Importance of Coagulation Factors as Critical Components of Premature Cardiovascular Disease in Familial Hypercholesterolemia.

For almost a century, familial hypercholesterolemia (FH) has been considered a serious disease, causing atherosclerosis, cardiovascular disease, and ischemic stroke. Closely related to this is the widespread acceptance that its cause is greatly increased low-density-lipoprotein cholesterol (LDL-C). However, numerous observations and experiments in this field are in conflict with Bradford Hill's criteria for causality. For instance, those with FH demonstrate no association between LDL-C and the degree of atherosclerosis; coronary artery calcium (CAC) shows no or an inverse association with LDL-C, and on average, the life span of those with FH is about the same as the surrounding population. Furthermore, no controlled, randomized cholesterol-lowering trial restricted to those with FH has demonstrated a positive outcome. On the other hand, a number of studies suggest that increased thrombogenic factors-either procoagulant or those that lead to high platelet reactivity-may be the primary risk factors in FH. Those individuals who die prematurely have either higher lipoprotein (a) (Lp(a)), higher factor VIII and/or higher fibrinogen compared with those with a normal lifespan, whereas their LDL-C does not differ. Conclusions: Many observational and experimental studies have demonstrated that high LDL-C cannot be the cause of premature cardiovascular mortality among people with FH. The number who die early is also much smaller than expected. Apparently, some individuals with FH may have inherited other, more important risk factors than a high LDL-C. In accordance with this, our review has shown that increased coagulation factors are the commonest cause, but there may be other ones as well.

Assessing cardiovascular disease: looking beyond cholesterol.

PURPOSE OF REVIEW: The low-density lipoprotein (LDL)-cholesterol level is a weak predictor of developing cardiovascular (CV) disease and can only explain a small proportion of CV risk. It is not used to determine CV risk on either the atherosclerotic cardiovascular disease (ASCVD) calculator in the United States, or the Qrisk3 in the UK.A study in JAMA in 2022 suggested that ' the absolute benefits of statins are modest and may not be strongly mediated through the degree of LDL reduction '. Perhaps it is time to look beyond cholesterol to a different causal model - the 'thrombogenic' model of ASCVD. RECENT FINDINGS: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) pandemic demonstrated that infectious agents damage the endothelium and the glycocalyx - the glycoprotein layer protecting underlying endothelial cells. There are numerous other conditions leading to this kind of damage, which can trigger thrombus formation, causing strokes and myocardial infarctions.Although these are acute events, they highlight a mechanism for the development of ASCVD which centres on endothelial damage and thrombus formation as both the primary causal mechanism for acute events, and the driver behind progression towards atherosclerotic plaque development. SUMMARY: The cholesterol hypothesis, that a raised LDL is directly causal for ASCVD, does not adequately explain cardiovascular risk in individuals, or populations. An alternative 'thrombogenic' hypothesis is proposed as a more valid causal model.

Serious flaws in targeting LDL-C reduction in the management of cardiovascular disease in familial hypercholesterolemia.

Recently, Polychronopoulos and Tziomalos reviewed research on the use of inclisiran and bempedoic acid in the management of cardiovascular disease (CVD) risk in people with familial hypercholesterolemia (FH). Their treatment recommendations were based on the general premise that high LDL-cholesterol (LDL-C) is inherently atherogenic, and that low levels of LDL-C need to be achieved to reduce CVD risk in FH individuals. However, their perspective on LDL-C is flawed at two levels of analysis: 1) They ignored the extensive literature demonstrating that CVD is not caused by high LDL-C; and 2) they failed to consider CVD treatment strategies that take into account the extensive literature that has shown that coagulation factors are more closely related to coronary events in FH than is LDL-C. In the following, we have briefly addressed each of these flaws in their review.

Dietary Recommendations for Familial Hypercholesterolaemia: an Evidence-Free Zone.

We have evaluated dietary recommendations for people diagnosed with familial hypercholesterolaemia (FH), a genetic condition in which increased low-density lipoprotein cholesterol (LDL-C) is associated with an increased risk for coronary heart disease (CHD). Recommendations for FH individuals have emphasised a low saturated fat, low cholesterol diet to reduce their LDL-C levels. The basis of this recommendation is the 'diet-heart hypothesis', which postulates that consumption of food rich in saturated fat increases serum cholesterol levels, which increases risk of CHD. We have challenged the rationale for FH dietary recommendations based on the absence of support for the diet-heart hypothesis, and the lack of evidence that a low saturated fat, low cholesterol diet reduces coronary events in FH individuals. As an alternative approach, we have summarised research which has shown that the subset of FH individuals that develop CHD exhibit risk factors associated with an insulin-resistant phenotype (elevated triglycerides, blood glucose, haemoglobin A1c (HbA1c), obesity, hyperinsulinaemia, high-sensitivity C reactive protein, hypertension) or increased susceptibility to develop coagulopathy. The insulin-resistant phenotype, also referred to as the metabolic syndrome, manifests as carbohydrate intolerance, which is most effectively managed by a low carbohydrate diet (LCD). Therefore, we propose that FH individuals with signs of insulin resistance should be made aware of the benefits of an LCD. Our assessment of the literature provides the rationale for clinical trials to be conducted to determine if an LCD would prove to be effective in reducing the incidence of coronary events in FH individuals which exhibit an insulin-resistant phenotype or hypercoagulation risk.

The new European guidelines for prevention of cardiovascular disease are misleading.

Introduction: The European Society of Cardiology and European Atherosclerosis Society (ESC/EAS) have recently published three major revisions of their guidelines for the management of chronic heart disease, blood lipids, and diabetes. Areas covered: We have scrutinized these guidelines in detail and found that the authors have ignored many studies that are in conflict with their conclusions and recommendations. Expert commentary: The authors of the guidelines have ignored that LDL-cholesterol (LDL-C) of patients with acute myocardial infarction is lower than normal; that high cholesterol is not a risk factor for diabetics; that the degree of coronary artery calcification is not associated with LDL-C; and that 27 follow-up studies have shown that people with high total cholesterol or LDL-C live just as long or longer than people with low cholesterol. They have also ignored the lack of exposure-response in the statin trials; that several of these trials have been unable to lower CVD or total mortality; that no statin trial has succeeded with lowering mortality in women, elderly people, or diabetics; and that cholesterol-lowering with statins has been associated with many serious side effects.

Formal comment on "Systematic review of the predictors of statin adherence for the primary prevention of cardiovascular disease".

Statins have been prescribed for primary prevention of cardiovascular disease (CVD) for nearly 3 decades. Throughout this period key opinion leaders in the field have been dismayed by the high rate of non-adherence of patients to follow their statin regimen. Hope et al., [1] have addressed this issue by providing a systematic review of research on predictors of statin adherence for primary prevention of CVD. However, their review does not address the ongoing debate as to whether statin treatment is warranted for primary prevention of CVD, nor does it adequately address concerns regarding adverse effects of statins. We have therefore written a commentary which provides a broader perspective on the benefits versus harms of statin therapy. Our perspective of the literature is that non-adherence to statin treatment for primary prevention of CVD is justified because the meager benefits are more than offset by the extensive harms.

Inborn coagulation factors are more important cardiovascular risk factors than high LDL-cholesterol in familial hypercholesterolemia.

High low-density-lipoprotein cholesterol (LDL-C) is routinely described as the main cause of cardiovascular disease (CVD) in familial hypercholesterolemia (FH). However, numerous observations are in conflict with Bradford Hill's criteria for causality: a) degree of atherosclerosis is not associated with LDL-C; b) on average the life span of people with FH is about the same as for other people; c) LDL-C of people with FH without CVD is almost as high as in FH patients of the same age with CVD; and d) questionable benefit or none at all have been achieved in the controlled, randomized cholesterol-lowering trials that have included FH individuals only. Obviously, those individuals with FH who suffer from CVD may have inherited other and more important risk factors of CVD than high LDL-C. In accordance, several studies of FH individuals have shown that various coagulation factors may cause CVD. Equally, some non-FH members of an FH kindred with early CVD, have been found to suffer from early CVD as well. Cholesterol-lowering has only been successful in an animal experiment by using probucol, which has anticoagulant effects as well. We conclude that systematic studies of all kinds of risk factors among FH individuals are urgently required, because today millions of people with FH are treated with statins, the benefit of which in FH is unproven, and which have many serious side effects. We predict that treatment of FH individuals with elevated coagulation factors with anticoagulative drugs is more effective than statin treatment alone.

LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature.

INTRODUCTION: For half a century, a high level of total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C) has been considered to be the major cause of atherosclerosis and cardiovascular disease (CVD), and statin treatment has been widely promoted for cardiovascular prevention. However, there is an increasing understanding that the mechanisms are more complicated and that statin treatment, in particular when used as primary prevention, is of doubtful benefit. Areas covered: The authors of three large reviews recently published by statin advocates have attempted to validate the current dogma. This article delineates the serious errors in these three reviews as well as other obvious falsifications of the cholesterol hypothesis. Expert commentary: Our search for falsifications of the cholesterol hypothesis confirms that it is unable to satisfy any of the Bradford Hill criteria for causality and that the conclusions of the authors of the three reviews are based on misleading statistics, exclusion of unsuccessful trials and by ignoring numerous contradictory observations.

Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review.

OBJECTIVE: It is well known that total cholesterol becomes less of a risk factor or not at all for all-cause and cardiovascular (CV) mortality with increasing age, but as little is known as to whether low-density lipoprotein cholesterol (LDL-C), one component of total cholesterol, is associated with mortality in the elderly, we decided to investigate this issue. SETTING, PARTICIPANTS AND OUTCOME MEASURES: We sought PubMed for cohort studies, where LDL-C had been investigated as a risk factor for all-cause and/or CV mortality in individuals ≥60 years from the general population. RESULTS: We identified 19 cohort studies including 30 cohorts with a total of 68 094 elderly people, where all-cause mortality was recorded in 28 cohorts and CV mortality in 9 cohorts. Inverse association between all-cause mortality and LDL-C was seen in 16 cohorts (in 14 with statistical significance) representing 92% of the number of participants, where this association was recorded. In the rest, no association was found. In two cohorts, CV mortality was highest in the lowest LDL-C quartile and with statistical significance; in seven cohorts, no association was found. CONCLUSIONS: High LDL-C is inversely associated with mortality in most people over 60 years. This finding is inconsistent with the cholesterol hypothesis (ie, that cholesterol, particularly LDL-C, is inherently atherogenic). Since elderly people with high LDL-C live as long or longer than those with low LDL-C, our analysis provides reason to question the validity of the cholesterol hypothesis. Moreover, our study provides the rationale for a re-evaluation of guidelines recommending pharmacological reduction of LDL-C in the elderly as a component of cardiovascular disease prevention strategies.

Does insulin resistance cause atherosclerosis in the post-prandial period?

Insulin resistance would appear to be a causal factor for the development of early occlusive atherosclerosis. This paper proposes that post-prandial insulin resistance, in association with raised levels of cortisol and catecholamines, plays the major role, and may even be the primary causative factor. Therefore, factors that lead to insulin resistance in the post-prandial period, specifically stress, will accelerate the development of CHD. This may explain the low rate of CHD in France, as their eating habits (in common with many other Mediterranean countries) are more relaxed than those in Northern Europe.