in those over 60 years, a recent systematic review concluded that LDL cholesterol is not associated with cardiovascular disease and is inversely associated with all-cause mortality.8 A high TC to HDL ratio drops rapidly with dietary changes such as replacing refined carbohydrates with healthy high fat foods.
A simple way to combat insulin resistance (chronically high levels of serum insulin) and inflammation
Compared with physically inactive individuals, those who walk briskly at or above 150 min/week can increase life expectancy by 3.4-4.5 years independent of body weight.9 Regular brisk walking may also be more effective than running in preventing coronary disease. And just 30 min of moderate activity a day more than three times/week significantly improves insulin sensitivity and helps reverse insulin resistance (ie, lowers the chronically elevated levels of insulin that are associated with obesity) within months in sedentary middle-aged adults. This occurs independent of weight loss and suggests even a little activity goes a long way.
Another risk factor for CHD is environmental stress. Childhood trauma can lead to an average decrease in life expectancy of 20 years. Chronic stress increases glucocorticoid receptor resistance, which results in failure to down regulate the inflammatory response. Combining a complete lifestyle approach of a healthful diet, regular movement and stress reduction will improve quality of life, reduce cardiovascular and all-cause mortality.10 It is time to shift the public health message in the prevention and treatment of coronary artery disease away from measuring serum lipids and reducing dietary saturated fat. Coronary artery disease is a chronic inflammatory disease and it can be reduced effectively by walking 22 min a day and eating real food. There is no business model or market to help spread this simple yet powerful intervention.
Ref #9 - Leisure Time Physical Activity of Moderate to Vigorous Intensity and Mortality: A Large Pooled Cohort Analysis
Plos Med - November 6, 2012 -
Leisure Time Physical Activity of a Moderate to Vigorous Intensity and Longevity
a lack of leisure time physical activity when combined with obesity is associated with markedly diminished life expectancy.....a lack of activity and a high BMI (obese class II+) were associated with 7.2 y of life lost relative to meeting recommended activity levels and being normal weight. For comparison, long-term cigarette smoking reduces life expectancy by approximately 10 y . Our findings highlight the important contribution of physical activity to longevity
A physical activity level equivalent to brisk walking for up to 75 minutes per week was associated with a gain of 1.8 years in life expectancy relative to no leisure time activity. Being active-having a physical activity level at or above the WHO-recommended minimum of 150 minutes of brisk walking per week-was associated with an overall gain of life expectancy of 3.4-4.5 years
A high level of moderate to vigorous leisure time physical activity was associated with a lower risk of mortality during follow-up and a longer life expectancy after age 40 (Figure 1; Tables 3 and S1). Compared to no leisure time physical activity (0 MET-h/wk), low levels of leisure time physical activity, i.e., 0.1-3.74 MET-h/wk and 3.75-7.4 MET-h/wk, had multivariable-adjusted HRs of 0.81 (95% CI: 0.79-0.83) and 0.76 (0.74-0.78), and life expectancies that were higher by 1.8 (1.6-2.0) and 2.5 (2.2-2.7) y, respectively. Levels at or just above the minimum level recommended by guidelines (7.5-14.9 MET-h/wk) were associated with even lower risks of mortality (HR = 0.68; 95% CI: 0.66-0.69) and higher life expectancies (3.4 y higher; 95% CI: 3.2-3.6). Finally, levels at two times (15.0-22.4 MET-h/wk) and three or more times (22.5+ MET-h/wk) the minimum recommended level were associated with further, albeit diminishing, reductions in risk of mortality. The respective HRs were 0.61 (0.59-0.63) and 0.59 (0.57-0.61), and life expectancies were higher by 4.2 (4.0-4.5) and 4.5 (4.3-4.7) y. Similar results were obtained in models excluding deaths during the first 5 y of follow-up (27,804 deaths excluded; HR for 22.5+ versus 0 MET-h/wk = 0.67; 0.65-0.70). Our spline curves showed that the dose-response relationship was curvilinear (pnonlinear<0.01), with the greatest gains in years of life expectancy occurring at approximately 15+ MET-h/wk (Figure S1), equivalent to approximately 300 min of brisk walking per week. Trends were similar regardless of age (Table S2), suggesting no violation of the proportional hazards assumption.
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1 de Souza RJ, Mente A, Maroleanu A, et al. Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 diabetes: systematic review and meta-analysis of observational studies. BMJ 2015;351:h3978.
2 Schwingshackl L, Hoffmann G. Dietary fatty acids in the secondary prevention of coronary heart disease: a systematic review, meta-analysis and meta-regression. BMJ Open 2014;4:e004487.
3 Mozaffarian D, Rimm EB, Herrington DM. Dietary fats, carbohydrate, and progression of coronary atherosclerosis in postmenopausal women. Am J Clin Nutr 2004;80:1175-84.
4 Rothberg MB. Coronary artery disease as clogged pipes: a misconceptual model. Circ Cardiovasc Qual Outcomes 2013;6:129-32.
5 Malhotra A. The whole truth about coronary stents: the elephant in the room. JAMA Intern Med 2014;174:1367-8.
6 Chakrabarti S, Freedman JE. Review: nutriceuticals as antithrombotic agents. Cardiovasc Ther 2010;28:227-35.
7 Ramsden CE, Zamora D, Majchrzak-Hong S, et al. Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota coronary experiment (1968-73). BMJ 2016;353:i1246.
8 Ravnskov U, Diamond DM, Hama R, et al. Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review. BMJ Open 2016;6:e010401.
9 Moore SC, Patel AV, Matthews CE, et al. Leisure time physical activity of moderate to vigorous intensity and mortality: a large pooled cohort analysis. PLoS Med 2012;9:e1001335.
10 Blackburn EH, Epel ES. Too toxic to ignore. Nature 2012;490:169-71.
Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review
Assessments of the association between serum cholesterol and mortality have been studied for decades, and extensive research has shown a weak association between total cholesterol and mortality in the elderly; several studies have even shown an inverse association. It is therefore surprising that there is an absence of a review of the literature on mortality and levels of LDL-C, which is routinely referred to as a causal agent in producing CVD4 and is a target of pharmacological treatment of CVD.
Our literature review has revealed either a lack of an association or an inverse association between LDL-C and mortality among people older than 60 years. In almost 80% of the total number of individuals, LDL-C was inversely associated with all-cause mortality and with statistical significance.
These findings provide a paradoxical contradiction to the cholesterol hypothesis. As atherosclerosis starts mainly in middle-aged people and becomes more pronounced with increasing age, the cholesterol hypothesis would predict that there should be a cumulative atherosclerotic burden, which would be expressed as greater CVD and all-cause mortality, in elderly people with high LDL-C levels.
Our results raise several relevant questions for future research. Why is high TC a risk factor for CVD in the young and middle-aged, but not in elderly people? Why does a subset of elderly people with high LDL-C live longer than people with low LDL-C? If high LDL-C is potentially beneficial for the elderly, then why does cholesterol-lowering treatment lower the risk of cardiovascular mortality? In the following we have tried to address some of these questions.
A common argument to explain why low lipid values are associated with an increased mortality is inverse causation, meaning that serious diseases cause low cholesterol. However, this is not a likely explanation, because in five of the studies in table 1 terminal disease and mortality during the first years of observation were excluded. In spite of that, three of them showed that the highest mortality was seen among those with the lowest initial LDL-C with statistical significance.18 ,20 ,24
Is high LDL-C beneficial?
One hypothesis to address the inverse association between LDL-C and mortality is that low LDL-C increases susceptibility to fatal diseases. Support for this hypothesis is provided by animal and laboratory experiments from more than a dozen research groups which have shown that LDL binds to and inactivates a broad range of microorganisms and their toxic products.27 Diseases caused or aggravated by microorganisms may therefore occur more often in people with low cholesterol, as observed in many studies.28 In a meta-analysis of 19 cohort studies, for instance, performed by the National Heart, Lung and Blood Institute and including 68 406 deaths, TC was inversely associated with mortality from respiratory and gastrointestinal diseases, most of which are of an infectious origin.29 It is unlikely that these diseases caused the low TC, because the associations remained after the exclusion of deaths occurring during the first 5 years. In a study by Iribarren et al, more than 100 000 healthy individuals were followed for 15 years. At follow-up, those whose initial cholesterol level was lowest at the start had been hospitalised significantly more often because of an infectious disease that occurred later during the 15-year follow-up period.30 This study provides strong evidence that low cholesterol, recorded at a time when these people were healthy, could not have been caused by a disease they had not yet encountered.
Another explanation for an inverse association between LDL-C and mortality is that high cholesterol, and therefore high LDL-C, may protect against cancer. The reason may be that many cancer types are caused by viruses.31 Nine cohort studies including more than 140 000 individuals followed for 10-30 years have found an inverse association between cancer and TC measured at the start of the study, even after excluding deaths that occurred during the first 4 years.32 Furthermore, cholesterol-lowering experiments on rodents have resulted in cancer,33 and in several case-control studies of patients with cancer and controls matched for age and sex, significantly more patients with cancer have been on cholesterol-lowering treatment.32 In agreement with these findings, cancer mortality is significantly lower in individuals with familial hypercholesterolaemia.34
That high LDL-C may be protective is in accordance with the finding that LDL-C is lower than normal in patients with acute myocardial infarction. This has been documented repeatedly without a reasonable explanation.35-37 In one of the studies,37 the authors concluded that LDL-C evidently should be lowered even more, but at a follow-up 3 years later mortality was twice as high among those whose LDL-C had been lowered the most compared with those whose cholesterol was unchanged or lowered only a little. If high LDL-C were the cause, the effect should have been the opposite.
Our review provides the first comprehensive analysis of the literature about the association between LDL-C and mortality in the elderly. Since the main goal of prevention of disease is prolongation of life, all-cause mortality is the most important outcome, and is also the most easily defined outcome and least subject to bias. The cholesterol hypothesis predicts that LDL-C will be associated with increased all-cause and CV mortality. Our review has shown either a lack of an association or an inverse association between LDL-C and both all-cause and CV mortality. The cholesterol hypothesis seems to be in conflict with most of Bradford Hill's criteria for causation, because of its lack of consistency, biological gradient and coherence. Our review provides the basis for more research about the cause of atherosclerosis and CVD and also for a re-evaluation of the guidelines for cardiovascular prevention, in particular because the benefits from statin treatment have been exaggerated.38-40