ACC/AHA Guidelines: Not a Replacement for Clinical Contemplation

On May 19th the Journal of the American College of Cardiology published an illuminating paper by Pant et al. examining the impact of a dramatic change in one of the Cardiac Guidelines. The paper was entitled “Trends in Infective Endocarditis Incidence, Microbiology, and Valve Replacement in the United States from 2000 to 2011”. In 2007 the ACC/AHA Guidelines were radically shifted, advocating an enormous reduction in sub-acute bacterial endocarditis prophylaxis (SBEP) precautions. The rationale for the dramatic shift from an aggressive to a conservative stance emanated from two findings: a lack of RCT evidence for the need for SBEP precautions under most circumstances, and the growing problem of antibiotic resistance. Without claiming prescience or any other such miraculous gift, I will tell you that at the time I predicted a significant future rise in endocarditis. My belief was that the guidelines overshot their intentions. Some individuals, I surmised, have valvular heart disease that predisposes them to developing SBE yet fails to be “significant” enough to make them candidates for the revised SBEP recommendations.

For several years I bucked the system and continued my aggressive prophylaxis. Then I buckled. I followed the guidelines to a tee. Though none of my patients has developed SBE, I now question my decision to cave under the pressure of the guidelines. I have always been one to try to think through issues, to treat patients outside any preordained box and beyond an overly simplified algorithmic construct. But in this case I felt perhaps I should just go with the flow. In truth, it was just easier to do so. My liability was lessened and my decision-making efforts were simplified. Yet, in retrospect, seeing the predictable rise in streptococcal SBE, I have been forced to re-examine my decision. In doing so, once again I am confronted with our current fixation on RCTs as proof positive “evidence,” with all other levels of understanding being “non-evidence”.

The absence of RCTs in this construct is tantamount to a lack of evidence. This paradigm is of course false. Many levels of valid evidence exist and oversimplification, though appealing, is inherently flawed and theoretically dangerous. We see this now in eight years of follow up after the change in ACC/AHA SBEP Guidelines. We also see this in many other aspects of everyday practice. Though I chose an easier and perhaps idler path in this circumstance, I will now reverse my position and once again give greater thought to each SBEP recommendation I render. It will take longer to do so; more complex doctor-patient discussions will be required; and larger liability will fall upon my shoulders. But these are the elements required to be a better physician. I owe it to my patients, and equally importantly to myself, to do so. Having said this, pragmatic issues remain. How do we practice medicine in an efficient, cost-effective, economically sound, intellectually stimulating, personalized, high-level fashion, while adhering to the mounting pressure of regulatory changes and requirements? This is the question that requires our most focused attention yet typically receives short shrift. For modern American Medicine to enjoy the future we all believe it deserves, this question, along with its counterparts, deserves our full and undivided attention.

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Homocysteine and Folic Acid Supplementation: Another Medical “About Face”

On March 15, 2015 JAMA published on line the results of a superbly designed and potentially practice changing trial. The China Stroke Primary Prevention Trial (CSPPT), tested whether or not the addition of folic acid to anti-hypertension medication could reduce the occurrence of a first stroke. As three quarters of all strokes are “first strokes” and as strokes are a leading cause of death and disability worldwide, the question posed by this trial had far reaching implications. The trial met its endpoint so quickly and incontrovertibly that for ethical reasons it was prematurely terminated. Folic acid can reduce the risk of stroke. Those of us who have open-mindedly interpreted prior studies expected this finding; many others found the results to be shocking.

Important homocysteine related trials like HOPE 2 and others had already demonstrated either statistically significant reductions in stroke with folic acid supplementation or at least signals toward such an outcome. Yet many of the most “vocal” researchers, physicians, and reporters proclaimed that since heart attacks were not reduced with folic acid, “the homocysteine hypothesis was dead.” This perspective always bothered me. We had observational and even interventional trial data supporting the use of folic acid in certain settings. And stroke, the disorder we could impact with a simple vitamin, is horrific. Strokes are terrifying, disabling, and deadly. They are also extraordinarily common. So why would these doctors, scientists, and media members snub data supporting a simple and safe vitamin treatment to potentially reduce such events? It would be helpful to know the reason, as the same phenomenon is currently occurring in relation to omega-3 fish oils.

Plenty of data support fish oil supplementation yet a few trials do not. And as with homocysteine, it seems that the media and many scientists/doctors have chosen to focus their attention on the limited neutral – and oftentimes overtly flawed – data rather than supportive experimental, biologic, physiologic, clinical trial, and common sense evidence. Interestingly, one of the vital lessons gleaned from CSPPT is that those individuals with either specific genetic mutations or very low levels of folic acid received the greatest benefit (reduction of stroke) from taking folic acid. In parallel fashion, one of the key trial limitations of fish oil studies has been the persistent failure to measure blood levels of the omega-3 fatty acids DHA and EPA. It certainly stands to reason that those with lower levels of these critical fats will also gain the greatest advantage from their supplementation. So why not simply measure them? Well, in clinical practice, some of us do. And some of us even advise correcting abnormally low levels with simple and safe fish and fish oil pill consumption.

I am at once elated and disturbed by the CSPPT findings. They prove the efficacy of a simple therapy; yet, they broadcast the hubris of many in my field. Time and again we have had to make an about face in our opinions and recommendations. I see nothing inherently wrong in changing our position as more data emerge. What I struggle with is the egg on our face, the about face that occurs far too late, long after adequate data have told us what to do. Perhaps we will learn though. Maybe as more trials like CSPPT emerge, as more scientists and doctors with the conviction and devotion to finding a greater truth push tirelessly along their paths we will finally learn to be more open minded and accepting of ideas and findings even when they go against our grain.

For more information about the supplements and vitamins critical to your everyday health visit www.vitalremedymd.com.

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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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39. Leebmann J, Roseler E, Julius U, et al. Lipoprotein Apheresis in Patients with Maximally Tolerated Lipid Lowering Therapy, Lp(a)- Hyperlipoproteinemia and Progressive Cardiovascular Disease: Prospective Observational Multicenter Study. Circulation. 2013;128: 2567–2576.
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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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Our “Guardian Genes”: The Modern Doctor’s Holy Grail

Any doctor worth his salt recognizes that patients don’t always respond the way we anticipate they will. For example, utilizing the best of our scientific methodologies we know LDL is causally related to vascular disease. High LDL causes disease while low LDL mitigates it.  Yet, we occasionally see patients with extraordinarily high LDL and no disease, as well as those with very low LDL and severe disease. In some circumstances, patients with a vascular disease promoting mutation – as in Familial Hypercholesterolemia – will have severe and premature heart disease while their relatives with the same mutation somehow remain unscathed. How can this be? What we’ve all come to believe is that there must be protective genes that somehow offset the detrimental aspects of other genes. Let’s dub these desired genes “Guardian Genes”.

In the case of vascular disease promoting disorders, Guardian genes cause the exception, not the rule. They Teflon coat individuals who under normal circumstances should develop heart attacks and strokes. This wonderful rarity can unfortunately lead to a misunderstanding of disease processes as well as their cures. When someone speaks of grandma whose LDL was 300 and yet lived to the ripe old age of 100, sans MI or stroke, the take-home message often is, “Those doctors don’t know what they’re talking about. LDL is not the cause of heart disease. My LDL is only 200 and as grandma lived to 100 and with worse numbers, why should I take that statin medicine. Just look at the Internet and you can see how terrible those medicines are.” Unfortunately the Guardian genes are currently merely speculative. As such we cannot identify them. And, we know that intra-family variability in development of vascular disease supports the notion that theses guardian genes are inherited entirely separately from the disease promoting genes. What that means is just because grandma won the lottery, don’t bet your life (literally) that you did as well. In my own practice I’ve seen 70-year-old parents mourn the deaths of their 40-year-old sons and daughters who died of MIs. Though they shared the same bad genes, the parents did not suffer the unfortunate (and more predictable fate) of their children.

The bottom line here is that we doctors must base our treatment recommendations on the odds. We weigh and measure the pros and cons of therapeutic options (like the statins) against the likelihood that an individual patient will develop a serious event such as a heart attack, stroke, or even death. We use our best judgment based upon many facets of knowledge and understanding. We then make our recommendations hoping to stave off future adverse cardiovascular events. We never risk a patient’s life hoping he or she has inherited a guardian gene. Until we identify the elusive lifesaver guardian genes they will remain relegated to being the modern day Holy Grail of genetics. We all pray we will find them, but until that day we must continue to practice within the limits of our understanding. And while we do, we hope our patients understand that our suggestions and recommendations are born of both a deep understanding of the science of medicine and the burning desire to help our patients live the longest and best lives possible.

Learn more about preventive cardiology at www.preventivecardiologyinc.com.

For more information more about essential vitamins and supplements visit www.vitalremedymd.com.

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IMPROVE-IT Trial: the Day of Reckoning Approaches

Tomorrow morning a large crowd will gather here at the AHA meetings in frigid Chicago to learn the findings of the long-awaited IMPROVE-IT trial. The trial will demonstrate whether or not Ezetamibe (Zetia) added to a Simvastatin (Zocor) successfully decreased cardiovascular events in high-risk patients.

Many lipid specialists and cardiologists, myself included, have used Ezetamibe in combination with statins since the drug’s release. We believe wholeheartedly in the “lower LDL is better” hypothesis. Our clinical results, though anecdotal, have been uniformly exceptional. We fully anticipate that – barring confounding circumstances – the trial will be a winner.

Making this prospect even more impactful is the current NEJM publication by Dr. S. Kathiresan, (a brilliant Harvard Cardiologist/Geneticist) describing a novel genetic mutation that decreases LDL cholesterol, and concomitantly reduces ASCVD events. Where is this mutation you might ask: In the same receptor that is blocked by the drug Ezetamibe. Essentially individuals bearing such a mutation are born with the equivalent of continual Zetia use. This experiment of nature surely supports the speculation that Ezetimibe effectively lowers heart disease, even on top of statin therapy.

For now, we can only speculate about IMPROVE-IT’s findings. Tomorrow will bring some hard facts along with an assessment of how the findings will impact not only doctors’ use of Ezetamibe, but equally importantly, how health insurance companies will view the matter as well. Until tomorrow my admittedly unbiased fingers will be tightly crossed.

Learn more about preventive cardiology at www.preventivecardiologyinc.com.

For more information more about essential vitamins and supplements visit www.vitalremedymd.com.

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The National Lipid Association – A Glimmer of Hope

The field of Medicine is undeniably in turmoil. Patients are unhappy with long wait times in doctors offices coupled with ever shortening visits with their physicians. Doctors are dismayed by their unprecedented spike in “busy work,” instigated predominantly by insurance companies and governmental mandates. The fallout from more time spent on paperwork is of course less time spent with patients. There are after all only 24 hours in a day.  So it is eminently fair to say that neither doctors nor patients find themselves happy with the current course Medicine is following. Oftentimes outlooks are so bad that many of us in the field feel there is no hope. In essence we believe the battle has been lost; there is no chance of recovery.

Enter the National Lipid Association (NLA). Currently boasting over 3,000 active members, the NLA is a group of diverse doctors, nurses, dietitians, scientists, and exercise physiologists whose governing goal in participating in the organization is to improve healthcare. I just returned from the 2014 Annual NLA meetings in Orlando Florida and was once again struck by the authenticity of this sentiment. Meetings began as early as 6 AM and extended well into the evening hours. And the seats were not bare. They were filled by groups of highly focused and engaged individuals. Ranging from Cholesterol Guideline discussions, to basic science talks on drugs’ mechanisms of action, to lectures reinforcing the need to amplify our efforts to identify and treat patients with the not so rare but highly lethal disorder Familial Hypercholesterolemia, the topics were fascinating and irrefutably pragmatic. The attendees were riveted. Side conversations were plentiful, including promises of new clinical trials and better ways to help our patients. The pace was quick and the excitement, palpable. All this at a medical meeting!

Although uniformly doctors are troubled by Medicine’s fall from grace, rays of hope were clearly visible at the NLA meeting. Beneath our acrimony doctors, nurses, and others in medicine still have at their core the desire to help. We genuinely want to be the ones who people look to during their oftentimes-darkest moments. We also most definitively strive to keep people from experiencing such grim periods. The best way to achieve these goals is to continuously learn. Curiosity, inquiry, dialogue, knowledge, and caring are the cornerstones of the practice of Medicine. And these are the elements that beat at the heart of the National Lipid Association.

Learn more about preventive cardiology at www.preventivecardiologyinc.com.

For more information more about essential vitamins and supplements visit www.vitalremedymd.com.

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The Emory Symposium on Coronary Atherosclerosis Prevention & Education

Here’s a shoutout to my friend and colleague, Dr. Larry Sperling.

The renowned Emory Heart Center of the Emory University School of Medicine will be holding its 13th annual Emory Symposium on Coronary Atherosclerosis Prevention & Education June 4-8, 2014. This year’s event, which is titled “Emory Escape 2014“, will be held at the OMNI Amelia Plantation on lovely Amelia Island, Florida..

The challenge
Cardiovascular disease remains the number one cause of death of men and women in the United States, and is a major cause of disability. The American Heart Association has a stated goal to reduce deaths from cardiovascular disease and stroke by 20% by 2020. In order to achieve this goal, physicians and clinicians must gain the knowledge, skill and resources to integrate the latest research and clinical guidelines in the context of their own practice.

The event
At ESCAPE attendees will hear nationally renowned speakers discuss the recently released, 2013 ACC/AHA guidelines on hypertension, blood cholesterol, obesity, healthy living and risk assessment. In addition, there will be one day dedicated to lectures on CV prevention in “special population” patients, including patients with HIV, PCOS, breast cancer, connective tissue disease and post renal transplant. There will also be lectures on electrophysiology, interventional cardiology, heart failure, tobacco cessation, and women’s heart health. This conference will close the knowledge gaps between national guideline goals, practice, and research. Physicians and clinicians will have the opportunity to discuss with the speakers and other attendees how these principles can be applied to patient care in the context of their own practice in order to decrease cardiovascular disease risk.

In addition to the extensive educational curriculum, events will include pre-meeting workshops,  an attendee and spouse session and a family social and cookout.

Who should attend
Cardiologists, internists, family practitioners, emergency medical personnel, primary care physicians and nurses can all benefit from this conference.

Register online at www.eccri.emory.edu/escape – registration deadline May 4th

Call 1-800-THE-OMNI to make room reservations.

Hosted by: Emory University School of Medicine Department of Medicine Division of Cardiology.

Learn more about preventive cardiology at www.preventivecardiologyinc.com.

Learn more about essential vitamins and supplements at www.vitalremedymd.com.

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The Great FH Debate: Reinforcing the fact that “Time is Plaque”

Currently a debate rages in the world of Familial Hypercholesterolemia (FH).  Old school thinking is that this lipid disorder – typically caused by a mutation in one of three genes – is exceedingly rare. The initial teaching stated that the homozygous form (two mutations – one from mother and one from father, HoFH) occurs at a rate of one in a million, while the heterozygous form (one mutation from just one parent, HeFH) occurs at a rate of one in 500. Recent explosions in not only genetics, but also the acquisition of large volumes of patient data have put this prior supposition in question. Now, a recent study published in the European Heart Journal by Sjouke et al truly proves that we have grossly underestimated the prevalence of FH. Examining over 100,000 patients who were referred for genetic analysis, the authors found 74 patients with clinically significant mutations consistent with the homozygous form of FH (HoFH). Being abundantly cautious in their interpretation of data, the authors pared the number down to just 45, from which they conducted a mathematical calculation of the prevalence of FH. (Their minimalist rationale is beyond the scope of this blog, but suffice it to say that had they included all patients, the disease prevalence would be far greater). Their restrained assessment revealed the prevalence of HoFH in an unselected population to be 1 in about 300,000 while the prevalence of HeFH, 1 in 244.

Perhaps more striking and even earthshattering is what the authors discovered about the wide range of HoFH LDL-C levels. Older belief systems had maintained that the LDL-C in untreated HoFH should always exceed about 450 mg/dL. In their comprehensive and novel analysis however, the authors discovered untreated HoFH patients with LDL-C levels as low as 170 mg/dL. 170 mg/dL overlaps not only the HeFH population, but the non-FH population as well. The bottom line here once again is that as in diagnosing all other diseases, clinicians must maintain open minds when diagnosing FH. When considering FH, we must always look for a family history of premature vascular disease, very high LDL-C levels, signs of the disorder on physical examination, and the presence of aggressive coronary artery or cerebro-vascular disease in the patient we are evaluating. Most important is for all clinicians to keep FH on the tips of our tongues. Without considering the diagnosis, we will never make it. And without making the diagnosis, we will never treat it. Early treatment can be life saving so early diagnosis is of course paramount. In no other lipid disorder is the concept that “Time is Plaque” more apparent. FH patients bathe in their own LDL-C in utero and beyond. The longer they remain untreated the worse they do. So let’s think of FH and treat it when we see it. By doing so we can hope to prolong the lives of more than a million people right here in the USA.

Learn more about preventive cardiology at www.preventivecardiologyinc.com.

Learn more about essential vitamins and supplements at www.vitalremedymd.com.

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LDL Cholesterol: Sometimes the Simple Questions are the Most Revealing

Recently, after participating in a meeting attended by a few high-powered CVD researchers I returned home plagued by a most simplistic question: What is the purpose of LDL cholesterol? Please refrain from bursting into uncontrollable spasms of laughter; I am well aware that as a clinical lipidologist I never imagined such a question would have the capacity to keep me up at night. And yet it did. And so I called my faithful counsel, upon whom I can always rely to extricate me from any lipid conundrum. Tom Dayspring responded to my query unflustered, promptly sending me articles to help me find my way. I read them and this is what I realized. LDL cholesterol is essentially garbage. The story goes something like this.

Our livers manufacture triglyceride – (TG) and cholesterol – containing lipoprotein particles called VLDLs. This is old news. VLDL contains about 80% TG and 20% cholesterol. Its purpose is to nourish our organs. As these particles pass through the tiny capillaries of our various organs, enzymes called Lipoprotein Lipase (LPL) snip the fatty acids from their TG backbone, Glycerol. This too is old news. These released fatty acids are either used for energy or stored by our organs for future needs. The shrunken down VLDL particles, devoid of most of their TG energy content, are now re-dubbed. They have become LDL particles. They are cholesterol-rich. Their content represents what most people speak about after visiting their doctors – LDL-C or LDL cholesterol. Here’s where it gets intriguing. Although any lipid specialist can tell you that every single cell in our body has the capacity to make cholesterol, most believe that the cholesterol contained in LDL particles has some greater purpose. Our cells however do not need the cholesterol contained in LDL particles; nonetheless, most of us believe they use it. This belief is untrue. LDL-C is actually not utilized to any significant degree by any organ systems in human beings. Other animals may use some of it here and there, but not us. We just don’t need it. In fact, the goal of LDL particles is to get to the liver ASAP for disposal. Otherwise, these particles tend to land in places where we do not want or need them, our blood vessel walls to be more specific. You know how that story goes – plaque forms; plaque ruptures; heart attacks or strokes ensue…

So when people tell you not to worry about your high LDL-C levels, please reconsider abandoning your doctor’s LDL-C-lowering advice. And definitely don’t worry that low LDL-C levels will deprive your cells of their much-needed cholesterol. It won’t. Your cells are quite capable of making their own supply of cholesterol. On a somewhat esoteric note, it is true that the surface of LDL particles transports some vital nutrients around the body (vitamin E for one). This fact however does not imply that more LDL is better than less. We need just a tiny bit for non-cholesterol purposes. Excess does us no good, and in truth it does us a good deal of harm.

Learn more about preventive cardiology at www.preventivecardiologyinc.com.

For more information about the supplements and vitamins critical to your everyday health visit www.vitalremedymd.com.

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Omega-3 Fish Oils – Misleading and Erroneous Interpretations of Scientific Studies Can Cause Harm

Recent statistics demonstrate a small but pervasive decline in national sales of fish oil supplements. Before I continue, let me make it clear that I have a bias here. In 2007 I formulated VitalOils1000, the first omega-3 fish oil carefully and uncompromisingly concentrated and purified so as to enable the American Heart Association’s recommended 1,000 mg of combined EPA and DHA to be placed in a single enteric coated soft gel.

Now, seven years later, VitalOils1000 still stands alone among a sea of fish oil choices (sorry; I couldn’t resist). Needless to say, I am very proud of that accomplishment. So my conflict is clear; I want people to take VitalOils1000. I believe it’s good for them. In fact – that’s why I designed it. So I am disturbed by the decline in people’s consumption of fish oils. Though the “business” ramification of this decline bothers me, I am far more disturbed by its root cause. Falsely frightened people have crumbled under the illusory conclusions of a few poorly constructed trials and the even-more-poorly constructed conclusions derived by “critics” of these trials.

Consider first the fact that four decades of research spanning bedside to bench and back again have demonstrated the sweeping benefits of the omega-3 fatty acids DHA and EPA – fish oil’s “active ingredients”. That’s forty years of thousands of brilliant minds examining the omega-3 issue from a multitude of vantage points. Forty years of overwhelmingly positive conclusions! Then come a few – and I mean a few – poorly designed studies with at times truly ridiculous conclusions. As with most other aspects of news reporting, the negative draws more readers and listeners than the positive. And so the media ran with the story. Some doctors even jumped on the bandwagon. “Fish oil is not what we thought it was,” they concluded. In response, omega-3 experts from around the world voiced their discontent. But their voices were muted as they failed to resonate with fear. The scientists and doctors spoke with authority and knowledge, devoid of histrionics. And so their side of the story didn’t sell newspapers or airtime. The outcome we now witness is that some people prematurely “drank the media cool aide”. They stopped their fish oils.

The problem is that I and many others in this field are left with the great concern that these individuals have left themselves less well protected against a host of disorders than they had been while taking fish oils. Unless they’ve dramatically increased their fatty fish consumption, they have certainly placed themselves in a relative omega-3 deficient state. Think of this: the average American consumes about 100 mg of combined EPA and DHA daily while the average Japanese consumes eight times this amount. And the Japanese have far lower rates of heart disease and prostate cancer than do Americans. Yet, the scant research behind the omega-3 fear mongering cited concerns about the ineffectiveness of omega-3s in cardiovascular disease as well as the possibility of omega-3s predisposing to prostate cancer.

There are many other plausible explanations for these inconclusive trials (see my blog www.fpim.org). Throwing the fish out with the fish water is however not called for. And so my conclusion here is once again to read the primary research. Do you own homework – though it may be hard – and decide for yourself what you think is best. If you need help evaluating the literature, look for the opinions of those who are true leaders in this field – William Harris, PhD, Bruce Holub, PhD, Tom Brenna, PhD, Susan Carlson, PhD (not the owner of the supplement company), and Kevin Maki, PhD for starters. There are plenty of others but be sure to listen to the experts.

Sadly we can no longer rely upon the media’s “Medical Experts” to be our source of scientific veracity. They are too busy, and often forced to weigh in on disciplines far removed from their particular areas of expertise. They cannot possibly be expected to know everything about every medical field. I am sorry to leave you with the task of “doing your own homework”, but nowadays it is something we must all become accustomed to do.

For more information about the supplements and vitamins critical to your everyday health visit www.vitalremedymd.com.

Learn more about preventive cardiology at www.preventivecardiologyinc.com.

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