The doctor’s dilemma: Challenges in the diagnosis and care of homozygous familial hypercholesterolemia

This editorial by Dr. Baum was originally published in the Journal of Clinical Lipidology, Vol 8, No 6, December 2014 and re-published with permission.

“The demands of this poor public are not reasonable, but they are quite simple. It dreads disease and desires to be protected against it. But it is poor and wants to be protected cheaply. Scientific measures are too hard to understand, too costly, too clearly tending towards a rise in the rates and more public interference with the insanitary, because insufficiently financed, private house. What the public wants, therefore, is a cheap magic charm to prevent, and a cheap pill or potion to cure, all disease. It forces all such charms on the doctors.”
George Bernard Shaw THE DOCTOR’S DILEMMA: PREFACE ON DOCTORS (1909).

Scientific progress and the tower of babel
Many may have forgotten that Goldstein and Brown originally ascribed familial hypercholesterolemia (FH) to defective 3-hydroxy-3-methyl-glutaryl coenzyme A reductase.(1) The authors promptly corrected their proposition and concluded that a defect in the low-density lipo- protein (LDL) receptor was the basis of FH.(2) Although they had initially been incorrect, their mistake simply illustrated the norm in scientific discovery—and, they won the Nobel Prize in Medicine. Theories are proposed and tested; understanding is honed; and new theories are rewritten. Such iteration is at the heart of progress in science. And, it is a process in need of application by healthcare practitioners worldwide to improve the detection and treatment of people with FH. Specifically, today’s lexicon for FH has evolved to the point of clinical incomprehension.(3,4) Its complexities, ambiguities, and embedded misnomers (e.g., How can double or compound heterozygotes be homozygotes?) will often pose confusion, paradox, and dilemma for the clinician sufficient to impair clinical care; clarification is therefore required.(5–8)

Brief historical perspective
FH was originally defined as a life-threatening auto- somal-dominant, monogenic mutation of the LDL receptor that resulted in hypocatabolism of LDL particles and premature atherosclerosis.(9) Goldstein’s and Brown’s early interpretation of patient data and their use of the Hardy-Weinberg equation for monogenic disorders led to the long held dictum that homozygous FH (HoFH) occurs at a rate of 1 per 1 million, whereas heterozygous FH (HeFH), 1 per 500.(9–11) Unbeknownst to them at the time of their discovery, their scientifically precise definition of the prevalence of HoFH possessed inherent limitations, because it referred strictly to only those patients with a single and same mutation in the LDL receptor inherited from both parents. Now we have come to recognize great phenotypic variability in FH,(12) the worst phenotype being homo- zygous FH determined by the presence of two null alleles in the LDL receptor. Consanguinity additionally enhances the severity of HoFH as evidenced by the founder effects across the world.(10,11) And, many other mutations outside the LDL receptor can also lead to FH.(3,4,11,12)

Evolution of a definition
“HoFH is an infrequent inherited disorder usually caused by mutations in both LDL receptor alleles, which results in very high elevated plasma LDL cholesterol concentrations and very early morbidity and mortality due to accelerated atherosclerotic cardiovascular disease (ASCVD), usually before the patient turns 30 years old. In patients with HoFH, the main cause of mortality and morbidity is the aortic stenosis rather than involvement of the coronary arteries.”(9)  This was an original definition for HoFH written by the “fathers” of the disorder. This, as well as the original molecular definition, has itself mutated over the years. FH now includes autosomal dominant mutations in at least two other genes, PCSK9 and apoB 100.(3,4) To further confuse the issue, molecularly defined HoFH now includes both double heterozygotes and compound heterozygotes and may also rarely involve more than two mutations.(10,11) Double heterozygotes possess mutations in two of the aforementioned genes, whereas compound heterozygotes have two different mutations in one of the afore-mentioned genes. Strictly speaking, neither of these entities represents true homozygosity, yet clinically they do result in an HoFH phenotype, albeit with varying penetrance of LDL levels and consequent atherosclerotic cardiovascular disease (ASCVD). For this reason, the newer and less genetically precise terms have appropriately become embedded in our definition of HoFH. This expanded HoFH definition enables doctors to broaden their detection and care of such patients, an extraordinarily high-risk population in need of early and aggressive treatment.13,14 Markedly elevated plasma LDL cholesterol (LDL-C) levels exist even in utero, emphasizing both the genetic nature and very high lifetime risk of ASCVD risk of FH (Fig. 1).(15) Beyond our genetic redefinition of FH, we now recognize the disorder to perturb the entire lipoprotein system.(16) From a metabolic perspective, there is more than just reduced clearance of LDL; there is also coexistent overproduction of apoB, undercatabolism of remnant lipoproteins, and dysfunction of HDL.(16) These extended abnormalities are, however, embedded in the extent of residual LDL re- ceptor activity, which from a metabolic viewpoint could potentially be used to further define FH; however, such molecular testing is not yet readily accessible.(10) As a consequence of the aforementioned diagnostic ambiguities, physicians around the world often face artificial and inappropriate obstacles to optimally manage their patients with HoFH. In the United States, the use of novel agents—lomitapide and mipomersen—are restricted to clinically defined HoFH patients.(17–19) In most countries outside the United States, the United Kingdom, Spain, Japan, and Germany, the use of lipoprotein apheresis is not reimbursed, but if it is, a restricted definition of HoFH is required.(9,10) To enable clinicians to better treat their patients, an improved and pragmatic definition is required for the highest risk FH patients.

ASCVD fig 1Fig. 1 Threshold for ASCVD as a function of cumulative LDL-C exposure. This adaptation emphasizes the genetic aspect of FH, bringing the start point of LDL-C accumulation into the in utero period. Exposure to markedly elevated LDL-C levels occurs even before birth, further explaining the prematurity of ASCVD in such individuals. Additionally the figure introduces the suggested terminology, ‘‘very high-risk’’ and ‘‘high-risk’’ FH. Adapted from Horton JD, et al. J Lipid Res. 2009; 50 (Suppl):S172-S177.

Revision of earlier concepts
Over the past few years, it has become apparent that the current definition of HoFH (expanded from its origi- nal Goldstein and Brown view) is likely inadequate.(11,12) We now have evidence that the prevalence of HoFH may be one in 160,000,(12) whereas HeFH occurs somewhere between 1 in 200 and 1 in 300.(20,21) As noted previously, it is clear that three genes—LDL receptor, PCSK9, and apoB100—mutate and lead to the preponderance of FH cases.(3,4,7,8) There remain some important caveats, however. These estimates of prevalence actually exclude double heterozygotes as well as any potential de novo LDL receptor mutations. Moreover, the new prevalence calculations are approximate estimates of frequencies(12) not being calculated according a multilocus variant of the Hardy- Weinberg principle(22) and without considering population admixture. Additionally, phenotypic analyses in the Copenhagen study show a remarkably large number of patients with severe hypercholesterolemia.(20) It is not clear if this is the result of sharing an unhealthful diet or a high prevalence of inherited disorders, which would suggest genetic isolation.

With regard to double heterozygotes, although the expectation is for them to represent only 5% of the HoFH population, their prevalence in the largest study of geno- typed patients to date was the same as that of compound heterozygotes.(12) Double heterozygotes were removed however from prevalence statistics because such individuals possess a polygenic disorder (two genes to be precise). The authors therefore considered them to be unevaluable by Hardy-Weinberg.(12,22) However, a multilocus Hardy-Weinberg calculation could be performed, bringing a greater precision to the authors’ findings as well as our current understanding of FH prevalence.(12) Because the prevalence of double heterozygotes was much greater than anticipated, and as polygenic mutations are known to remain stable over generations, it is probably inaccurate to exclude these double heterozygotes from Hardy-Weinberg analysis. By doing so, we are left with prevalence estimates that fail to account for double heterozygotes with phenotypic or clinical HoFH.(3,4,23)

There is also the issue of typically requiring both parents to have either very high LDL or premature ASCVD to meet clinical HoFH criteria.(10,11) Two notions could argue against this requirement. First, there is the possibility of de novo mutations. Although little is known specifically about the incidence of de novo LDL receptor gene variants, we do know that this gene can be subject to many mutations.(4)

Recently, whole exome sequencing for the evaluation of other Mendelian disorders revealed a surprisingly high incidence of 83% de novo mutations in autosomal dominant disorders in the population assessed.(23) More than 1700 genetic variants in the LDL receptor have hitherto been identified (not all of which are pathogenic, however). Such a high prevalence of mutations in the LDL receptor does raise the question of whether or not it can also be subject to de novo mutations.(7,23) Second is the issue of nonpaternity, a very challenging matter in a clinical setting.(8) Nonpaternity occurs when the presumed father of a child is not the biological father and is rather frequent with estimates between 0.8 and 30%.(24) Further confounding the assessment of true HoFH is the fact that genotyping itself, probably owing to technical limitations in the main, is imperfect. It is far less sensitive than we would like. Estimates are that somewhere between 20% and 70% of patients manifesting as phenotypic or clinical possible to definite FH (HeFH and HoFH) can be overlooked through current genetic sequencing techniques.(7,8,25–27)

Communities subject to gene founder effects aside,(23) it therefore appears that the figures cited previously for the population prevalence most likely underestimate the true frequency of HoFH. HoFH, as expressed clinically, is therefore not only far more common than we previously considered, but it could be even more common than we are presently led to believe. Making matters more perplexing, we now have documentation of pathogenic mutations causing HoFH yet resulting in an untreated LDL-C as low as 170 mg/dL.(12) Such a low LDL challenges prior criteria for HoFH, many of which stipulated an untreated LDL-C .450 mg/dL (and treated LDL-C .300 mg/dL) in the HoFH individual.(10) An untreated LDL-C of 170 mg/dL not only breaches the current HeFH boundaries, but even overlaps with polygenic or common hypercholesterolemia (Fig. 2). Contributing to current scientific uncertainty and clinical ambiguity, polygenic mutations can sufficiently elevate plasma LDL-C to mimic FH.(26,28) Given the emerging new knowledge of the prevalence, phenotypic expression, and genetic etiology of FH, coupled with the recognition of our inability to clinically and even genotypically distinguish the heterozygous and homozygous entities, why make an arbitrary distinction between HeFH and HoFH?(10–12) We currently do not have the capacity to be scientifically precise in making this distinction. Therefore, from a practical perspective, we must either revise our definition of HoFH, or abandon the notion that such a definition should take a primary position in the clinical decision making process. Because a clinically pragmatic revision of the definition will only take us further from the true genetic meaning of the term, it might be best simply to acknowledge that the definitions of HoFH or HeFH should have a diminished role in the clinical management of patients after the diagnosis of FH has been made. Our view is that the phenotypic expression of the disease should drive the patient-centered therapeutic strategy.

FH fig 2

Fig. 2 Low-density lipoprotein-cholesterol levels in homozygous autosomal dominant hypercholesterolemia patients prior and after LLT. Plus indicates patients with two null alleles. Open diamond indicates patients with one null allele and one defective allele. Closed square indicates patients with two defective alleles. Horizontal lines indicate mean LDL-C levels. Statin-naive LDL-C levels were available for 32 homozygous autosomal dominant hypercholesterolemia patients. Treated LDL-C levels were avail-able for 43 homozygous autosomal dominant hypercholesterolemia patients. LLT, lipid-lowering therapy. Reprinted with permission from the European Heart Journal. Sjouke B, Kusters DM, Kindt I, et al. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype–phenotype relationship, and clinical outcome. Eur Heart J. 2014:ehu058.

Meeting the challenge with a clinical solution: improving the utilization of novel therapiesBy early 2013, two novel agents, lomitapide and mipomersen, were approved in the United States as adjunctive therapies for patients with HoFH aged $18 years.(19,29) Because HoFH is by definition an orphan or rare disease (affecting fewer than 200,000 people in the United States, or less than 1 in 1500), the Food and Drug Administration’s evaluation of these medications differed substantially from their standard pharmaceutical approval process. Additionally, orphan medications are exceedingly expensive, often more than $200,000 per patient per year. Thus, to prescribe these medications, physicians must attest that the patients for whom they are prescribing the drug meet the criteria for the given rare disease, in this case HoFH. Specifically, a prescribing doctor must state, ‘‘I affirm that my patient has a clinical or laboratory diagnosis consistent with HoFH’’.(29) In other words, a necessary barrier has been constructed to prescribing orphan drugs. Herein lies the specific major issue though. As argued previously, the demarcation between HeFH and HoFH can be challenging on both clinical and genetic grounds. Consequently,FH—including HoFH—is grossly underdiagnosed and similarly undertreated. It is estimated that less than 1% of FH patients in the United States have been adequately diagnosed.(7) Reeducation is in order; teaching medical practitioners to have FH as a fixture on their differential diagnostic list of LDL disorders is crucial.(5–8) Equally pressing, however, and of immediate concern in the United States, is the quandary of when to prescribe these novel medications to our patients, acknowledging also the lack of clinical endpoint trials, which for ethical reasons will never be undertaken.(19) It would be simple if the issue were clear-cut. This is far from the case, however, and can present the treating physician with a challenging clinical dilemma. Doctors must acknowledge the difficulties inherent in distinguishing HeFH from HoFH, but still determine whether a given patient presents with a clinical phenotype that is consistent with HoFH. Because FH can be a lethal condition in either heterozygous or homozygous forms our approach should be driven by the clinical manifestations of an individual patient’s specific, causative molecular or genetic defect.

The doctor’s dilemma resolved with a common language strategy: a pragmatic approach to managing clinically severe FH
We proffer the following clinically grounded approach that may simplify and enhance the care of adult patients with clinically severe FH, regardless of its genetic bases (Fig. 3).

Triage using established clinical tools
A family history of premature vascular disease, a marked and often isolated elevation of LDL-C, premature and/or aggressive vascular disease, a limited response to lipid-lowering therapy, and the presence of physical stigmata of FH must all be considered.(5–8) If, based on these considerations, there is a strong suspicion of FH, either the Simon Broome or the Dutch Lipid Clinic Network criteria should be employed.(5–8) Worldwide, the Dutch Lipid Clinic is more commonly used because it is considered more sensitive than Simon Broome.(7,8) Although it is commonly considered the system of choice to help clinicians diagnose FH (7,8) in Western populations, in other countries alternative criteria should be employed.(21,30) MEDPED is excluded here because its system hinges solely upon LDL-C levels and strictly requires knowing LDL-C in several family members.(31) In our opinion, this tool also bears ambiguities that may be confusing when cascade screening to detect new family members with FH. It is important for clinicians to recognize that LDL-C levels differ between the sexes and steadily rise through life.

suspicion of FH in adult fig 3

Fig. 3 Novel care pathway for identifying and treating patients with FH. In view of the recently recognized wide genetic and phenotypic variability of FH, this algorithm is intended to simplify and improve care of patients with this disorder. The algorithm shifts the impetus of therapeutic intervention choices from genetics to phenotypic/clinical expression. The individual patient with his or her unique manifestation of disease is emphasized.

Thus, an LDL-C adjustment should be contemplated when calculating the likelihood of FH, particularly when there is a family member with documented FH.(32) If patients do not meet FH criteria when assessed with the Dutch Lipid Clinic Network, they should be treated according to current lipid and cholesterol guidelines.(33–36)

Assessing ASCVD and an inadequate response to treatment
With severe/progressive ASCVD, or a clinically significant degree of subclinical disease, and probable or definite FH,(7,8) the patient could be considered to have a condition termed ‘‘high-risk FH.’’ Every effort using standard therapies should then be made to drive the LDL-C below 70 mg/dL.(6–8) Lipoprotein a (Lp(a)) should also be assessed.(37) Lp(a) is a potent, independent risk factor for coronary events in FH and an assessment of its plasma concentration and allelic size therefore has been incorporated into this protocol.(38) Very high plasma Lp(a) concentrations may mandate earlier introduction of lipoprotein apheresis (39–41) or, when available, apolipoprotein a antisense therapy.(16) If the level is $50 mg/dL, regardless of the LDL-C level, lipoprotein apheresis should be initiated. If an aggressive attempt to reach an LDL goal ,70 mg/dL is unsuccessful, the patient should be considered to have ‘‘very high-risk FH.’’(42) This classification would emphasize the urgency and concomitantly augment the intensity of treatment. Although ‘‘very high-risk FH’’ might include both patients with severe HeFH as well as those with severe HoFH, the US Food and Drug Administration attestation for the two novel agents lomitapide and mipomersen (17,18) could be satisfied on clinical grounds. Such a classification system is reasonable given our recent understanding of the greatly overlapping spectra of HeFH and HoFH. Both lipoprotein apheresis and/or these novel medications must be seriously considered in very high-risk individuals with FH. As further evidence for the efficacy and safety of PCSK9 inhibitors in severe FH grows and other therapies,(18,43,44) such as the CETP inhibitors, potentially achieve their clinical endpoints, the algorithm may be applied to these agents as well.(11)

Managing the FH patient free from ASCVD
In the absence of significant vascular disease (e.g., prior ASCVD event; peripheral artery disease; obstructive carotid artery disease; coronary artery calcification $75% forage/sex; coronary artery calcification $300; or a large burden of soft plaque or multiple plaques noted on coronary computed tomography angiography), the patient should be managed aggressively with conventional approaches, including therapeutic lifestyle changes.(7,8,34) Follow-up evaluation with imaging studies is recommended. The review intervals should be determined on clinical grounds, perhaps ranging from every other year to every 5 years. The frequency of imaging will depend on the severity of the patient’s residual LDL-C elevation as well as the initial degree of any vascular disease.(11,45,46) The key is to very aggressively manage those FH patients with poor prognostic indicators. Comorbidities such as tobacco abuse, hypertension, diabetes mellitus, and a markedly elevated Lp(a) should also be aggressively treated when possible.(7,8,11,33–37)

Reflections on the algorithm
At present, physicians must accept our inability to be certain of the exact genetic etiology of FH in patients in whom they have made a well-considered clinical diagnosis of the condition. Likewise, physicians practicing in the United States must not fear the attestation required to prescribe the aforementioned novel medications for FH. This is not a proclamation of the incontestability of the diagnosis of HoFH. The attestation simply states that HoFH remains solidly on the differential diagnostic list. The pragmatic solution that we propose is likely to widen use of novel medications and lipoprotein apheresis. However, their enhanced use is compatible with best clinical care for a condition that inadequately treated bears a uniquely high risk of ASCVD.(13,14,47)

It is also true that ASCVD outcome studies have not been performed with these novel agents, and their long-term safety has yet to be demonstrated.(19,48) Still, it is reasonable to infer emergent significant risk reduction when this highly at-risk population experiences LDL-C reductions of 25 –50% and greater.(8,11,13,14) Additionally, the proposed algorithm could be readily tested with large cohorts of FH patients, for instance within the context of national and international registries.(49,50) For example, patients defined in the proposed clinical algorithm should be incorporated into the ongoing registry, CASCADE FH. Through CASCADE FH, real-world cost/benefit analyses will become possible. Though the cost of more prevalent drug therapy and lipoprotein apheresis would be problematic, it is not unreasonable to assume that the increased use and effectiveness of these therapies could concomitantly drive down their costs. Included in such a cost analysis (which is beyond the scope of this article) must also be considerations regarding the costs averted by the prevention of ASCVD as well as the improved quality of life from prevention of clinical events and indirect cost savings to society.(13,14,51,52)

A biochemical distinction that may bear on the response to new therapies, particularly with PCSK9 inhibitors,(43,48) has been previously made among patients with severe FH on the basis of residual LDL-receptor functional activity measured in skin fibroblasts.(53) The notion of including such a measurement in the clinical assessment and triaging of patients has appeal, but the technical complexities restrict its application to research settings alone. Additionally, the skin fibroblast, having no role in maintaining our body’s cholesterol homeostasis, may not be the best model on which we should base clinical decisions. Plasma PCSK9 levels vary with LDL-C concentrations,(54) but whether this measurement has a role with clinical management of patients remains unclear.

Finally, the algorithm does not include children, but in this age group the diagnosis of ‘‘high-or very high-risk FH’’ may also be readily made on clinical grounds.(8,10,11) Guidelines recommend that all children with suspected FH be screened with measurement of LDL-C with or without a test for the family mutation, if known, by age 2 years and treated aggressively, including as indicated lipoprotein apheresis, by age 5 years and no later than 8 years.(8,11) There is very limited experience with the new therapies for lowering LDL-C in children. However, children deemed to have high risk FH could enter the algorithm at the stage of confirming subclinical ASCVD and/or aortic valve disease.(8,11)

Baum Challenges in HFH diagnosis and care

So is there a role for genetic testing in the care of FH?
The detection and management of FH includes the entire family. Cascade screening of close family members is part of our duty of care and, resources permitting, this is where there is an important role for genetically testing of index cases to identify the pathogenic mutation/s causative of FH.(5,8,55)

Genetic testing is most unlikely to alter the management of the index case once the clinical diagnosis has been made, but it can certainly make cascade screening more cost-effective and can especially increase the accuracy of diagnosis in children.(52,56–58) The treatment of severe FH in children, although outside the scope of this article, needs to be addressed along similar lines as the pre- sent proposal.(8,11,15,59,60)

Conclusion: enhancing the model of care for severe FH
The physician’s role is to offer each and every patient the best possible standard of care. This is the foundation of the modern era of patient-centered medicine. Instead of grappling with a diagnostic distinction we currently clearly cannot resolve, the time is ripe to focus attention on detecting and appropriately treating the entire spectrum of FH patients in dire need of current best standard of care. Risk stratification and identification of the most severe of these patients should be based on their phenotypic, not genotypic diagnosis, although a genetic diagnosis may be useful in cascade screening families. Patients who have ‘‘high-risk FH’’ or ‘‘very high-risk FH’’ are at extremely high peril of progressive and life-threatening ASCVD. Recalling the adage that inspired an accelerated speed of treatment during the early thrombolytic days, ‘‘time is muscle,’’ we now can use a comparable dictum for this type of FH patient. These individuals share time urgency. Most definitely for them, “time is plaque.”

Future considerations also include the following: improved biochemical typing of the severity of FH and the response to therapy, such as PCSK9 inhibitors, would require the development of simple, precise, accurate and practicable methods for assessing residual LDL-receptor function. Novel imaging methods for detecting inflammation in unstable coronary plaques (61,62) as well as genetic tests to assess individual susceptibility to the side effects of existing (63) and new therapies for FH could in the future be incorporated into the clinical care pathway.

Finally, the algorithm presented is based on our own personal experience of managing caseloads of patients with severe FH who have presented us with clinical challenges and dilemmas. We acknowledge that the proposition is based on expert opinion and therefore constitutes a view- point that requires future testing. It should also be noted however that all guidelines concerning management of HoFH are mainly based on expert opinion (European Atherosclerosis Society/European Society of Cardiology; National Lipid Association; American Hospital Associa- tion/American College of Cardiology; National Institute for Health and Care Excellence; International Familial Hyper- cholesterolemia Foundation). We have remained within current guidelines for FH diagnosis and expanded our therapies in response to our growing understanding of the wide range of FH phenotypic expression as well as clinical predictors of higher risk. The care pathway proposed is a nonprescriptive living document, and as such will need to be investigated and further evaluated, including assessing its effectiveness, utility, and cost-benefit. This is necessary to revise and enhance the protocol and to also allow the incorporation of novel diagnostic and therapeutic capabilities referred to previously that need evaluation in their own right. The algorithm, however, offers clinicians a simplified and pragmatic pathway for more effectively managing high-risk FH patients and lays a new foundation for improvements in international models of care for FH.

Seth J. Baum, MD
University of Miami Miller School of Medicine Miami, Florida E-mail address: sjbaum@fpim.org
E.J.G. Sijbrands, MD, PhD
Department of Internal Medicine Erasmus MC Rotterdam, The Netherlands
Pedro Mata, MD, PhD
Fundacion Hipercolesterolemia Familiar Madrid, Spain
Gerald F. Watts, DSc, PhD, MD
Lipid Disorders Clinic Cardiovascular Medicine Royal Perth Hospital School of Medicine and Pharmacology University of Western Australia, Australia

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40. Schettler V, Neumann CL, Hulpke-Wette M, Hagenah GC, Schulz EG, Wieland E. Current view: indications for extracorporeal lipid apheresis treatment. Clin Res Cardiol Suppl. 2012;7:15–19.
41. Thompson GR. The evidence-base for the efficacy of lipoprotein apheresis in combating cardiovascular disease. Atheroscler Suppl. 2013;14:67–70.
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49. O’Brien EC, Roe MT, Fraulo ES, et al. Rationale and design of the familial hypercholesterolemia foundation CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia registry. Am Heart J. 2014;167:342–349.e317.
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55. Umans-Eckenhausen MAW, Defesche JC, Sijbrands EJG, Scheerder RLJM, Kastelein JJP. Review of first 5 years of screening for familial hypercholesterolaemia in the Netherlands. Lancet. 2001; 357:165–168.
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60. Descamps OS, Tenoutasse S, Stephenne X, et al. Management of familial hypercholesterolemia in children and young adults: Consensus paper developed by a panel of lipidologists, cardiologists, paediatricians, nutritionists, gastroenterologists, general practitioners and a patient organization. Atherosclerosis. 2011;218:272–280.
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Cholesterol and Vascular Disease Part 3: How Tiny LDL Particles Can Cause Such Harm

September is National Cholesterol Education Month. In support of this important educational initiative we are republishing our six part series on cholesterol and the role it plays in cardiovascular disease.

Note: Seventy-one million American adults have high cholesterol, but it is estimated that only one-third of them have the condition under control.

Previously we discussed the relevance of LDL particles, emphasizing their role as the main drivers of vascular disease. We did not, however, discuss how they wreak such havoc upon our blood vessels. Today we will do so.

LDL particles do wonderful things. They transport cholesterol and triglycerides to various parts of our body for fuel, storage, or even to serve as building blocks for other important molecules. They even transport vitamin E to our brains in order to enhance growth and development in infants, and proper brain function in adults. So how can something so good, be so bad? The answer lies in numbers. The aphorism “too much of a good thing can be bad” applies perfectly to LDL particles; they are necessary for a healthy body, but only in small quantities. The numbers most of us possess are so far out of range, they are literally killing us. But how? What happens when these tiny particles make their way beneath the delicate yet vital single cell layer (called the endothelium) that lines our blood vessels? Read More…

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Cholesterol and Vascular Disease: Part 2: LDL-Cholesterol is Important, but LDL-Particle Number is Far More Revealing

September is National Cholesterol Education Month. In support of this important educational initiative we are republishing our six part series on cholesterol and the role it plays in cardiovascular disease.

Note: Seventy-one million American adults have high cholesterol, but it is estimated that only one-third of them have the condition under control.

We left off with part 1 of the Cholesterol and Vascular Disease blog concluding that the two key assumptions made by cholesterol scientists in the 1940s and ‘50s were wrong. These assumptions were: 1. All LDL particles are the same size and 2.  All similarly-sized LDL particles have the same cholesterol content. Had these assumptions been correct there would have been no need to evaluate any other LDL parameter beyond LDL cholesterol. Given the fact that they are wrong however, means that looking simply at LDL cholesterol allows for the persistence of significant and dangerous “hidden risk”.  And risk that is hidden is risk that will not be corrected. Therefore we must dig deeper into this issue and how it can translate into a higher risk for developing arterial plaque.

First, let’s deal with the size issue. We now know that many individuals have very small LDL particles, while others have large, normally-sized particles. The larger the LDL particles, the more cholesterol they can fit within them. Smaller particles on the other hand cannot carry nearly as much cholesterol as their larger brethren. (That is simple enough. A large bucket holds far more water than a tiny cup.) Read More…

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Cholesterol and Vascular Disease: Part One – The History of Cholesterol

September is National Cholesterol Education Month. In support of this important educational initiative we are republishing our six part series on cholesterol and the role it plays in cardiovascular disease.

Note: Seventy-one million American adults have high cholesterol, but it is estimated that only one-third of them have the condition under control.

For over twenty years I have practiced and taught Cardiology. Starting in the invasive and hospital-based world (performing angioplasties, stents, atherctomies, lasers, and electrophysiologic procedures) and then segueing into prevention, cholesterol abnormalities, and cutting-edge non-invasive imaging of the carotid and coronary arteries, I have had the unique and great fortune to participate in exceptionally diverse aspects of cardiovascular health and illness. I have learned a great deal along the way and some of these experiences have been shared in articles and books I’ve written. Now I’d like to clarify one of the murkiest issues I’ve encountered in all my years of practice – the cholesterol conundrum. This post is the first of a series that will hopefully clarify the cholesterol debates that currently perplex numerous patients and physicians.

In the early 1900s a young medical student named Anitschkow made the initial association between cholesterol and vascular disease. He fed unsuspecting rabbits a high cholesterol diet. After they had enjoyed a number of tasty meals he sacrificed them in order to examine their aortas (the very large blood vessel that runs from our heart to our legs). What he found was revolutionary. The rabbits that consumed their normal low fat diets were just fine, but the cholesterol-fed rabbits had all developed severe plaques in their aortas. Of course none of the rabbits was lucky (they were all killed) but had they been allowed to live, the ones with normal diets would have done great, while those who had consumed large quantities of cholesterol would have suffered from heart attacks, strokes and premature death. Read More…

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Knowledge Reveals Profound Ignorance: the Hallmark of Medicine

I’ve said this many times before, Medicine Is a process, one that replaces old ideas with new understanding. HDL offers a perfect example. We all know HDL to be “the good cholesterol”. Simple, correct? HDL is the cholesterol that protects us from heart attacks and strokes; that’s its job. Low HDL implies risk while high HDL, protection. Enter the science of the past decade. Everything has changed. We’ve discovered that raising HDL in patients already on statin medications does not (as we previously believed) necessarily equal risk reduction. Far more profound than this realization is the fact that HDL is NOT “the good cholesterol”. Yes, it is a carrier of cholesterol, and yes it helps reduce the risk of heart attack, but NO it is NOT cholesterol.

It turns out that HDL is an extraordinarily complex structure with many phases of life and many forms and functions. HDL can be a disc and it can be a sphere. It can be very large or very small. Its surface can carry over 200 different types of fats and about 200 various forms of proteins. And, specific combinations of these fats and proteins will imbue the HDL particle with specific functions. HDL particles can help us fight infections, carry vitamins and nutrients throughout our bodies, protect LDL particles from oxidation, and shuttle proteins around the body to be given to more needy recipients. The list goes on. HDL is amazing. And the more amazing we know it to be the more we must admit how little we understand HDL. So if HDL is so complex, imagine how intricate our entire bodies are. The bottom line, please be patient with your doctor. He or she is trying desperately to understand and work with an ever-expanding field of information. Please understand that what may seem to be mistakes in science are often simply the byproducts of growth and development. We all aspire to the same goal, the expansion of health and reduction of illness. We really are all on the same team.

Visit vitalremedymd.com for preventive healthcare solutions.

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Familial Hypercholesterolemia – a Common Yet Life-Threatening Genetic Disorder

This article was originally published on HomeCareforYou.com.

You or someone you love might be harboring an undetected threat called Familial Hypercholesterolemia (FH). As genetic disorders go, FH is quite common. In fact, the condition occurs five times as frequently as Cystic Fibrosis. FH victims typically have severely elevated cholesterol; their disorder frequently remains undetected; and most patients develop vascular disease very early in life. These people often die from heart attacks in their forties and fifties. One consequence of the explosion in our understanding of genetics has been the discovery of more than 1600 genetic mishaps that can lead to FH. In the general population this disorder occurs in one out of every 500 people. Specific populations called founder groups (groups of people who are descendants of a genetically similar small population) such as French Canadians, Christian Lebanese, and South African Ashkenazi Jews have a prevalence of this malady that can be as high as one in sixty-seven people.

So what is FH and how does it harm so many?
cholesterol meterIn order to understand this ailment we must first review a few basic elements regarding cholesterol and its main transporter, LDL (Low Density Lipoprotein). Cholesterol is the building block for many key components in our body. LDL is a spherical lipoprotein particle that carries cholesterol. Think of it as a floating bubble that carries its freight— cholesterol and triglycerides—from one part of our body to another. This LDL “bubble” serves as a barrier “protecting” us from what would otherwise be the consequence of cholesterol floating freely in the blood. The result of that scenario would be instant death; free cholesterol would form razor-sharp crystals shredding anything in its path. LDL particles obviously provide a valuable function as our body’s dominant cholesterol transporters, but they have been dubbed the “bad cholesterol” because overly-abundant levels of these lipoproteins clearly lead to heart attacks and strokes. Thousands of studies have proved this; it is one of the few “facts” we have in modern medicine. As a result of our understanding of the detrimental consequences of high LDL, medications such as the statins have been created to lower LDL levels and in turn diminish our chances of experiencing a heart attack or stroke.

Lowering LDL with statins
Most of us know that the fundamental medication in cholesterol management is the statin. Statins work by blocking a critical enzyme in the multi-stepped process of cholesterol synthesis. This enzyme is present in every cell in the body. In response to the statin-induced cholesterol decline within our cells, affected cells deliver a greater number of LDL receptors to their surface. Think of receptors as adhesive-coated indentations in the cell membrane. These receptors capture the LDL “bubbles” as they float by in the blood. The receptor with its bonded LDL particle is then brought inside the cell. Within the cell, the cholesterol contained within the LDL particle can be utilized in any way the cell deems fit. For instance, it can be a building block for Vitamin D in the skin, bile acids in the liver, or testosterone in the testes. Once a cell has acquired enough cholesterol to serve its manufacturing needs, it stops overproducing LDL receptors. All cells engage in this process, but our liver is the organ that manufactures the majority of LDL receptors, thereby most meaningfully diminishing the content of LDL within our blood. To maintain a healthy balance of LDL within our bodies it is essential for our cells – particularly within our liver – to be able to produce LDL receptors, position them on their surface, and capture their prey—LDL particles.

The Malady of FH
Patients with Familial Hypercholesterolemia possess a genetic defect that disrupts their LDL receptors. In some cases the patient manufactures too few receptors; in others, the receptors themselves are defective. Even though they capture LDL, faulty receptors are unable to successfully bring their cargo into the cell. This defect results in a situation wherein the cell “effectively” lacks LDL receptors. There are two types of FH patients, those who have inherited one faulty gene from one parent (the common variety – 1 in 500) and those who have inherited one faulty gene from both parents (the extraordinarily rare form – 1 in 1,000,000). When an individual receives an abnormal gene from only one parent, he or she is known as heterozygous for the particular genetic flaw involved. An individual is homozygous for a disorder when both parents contribute abnormal genes. Because of the nature of the FH genetic defect, heterozygous individuals–those possessing only one genetic error from one parent–will experience the disorder, albeit in a less aggressive form than their homozygous counterparts. As this defect causes suboptimal LDL receptors, patients develop extraordinarily high LDL cholesterol levels. A typical heterozygous patient will have LDL cholesterol in the 200s. Homozygotes have LDL cholesterols over 500! So here is the problem. From conception on, FH patients’ bodies are bombarded with excess LDL cholesterol. Their arteries, tendons, eyes… everything is soaked in cholesterol. In contrast to patients who do not have this disorder, afflicted individuals have a markedly prolonged burden of high LDL. They bathe in cholesterol their entire life. That is why these individuals develop premature cardiovascular disease. In fact, patients with FH have a 12-fold higher risk of coronary artery disease compared with their own unaffected relatives. FH patients have a fifty percent mortality by the age of sixty if they are inadequately treated. And even more frightening, FH patients typically live their lives in the dark, undiagnosed and untreated. With- out being properly recognized, appropriate and life-saving care cannot possibly be rendered. Thus, our charge is crystal clear: Doctors must improve our ability to identify these patients early on in life and by so doing treat them appropriately and diminish their risk of dying young.

The FH patient
Let’s truly “look at” the patient with FH. In order to be able to recognize and appropriately treat these individuals, doctors and patients must be familiar with what this disorder looks like. First it’s critical to know that LDL cholesterol levels fluctuate throughout our lifetimes. We are born with our lowest levels, and after puberty LDL steadily rises throughout the rest of our lives. So pediatricians must appreciate that an LDL cholesterol of 160 might indicate the presence of FH, whereas in an adult this same LDL cholesterol level would be considered only moderately elevated. It is also important to understand that men and women have very different cholesterol levels. Until menopause, women have lower total cholesterol, LDL cholesterol, and triglyceride levels; and higher HDL cholesterol levels than men. Unfortunately, after menopause each of their lipid parameters deteriorates. Thus, physicians need to have a solid grasp of the influence that gender and age have on all lipid values (my lecture on this can be found at (http://aspconline.org/resources/ highlights.php). You can see that there is often great complexity in interpreting lipid and lipoprotein values; it is therefore important at times for patients to see lipid specialists in order to receive more refined therapy (To find a lipid specialist near you, visit www.lipid.org). We know what FH patients’ lipids look like, and we know that their vascular tree is severely diseased by an overabundance of LDL, but what other manifestations result from such high lifetime LDL levels? In addition to vascular disease, there are also disfiguring non-arterial consequences of FH. A life-time of markedly elevated LDL cholesterol can lead to an accumulation of fat in unusual parts of our bodies. Our tendons are often affected where fatty deposition can lead to palpable lumps called xanthomas. The Achilles tendon is a frequent target of this aberrant fat accumulation. Tendon xanthomas can easily be seen by the naked eye. Our palms can also be affected, with an abnormal yellowish discoloration in their creases called palmar xanthomas. Another area for physicians to focus their attention is our eyes. In the corner of the eye, adjacent to the nose, we can at times see yellowish deposits called xanthelasmas. In the eye itself, we sometimes see light-toned fatty deposits called corneal arcus. These tend to occur on the bottom and top of the cornea at the edge of the iris (the-colored part of the eye) because that is where the density of blood vessels is greatest. Seeing tendon and palmar xanthomas, or corneal arcus in patients under the age of forty-five, essentially confirms the diagnosis of FH.

Treatment Options
In 2011, initiating an FH call to action, the National Lipid Association released guide- lines to improve the identification and treatment of these patients. The NLA guidelines emphasize early detection; we now know that under appropriate circumstances very young children (even two years old in some cases!) should be screened. Once a patient has been diagnosed with FH, it is important not to stop there, but to perform “cascade” testing. This is a rigorous search of the patient’s relatives to determine who among them might also have the disease. Through proper cascade testing, doctors can discover many additional patients who would otherwise have been left untreated. Along with the National Lipid Association, other organizations such as the American Society for Preventive Cardiology and The FH Foundation are doing their part to raise FH awareness. Pharmaceuti- cal companies such as Genzyme and Aegerion are also help- ing out. Pharmaceutical companies frequently sponsor scientific educational conferences, enabling doctors to remain current with the ever-changing landscape of medical knowledge. They build websites devoted strictly to educating the lay public, allowing all people to more effectively become their own advocates. And of course they also create the medications, such as statins, that lower our risk of heart attack and stroke. In the case of FH, Gen- zyme has fashioned a novel medication, Mipomerson, in order to more effectively manage patients with extraordinarily high LDL levels. Aegerion has created Lomitapide another unique LDL-lowering agent. Other innovative agents are in the works. Those of us who specialize in the management of severe lipid disorders are thrilled to have access to ground-breaking medications that will hopefully make an even greater dent in the damage inflicted by FH. Finally, let’s examine the state-of-the-art management of FH individuals.

First and foremost, diet and exercise are always paramount in maintaining optimal cardiovascular health. For FH patients though, more aggressive treatment is always needed. To “get them to goal”, combination therapy is uniformly required, which means using a statin as the foundation and then adding two, three, or even four other medications. Novel agents such as Lomitapide (Aegerion) and Mipomerson (Genzyme) were recently FDA-approved for the treatment of severely afflicted FH patients. These medications represent a new and welcome addition to Lipidologists’ medical armamentarium. Even still, many of these patients require more aggressive interventions. One of the best modalities available is LDL-Apheresis. In a manner similar to dialysis (minus the fatigue and potential side-effects), patients are connected to a filtering machine through two IV lines. Blood is withdrawn from one IV, circulated through a series of filters, and returned to the body through the other IV. Typically the two-hour procedure is performed in an outpatient- setting once every other week. Each treatment results in a 60 percent to 80 percent reduction in LDL (other pro-atherogenic substances are also removed). Over the ensuing two weeks, the LDL rises steadily until it can be lowered once again with another treatment. Despite the fact that LDL gradually increases between treatments, studies have demonstrated a nearly 75 percent reduction in cardiovascular events when patients are treated with LDL-Apheresis. Thus, LDL-Apheresis is a viable option for difficult-to-treat heterozygotes and mandatory for all homozygotes. (To find a center near you, visit www.lipid. org) Familial Hypercholesterolemia is a frequently undiagnosed genetic disorder adversely affecting patients’ lipids and leading to premature heart attack, stroke, and death. A solid understanding of age and gender associated lipid fluctuations, physical signs of FH, and the nuances of cholesterol management is essential for doctors to diagnose and treat this disease. Somewhere between 600,000 and one million Americans suffer from FH. Consequently we must do our best to understand, manage, and perhaps most important of all, “spread the word” about this insidious but conquerable threat. It is a mission that can be accomplished only through the coordinated efforts of doctors, scientists, medical associations, industry, and patients themselves. Fortunately, this is what we find taking place today.

Please read more about preventive cardiology at www.preventivecardiologyinc.com.

Images courtesy of HomeCarForYou.com

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Cholesterol and Vascular Disease Part 5: Non-Statin Cholesterol Medications

Last week, in part 4 of this blog series we spoke about the statins. This week we will look at other cholesterol medications. Another very effective method for decreasing LDL is by combining a statin with other drugs.

Medications

  • One of the most effective add-on medications is Ezetimibe. This medicine works by blocking cholesterol absorption in our small intestine. It’s not just the cholesterol we eat that is blocked; more importantly it’s the enormous amount of cholesterol that is recycled daily between our liver and intestine. At this point, clinical trials have failed to demonstrate a reduction in heart attack and stroke by using Ezetimibe. Still, many lipid specialists (me included) believe that future trials will demonstrate its importance in particular patient populations.
  • Another important class of cholesterol-lowering drug is called the bile acid sequestrants. Welchol is the most commonly utilized of these medications. By blocking the reabsorption of bile acids in our intestine our liver is forced to produce more bile acids from their precursor, cholesterol. Interestingly, WelChol also has the added benefit of lowering blood sugar and increasing HDL. Patients with very high triglycerides should be careful of this medication because it can increase triglycerides further. Like Ezetimibe, WelChol is best used in combination with a statin.
  • Niacin, vitamin B3, is also often used in cholesterol management. It’s best known for its impact on raising HDL and lowering triglycerides. Niacin also has an effect on LDL however. It increases LDL particle size, and by so doing, can actually decrease LDL particle number. Niaspan is the pharmaceutical version of niacin that is most commonly utilized by the physicians. It’s method of action is poorly understood and quite complex. Like WelChol and Ezetimibe, niacin is also best used in conjunction with a statin.
  • Fenofibrates represent yet another class of medications that is used for cholesterol management. Their dominant effect is to lower triglycerides and raising HDL. At this point clinical trials have not found them to be effective in decreasing cardiovascular events, but they are improving lipids and lipoproteins.
  • The active ingredients in fish oil, DHA and EPA, can also have an effect on lipids and lipoproteins. They can lower triglycerides, increase HDL, and sometimes increase particle size and by so doing decrease particle number. In patients with very high triglycerides, fish oils can at times increase LDL cholesterol. Their method of action is also quite complex and beyond the scope of this blog.

Diet and Exercise

In managing cholesterol abnormalities we should never neglect the value of diet and exercise.  A healthful diet will unquestionably improve your lipid and lipoprotein profile. Even when taking a statin, a healthful diet must be maintained.  In fact, there is a specific dietary program called the Portfolio Diet that is geared specifically to lower cholesterol. Exercise can also benefit your lipid and lipoprotein profile. Daily exercise for 30-60 min. can significantly decrease your LDL particle number, increase your HDL, and lower your triglycerides. The bottom line, if you’re physically capable, exercise every day.

A few other cholesterol management strategies are either in the pipeline, or utilized only in very high risk patients. They will be the subject of next week’s blog, part 6 in this series, Cholesterol and Vascular Disease.

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Cholesterol and Vascular Disease Part 4: The Great Statin Debate

It has been unequivocally established that high levels of LDL can lead to heart attacks and strokes. Parts 1- 3 of this blog described the history of cholesterol, the superiority of LDL particles over LDL cholesterol, and the pathophysiology associated with an overabundance of LDL particles. In addition to our understanding of the biological process whereby LDL particles cause vascular disease, we also have a plethora of clinical trials demonstrating the efficacy of lowering LDL.

Everyone–lay people, physicians, and scientists–is plagued by the overabundance of clinical trials involving all aspects of health and medicine, many of which clearly contradict one another. In order to practice medicine in a fashion that appropriately considers the outcomes of these clinical trials, one must find a way to make sense of them. My approach has been to evaluate the clinical trials not just individually, but as a whole. I look for trends. When studies repeatedly reach the same conclusions (especially when they pathophysiologically “make sense”) I feel much more comfortable concluding that they are correct. In the case of LDL we find a commonality that is indisputable. The studies repeatedly demonstrate that statins–a class of cholesterol lowering medications I will momentarily describe–uniformly decrease the risk of cardiovascular events by about 30%. This event reduction is consistent among patients in the setting of both primary and secondary prevention. And so we must listen to the studies and lower our patients’ LDLs accordingly.

Statins are the class of medication for cholesterol management that unequivocally possess the greatest amount of science supporting their use. These medications work by blocking a critical enzyme in our body’s production of cholesterol. In response to lower levels of cholesterol within our cells, the cells increase surface receptors to bring in more LDL particles. The result is a diminution in the number of LDL particles – as well as the LDL cholesterol – in our bloodstream. Read More…

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Cholesterol and Vascular Disease: Part 2: LDL-Cholesterol is Important, but LDL-Particle Number is Far More Revealing

We left off with part 1 of the Cholesterol and Vascular Disease blog concluding that the two key assumptions made by cholesterol scientists in the 1940s and ‘50s were wrong. These assumptions were: 1. All LDL particles are the same size and 2.  All similarly-sized LDL particles have the same cholesterol content. Had these assumptions been correct there would have been no need to evaluate any other LDL parameter beyond LDL cholesterol. Given the fact that they are wrong however, means that looking simply at LDL cholesterol allows for the persistence of significant and dangerous “hidden risk”.  And risk that is hidden is risk that will not be corrected. Therefore we must dig deeper into this issue and how it can translate into a higher risk for developing arterial plaque.

First, let’s deal with the size issue. We now know that many individuals have very small LDL particles, while others have large, normally-sized particles. The larger the LDL particles, the more cholesterol they can fit within them. Smaller particles on the other hand cannot carry nearly as much cholesterol as their larger brethren. (That is simple enough. A large bucket holds far more water than a tiny cup.) Therefore, if you have very tiny LDL particles, you need many more of them to generate an LDL cholesterol content (LDL-C) than someone with very large particles. (Back to the water analogy –  If you need to carry a quart of water and you have one quart-sized bottle, you can carry all the water in one bottle. If you have only cups available, you will need four of them to carry the same amount of water.) The result of this disparity in LDL size is that two people with the same LDL-C (130 mg/dL for example) will have very different LDL particle numbers when their LDL particles are very different sizes.

The second erroneous assumption was that similarly-sized LDL particles always carry the same amount of cholesterol within them.  This too has turned out to be false.  Under certain metabolic conditions – diabetes, obesity, overweight, high triglycerides, low HDL– LDL particles tend to be under-filled. Once again in these patients in order to generate a particular LDL-C level, more particles are required.  (Back to the water analogy – if you have only cups available to fill, but are permitted to fill them only half way, it will take twice as many cups to carry the same amount of water as your friend who is allowed to fill the cups to the very brim.) Therefore, two individuals with precisely the same LDL-C can have vastly different LDL-Ps. So the bottom line is that LDL-C is NOT a good surrogate for LDL-P after all. OK, you buy that, but you might now be asking yourself,” Does it really matter if I have a lot of LDL particles?” A common and excellent question with a simple answer – YES! This is because more particles translate into a higher risk for developing plaque.  And the reason this is so, is actually quite intuitive. The more LDL particles a person has bouncing around in the blood stream, the more likely the particles are to encounter and penetrate the walls of his/her arteries. (The shotgun vs. the pistol is another helpful analogy. Even if you are an expert marksman, you are much more likely to hit your target with a shotgun than a single-shot pistol.) This is important because the penetration of our arteries by LDL particles initiates the process of atherosclerotic plaque formation. Yes, it all begins with a single particle. Next week we will discuss how such simple LDL particles can initiate a process that still kills more Americans than any other disease.

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Cholesterol and Vascular Disease: Part One – The History of Cholesterol

For over twenty years I have practiced and taught Cardiology. Starting in the invasive and hospital-based world (performing angioplasties, stents, atherctomies, lasers, and electrophysiologic procedures) and then segueing into prevention, cholesterol abnormalities, and cutting-edge non-invasive imaging of the carotid and coronary arteries, I have had the unique and great fortune to participate in exceptionally diverse aspects of cardiovascular health and illness. I have learned a great deal along the way and some of these experiences have been shared in articles and books I’ve written. Now I’d like to clarify one of the murkiest issues I’ve encountered in all my years of practice – the cholesterol conundrum. This post is the first of a series that will hopefully clarify the cholesterol debates that currently perplex numerous patients and physicians.

In the early 1900s a young medical student named Anitschkow made the initial association between cholesterol and vascular disease. He fed unsuspecting rabbits a high cholesterol diet. After they had enjoyed a number of tasty meals he sacrificed them in order to examine their aortas (the very large blood vessel that runs from our heart to our legs). What he found was revolutionary. The rabbits that consumed their normal low fat diets were just fine, but the cholesterol-fed rabbits had all developed severe plaques in their aortas. Of course none of the rabbits was lucky (they were all killed) but had they been allowed to live, the ones with normal diets would have done great, while those who had consumed large quantities of cholesterol would have suffered from heart attacks, strokes and premature death. Years went on and more and more scientists studied cholesterol and its effect on our bodies. In the 1940s, a technique called analytic ultracentrifugation was developed to study the fat within our blood. Scientists learned a great deal from this technology but one discovery stands out most for me. They learned that cholesterol does not float freely in our blood. It circulates instead securely contained within a variety of tiny particles called lipoproteins. These particles are used to shuttle cholesterol from one part of our body to another. Their job is to prohibit cholesterol from being exposed to contents in our blood stream – by protecting the cholesterol these particles prevent its crystallization, a phenomenon that if it occurred, would have devastating consequences.

The major lipoproteins – remember, these are the carriers of cholesterol – are called LDL, HDL, VLDL and Chylomicrons. Our livers make VLDL particles while our intestines make chylomicrons. LDL is the most atherogenic particle (causing plaque build-up), while HDL is an athero-protective particle (decreases plaque). The scientists and physicians of that time understood this and therefore wanted to establish a way to test patients and ultimately treat them for cholesterol disorders. They knew that counting the number of LDL lipoprotein particles would have been optimal, but the ultracentrifugation machines were too large and costly to place throughout the nation. They made a couple of assumptions and concluded that testing for the amount of cholesterol contained within all of our LDL particles could serve as an accurate surrogate marker for the number of LDL particles (LDL-P). They believed LDL-C (the amount of cholesterol within our LDL particles) would track beautifully with LDL-P. And so, LDL-C was dubbed the gold standard for cholesterol measurement and therapeutic interventions. Unfortunately the assumptions they made to dub LDL-C the gold standard by default were dead wrong.

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