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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Fish Oil: It Conveys Much More Than Cardiovascular Health

woman jogging at sunrise
Numerous studies have evaluated the effects of the omega-3 fatty acids, DHA and EPA, on cardiovascular health. Overwhelmingly, scientists and clinicians involved in such research believe that omega-3 fatty acids play various beneficial roles in preserving optimal vascular and cardiac health: Anti-Inflammatory, Anti-Thrombotic, Anti-Arrhythmic, and TG-Lowering effects are considered to be the most relevant. Recently, Smith et al. published a fascinating and novel clinical trial looking at a non-cardiovascular yet widespread adverse aspect of aging: muscle mass decline. They published their findings in the American Journal of Clinical Nutrition: Fish oil–derived n–3 PUFA therapy increases muscle mass and function in healthy older adults. All parameters evaluated improved with the administration of 3,200 mg of daily DHA+EPA. Thigh muscle volume, handgrip strength, one-repetition maximum (1-RM) lower- and upper-body strength, and average power during isokinetic leg exercises all demonstrated statistically significant improvement. Improving muscle strength as we age can have far-reaching beneficial consequences that could reduce both morbidity and mortality. Thus, these findings need to be further studied in larger and even more consequential trials. But what additional meaning can we garner from their trial?

I believe that beyond their fascinating and clinically pertinent findings there actually lies a far more evocative message. It is simply that we should be extraordinarily cautious about abandoning the evaluation of therapies (even dietary) when they make biological and physiological sense. Fish oil consumption is woefully low in the US when compared to the far more healthy Japanese population. Our life expectancies are far shorter and various cancers occur more frequently in the US. It is scientifically quite plausible that our deficiency in omega-3 fatty acids plays a significant role in our relatively diminished health. But, after the publication of a few clinical trials failed to demonstrate the cardiovascular benefit of fish and fish oil in select patient populations, some physicians truly abandoned their prior admonitions for patients to augment fish consumption. They were derailed by the controversial results of just a few trials (that many exceptional researchers consider to be flawed in the first place). This type of knee jerk reaction has no place in medicine. It is dangerous and counterproductive. To protect our patients and maintain our scientific integrity, we must always practice with open and attentive minds. Once again I implore my scientific colleagues as well as the oftentimes superficially inquisitive media to follow the science, not the hype.

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The American Society for Preventive Cardiology 30 Years and Counting


July 30, 2015 marks the start of the ASPC’s Annual meeting, taking place once again at the spectacular Boca Raton Resort. This year, in addition to our world-class faculty, new elements will be added to the meeting – poster presentations to be published in Clinical Cardiology as well as a Level 1 Expert’s Course in Preventive Cardiology. Over the next three months I will certainly write more about the conference and I hope many of you will avail yourselves of its offerings. (For more complete information please visit

Today however, on the heels of the Dallas Cardio-Metabolic Health Congress (CMHC) I am compelled to write this brief note about the ASPC. The reason is simple. As I sat in the speaker’s row with my friends and colleagues Drs. Jamie Underberg, Amit Khera, and Michael Miller it became clear that the thirty-year-old organization is now firmly entrenched in mainstream education. You see, Dr. Underberg sits on the ASPC’s Board of Directors while Dr. Khera is the Secretary; I am the President Elect, and Dr. Miller is a Past President. It was truly heartwarming to have us all gathered together for the sole purpose of helping to educate our colleagues about issues such as Familial Hypercholesterolemia (FH), Hypertriglyceridemia, Lipid and Cholesterol Guidelines, and the future of HDL research and therapies.  The ASPC is growing at a gratifyingly rapid rate, as more and more physicians, ARNPs, and other healthcare practitioners embrace the doctrine that cardiovascular disease prevention must preempt intervention in order for our nation and the world at large to be able to truly enjoy optimal health. If you are not already a member of the ASPC, please consider becoming one. Also, I encourage everyone interested in prevention to join us in July. I promise you will not be disappointed.

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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.

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Hot Off the Press

In medical school we learned about a life threatening form of polydipsia. A subset of patients with schizophrenia consume so much water their sodium can fall to levels unable to sustain life. Twenty liters per day often leads to not just severe illness, but death. How could this be? Water is life’s elixir, and therefore more must be better; correct? Well, simply put, the answer is no. Our kidneys can only handle a water intake of less than one liter per hour. When people exceed this limit, blood becomes diluted; sodium levels fall; and cells swell. As our brain is encased in bone, it has nowhere to go when it swells. Consequently swollen brain cells can lead to permanent damage and even death. It’s not just the unfortunate schizophrenic patients who succumb to such a fate; others do as well. One woman died after drinking six liters in just three hours during a “water drinking competition.” Others have died similarly during college hazing. The point is that a rapid, excessive and unnatural intake of our most vital ingredient for life can kill us in a matter of hours. More is definitely not always better. Aristotle was correct in his dictum of moderation. So where am I going with this you might ask. Let’s consider the most recent “negative” fish oil study by Dr. Voest that was published in a most reputable journal. (For my take on other similar articles please see prior blog posts).

Based upon the fact that some cancer cells can produce long chain fatty acids, Dr. Voest hypothesized that the omega-3 fatty acids in fish could blunt the effect of chemotherapy (such a thought process itself lacks strong scientific validity). Testing his hypothesis he administered 100 microliters of fish oil to 20 gm mice. He was right; fish oil did blunt the effects of chemotherapy. And so his findings were published in the prestigious JAMA Oncology. But let’s look at his study in proper perspective. Ignore the fact that mice are not the optimal animals to study here. Also, ignore the fact that tumor cells produce many substances that have nothing to do with their “desire” to counteract chemotherapy.  Simply examine the administered dose. One hundred microliters of fish oil for a 20 gm mouse is equivalent to 400 ml of fish oil for an 80 kg (175 pound) man. Can you imagine guzzling nearly a half-liter of fish oil? The very thought is life threatening! That’s also tantamount to swallowing around 400 fish oil capsules. Who in his right mind would do that? I’d guess no one. The study therefore has no clinical relevance. The author’s conclusion that patients should avoid fish the day prior to receiving chemotherapy has no basis in science. Yet, the study is on the news; patients are concerned that fish causes cancer; doctors who don’t fully understand this area of medicine will become as alarmed as the patients; doctors’ offices will once again be flooded with unnecessary and distracting queries born of inappropriate trial conclusions; and some people who desperately need to consume fish will place themselves in harm’s way by eschewing vital nutrients. The fallout is, and will continue to be, monumental.

Why such studies are done, and why they are published in top-notch journals eludes me. I understand why the media exploits them; they are fodder for ratings. Still, I will continue to proclaim that such studies must be quelled, and the media must become more cautious. It is fine to conjecture, study, and test hypotheses no matter how outlandish they may seem. What is not acceptable however is perpetuating false conclusions as though they are hardened facts. Such a practice – which is prevalent today – leads both doctors and patients astray and pulls us from important issues, those that can truly save lives and help humanity. Let’s get back on track and re-emphasize honesty in medicine as our prime agenda. Honesty should always trump a good story.

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Save the Date: It’s the American Society for Preventive Cardiology’s 40th Anniversary – The July 2015 Conference is Shaping up to be Extraordinary

That’s a long title for this week’s blog, but it’s tough to shorten. Planning a conference is quite a challenge: The venue is chosen; topics are selected; speakers are invited; and the word is disseminated. Many people’s hands are in the mix – in the case of the ASPC, our management company as well as members of the planning and executive committees work tirelessly to create a conference that will meet and exceed its intent. This year’s ASPC meetings, again at the beautiful Boca Raton Resort, will bring together attendees from across the country (and likely outside the US as well) in order to learn from some of our nation’s most renowned experts in genetics, vascular disease, hypertension, diabetes, women’s heart health, inflammation, thrombosis, CVD risk reduction strategies, familial hypercholesterolemia, lipids and lipoproteins, novel medications…

Our goal is to highlight the most cutting edge as well as tried and true approaches for ASCVD prevention so clinicians eager to improve their strategies to combat and prevent the toll of vascular disease among their patients can more effectively do so. Conference attendees are among the most dedicated of our country’s healthcare practitioners – cardiologists, internists, obstetricians, family practitioners, nurse practitioners, physicians’ assistants, pharmacists, dietitians, and many others. The Boca Raton Regional Hospital supports the program and offers its physicians the opportunity to attend this one-of-a-kind meeting. Groups such as WomenHeart, and chapters of the ACC and AHA (and others) typically endorse the meetings as well. This year, in honor of the ASPC’s 40th Anniversary, the meetings will offer its attendees two new opportunities. First, abstracts from trainees across the globe will be evaluated for presentation. Second, we will offer the inaugural Expert’s Course in ASCVD Prevention. Diplomas will be awarded to those who successfully complete the course. So who are our speakers – professors and experts in their disciplines from Harvard, Hopkins, Emory, The Mayo, Columbia, UCSD, Tulane, Minnesota, NYU, and other outstanding institutions. And when is the meeting – July 31 through August 2nd. Put it on your calendar – you and your patients will be very happy you did. See you in July!

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The 2015 Dietary Guidelines: Defining a Healthful Diet

The 2015 Dietary Guidelines have been released, and some supposedly significant changes, advised. Cholesterol intake is no longer limited. Saturated fat is to represent < 10% of daily caloric intake. Sustainability considerations are now to be considered. Simple sugars are anathema and caffeine is okay. Vegetables and fruits remain highly emphasized. Has much changed? Not really. Most of us in Cardiology and Lipidology dropped the cholesterol ban a decade ago. We typically emphasize fresh fruits and vegetables, low fat meat that is organic and devoid of antibiotics, and a limitation of simple sugar. Most of us don’t consider sustainability issues when advising our individual patients. Many of us believe that world issues – including economics – should stay out of the exam room and remain in the courtroom. (I am a member of that camp). But what is the layperson to do with these Guidelines? Does he or she have to make dramatic changes in his or her diet? The answer of course depends upon the individual patient’s status. Is weight loss necessary; does the patient have cardiovascular disease or very high LDL cholesterol, for instance? Let’s first look at the history of man, briefly examine the state of dietary literature, and then make some generalizations.

Anthropology unequivocally demonstrates that human beings are omnivores. In fact, all of our primate relatives also rely upon meat in the wild. They even need it in captivity. When the Washington DC Zoo attempted to breed the Amazon Golden Marmoset monkey, they failed miserably. It was not until meat was added to their diet that the monkeys begin to thrive and reproduce. Since the beginning of our tour on earth we have also eaten meat. In fact, for the first 4 million years of our existence, meat was our main source of nourishment. About 10,000 years ago we introduced farming and animal husbandry. Most farming was done to feed our animals as they represented our most desirable food source. Recently we have fallen prey to our own impact on nourishment – we have started processing, and ruining, our food. Sugar has been added; nutrients have been stripped from grains; grains are squeezed (instead of eaten whole) to produce oils; and animals have been raised in pens, limiting their ability to develop lean muscle mass, and also often requiring the introduction of antibiotics. We have created a food supply that is most likely killing us.

In response to our understanding of the role cholesterol plays in heart disease – and it does play a significant one – we have introduced guidelines to try to reduce cholesterol. Saturated fat eaten to excess does raise LDL (not a good thing), but cholesterol consumption has little impact on our LDL levels. Therefore the current Guidelines did what was appropriate and removed restrictions on cholesterol consumption while maintaining limitations on saturated fat. They also appropriately implore us to eschew sugar. No one will argue against the latter recommendation (except perhaps the sugar industry). But are there studies to support such advice? Unfortunately, beyond PrediMed (which demonstrated the cardiovascular advantage of a Mediterranean diet) no high level studies have been performed. Many observational studies exist, but doing a solid dietary trial is actually immensely difficult. Thus we are left to rely upon our understanding of basic science, animal experiments, pathophysiology, and anthropology. The conclusion for most of us I believe follows Aristotle’s ancient tenet of moderation. We should consume natural foods whenever possible, avoid processed foods, eat copious quantities of vegetables, consume ample fruit, and don’t worry so much about consuming lean meat, fatty fish, and some chicken as well. We should do this in the context of seeing our physicians, discussing our own personal issues, and modifying our diets to adjust to individual needs when indicated. Eating has become a complex endeavor, yet it ought to be much more straightforward. What we need though is access to the aforementioned natural food, the type of food that has been unscathed by human hands. And therein, unfortunately, lies the rub.

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Heart Month 2015: We’ve come a long way but still have “miles to go before we sleep”

So many strides have been made in the management of ASCVD (atherosclerotic cardiovascular disease): our understanding of its pathophysiology, our ability to thwart an erupting heart attack, our techniques to destroy brain threatening strokes, and methods to correct valves and aneurysms through tiny holes in the body have all blossomed over the last few decades. Still many questions remain. What’s the optimal diet? Is it low fat, high fat, high protein, high complex carbs, no fat, only omega-3 fats…? How much exercise do we really need? And what’s the best form of exercise? What’s the optimal role for cardiac imaging? Who should get a bypass and who, a stent? How long should dual antiplatelet therapy continue after a drug eluting stent? What’s the optimal blood pressure? Why do men and women have such divergent responses to CVD and its therapeutic interventions? How low should we drive cholesterol levels?  When is the best time to start driving these levels down? Why do we continue to have such a high residual risk of a CVD event even after seemingly doing everything right? Why is peripheral arterial disease (PAD) such a fearsome predictor of future stroke and heart attack? The list is interminable. That’s not hyperbole. And the infinite list of remaining questions is at the same time both frustrating and invigorating. Though we’d like to have all the answers and all the solutions to our woes, this never-ending list humbles us and reinforces the miracle of our being. We are truly the most fascinating and remarkable living “machines”.  For today though, and this Heart month, let’s focus a moment on familial hypercholesterolemia (FH), another source of both recent advances as well as remaining controversies.

FH is a potentially devastating form of genetic high cholesterol. Its victims possess important genetic mutations that beget likely premature heart disease and lifelong angst. Parents pass the disease to their children, concomitantly bearing the crosses of guilt and fear. Many questions involving FH remain: How many undiagnosed patients are there with FH? How do we precisely distinguish HoFH from HeFH? How do we increase patients’ access to therapies such as lipoprotein apheresis, lomitapide and mipomersen when indicated? How do we choose these therapies for a given patient? After all, all patients, as all people, are different. Fortunately many are laboring to find answers to the FH questions. Leading the charge is Katherine Wilemon and the FH Foundation (FHF). Growing at an unprecedented rate and having the support of the world’s brightest FH scientific and medical minds as well as generous pharmaceutical sponsors, the foundation is spearheading programs to find those with FH so they can be properly treated. Through its website, the FHF is bringing patients together so they can find common solace. The group is also cataloguing patients with FH so scientists can better study the disease and in so doing defeat it. The list goes on.

Perhaps the best way to understand all that the foundation is doing and plans to do is for you to join us for an FH Foundation tweetathon at 8PM Thursday February 19th. Just go to #KnowFH and join the thousands of others who will be discussing what’s old, what’s new, and what’s in store for the future of those with FH. Speak to you Thursday!

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Doctor’s Prescriptions for Their Patients: Old Frustrations Persist

In a perfect world with boundless resources, patients would always have access to every doctor’s prescription. But our world is not perfect and our nation is in deep debt. Consequently every day doctors across the country receive denials for medications and procedures that we have prescribed. We know our patients need these medical interventions yet our hard earned positions as practicing physicians (requiring decades of study) are no match for the far less qualified employees of insurance companies. Oftentimes our prescriptions are lifesaving. Yet we are told patients can’t have what we’ve ordered. What we have ordered is simply “too costly”. We are forced to choose something else, even if it is an inferior approach and leaves our patients – those people we have all sworn oaths to protect – relatively unprotected. So, with resources limited to such a degree that we have lost access to solutions we know to be beneficial, what are doctors and patients to do? Let’s look at a disorder deserving great attention and intervention; yet oftentimes remaining hidden in the shadows. The disease is called FH (Familial Hypercholesterolemia) and it occurs in about 1 out of every 200 people.

One of the disorder’s characteristics that makes it difficult to diagnose is the wide variation in how it manifests; some people have LDL cholesterol levels well over 200 (I’ve seen levels over 500) while others are not so badly impacted. Some patients have heart attacks in their teens while others never experience such premature disease. One of modern day medicine’s most well established “facts” is that the lower a person’s LDL, the less likely he or she is to have a heart attack or stroke. Now consider those individuals with FH in whom we simply cannot, no matter how hard we try, adequately reduce their LDL utilizing insurance approved modalities such as statins and dietary modifications. Such people may have already suffered heart attacks at very young ages. They are at extraordinary risk for a future heart attack or stroke. Yet, their insurance carriers still often create impenetrable barriers for access to additional medications as well as LDL apheresis, a method that was FDA approved in the 1990s, and lowers LDL by a whopping 70%. Carriers bemoan the costs of the medications or procedure and cite a lack of adequate “outcome data” as their reason for denial. Though doctors explain that it is now accepted as doctrine by lipid experts across the globe that lowering LDL by any means provides dramatic CVD risk reduction, they remain intransigent. We share our knowledge of Mendelian Randomization studies, which have proved beyond a shadow of a doubt (in the framework of present-day science) that lowering these patients’ LDL levels will vastly decrease their chance of suffering repeated heart attacks, strokes, stents, and bypasses. Still their ears and minds are shut. We, the doctors, are powerless. And our patients suffer the consequences. And, compounding the problem, there is currently active consideration among insurers to make it even more difficult for patients to receive LDL apheresis.

The New Year has just begun and my colleagues and I have already received a plethora of complaints from patients bemoaning the fact that their insurance carriers have increased their medication costs to such a degree that for many they can no longer afford to take them. What will happen to these patients? Will they develop unnecessary heart attacks or strokes? Will they need unwanted and otherwise preventable procedures like bypass surgery and stents? I do worry they will fare less well than had they been permitted to follow the care so cautiously outlined by their treating physicians. And medical evidence does support my concern. I believe an outcry from patients is needed. Doctors will continue to make our case, but until the voices of worried patients achieve adequate volume, I fear the status quo will reign.

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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.”

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:
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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