Dr. Libby’s discussion on Atherosclerosis as an Inflammatory disease: The Unstable Atherosclerotic Plaque (Dr. Peter Libby – Boston, MA, USA)
Dr. Libby started out by eloquently discussing “event reality” – basically a thrombus that blocks the flow of blood rather than a cholesterol build-up. We all know the strongest evidence for this comes from the IVUS work. Prior to IVUS, post embolitic angiography – the cardiologists were amazed to discover that the lumen was clear post clot extraction.
There are 4 mechanisms that cause heart attacks – basically 75% of all heart attacks occur from the rupture of the fibrous cap leading to thrombus. The second mechanism (claiming 20% of fatal coronary events) is the erosion of the endothelium (although not mentioned, we believe that MPO may have a role here). The two other mechanisms for the causality of MI include the rupture of a calcium module and intraplaque hemorrhage. These two later mechanisms are felt to be quite minor.
Fibrous cap integrity is largely due to interstitial collagen – this collagen is mainly synthesized by the smooth muscle cells and a lot of proline is needed to make this collagen. Inflammation inhibits the process of collagen synthesis. The other important factor is the catabolism (breakdown) of collagen – only a few enzymes have this ability – these are in the matrix mellaproteinase family (MMP) – they do have the ability to cleave the collagen protein which opens the matrix up for degredation. These proteases are produced in monocytes (obviously inflammation is critical for the metabolism of collagen). When you have inflammation – less collagen – making the fibrous cap much more prone to rupture.
Thrombus formation: Inflammation renders the plaque more thrombogenic by increasing tissue factor and CD4- ligand. When the integrity of the fibrous cap is disrupted – blood is exposed to these very thromogenic substances – this then results in the very thrombolytic clot.
Understanding atherosclerotic biologically should lead to new medical therapies to prevent atherothrombotic cardiovascular events. We must concentrate on reducing the inflammation of the arterial wall which should lead to stabilization of plaque. Dr. Libby did state that interventional techniques are effective to treat symptoms such as angina but do not address the underlying pathology and disease of atheroslcerosis. He called for medical management to treat the biology of the disease and intervention to treat some of the symptoms associated with the disease. Interventions do not modify the biology of atherosclerosis. ****This of course validates the BaleDoneen Method****
He went on to ask the question of why lipid lowering therapy was beneficial? Bottom line is that this type of therapy reduces inflammation and thrombogenicity of atherosclerosis.
Commentary by Dr. Crea (Rome Italy) – Dr. Crea went on to state that plaque structure is not as important as plaque activity. Crea went on to say that we need better understanding of what triggers the instability of plaque.
***BaleDoneen message on this***This is a very important message to remember – it takes constant vigilance to keep the disease stable – ALWAYS couple structure with biomarkers when evaluating the safety of the patient and the effectiveness of treatment. This is critical in patients with known atherosclerosis undergoing global risk reduction. One of the most important elements to monitor on a regular basis is the inflammation of the atherosclerotic process.
Insights into HDL Function from Lipidomic and Proteomic Analysis: By Dr. MJ Chapman (Paris, France)
Dr. Chapman discussed the amazing complexity of HDL and the heterogenicity even within the 5 subparticles that we are familiar with using electrogel phoresis. There is an incredible mix of lipidomic elements and various proteins within the subclasses of HDL. The particular mixture of these lipid and protein substances make a difference in the antioxidant, anti- apoptosis, anti-thrombogenic, anti-inflammatory, as well as reverse cholesterol transport ability of each HDL molecule itself.
Bottom line: it will be years before we have anything close as to the final conclusion on HDL. For now, it still seems reasonable to measure HDL 2b as the strongest indicator for possible reverse cholesterol transport.
More additions from the ISA 2009 – from compiled lectures from each of us over pst few days…….
Only produced in adiposities and inversely associated with cardiovascular risk. It inhibits monocyte adhesion to the endothelium and inhibits smooth muscle cell proliferation and inhibits cholesterol ester scavenger receptors. The term “a firefighter for cardiovascular disease” seems appropriate for adiponectin.
DHEA: Low Serum Levels of DHEA Predict Death from Cardiovascular Disease in Older Men – Tivesten et al – Sweden.
Low levels predict cardiovascular death in older men. The data comes from 2,639 Swedish Men aged 69-80 years of age followed for 4.5 years. There were 328 deaths during this time frame. Four quartiles of DHEA levels – the three low quartiles that were low were statistically significant for CV death in these men by 49% adjusted for age, smoking, BMI, DM, HTN, Apo/ApoA1, hsCRP, and known Cardiovascular disease. There was no association with increased cancer risk but it is important to recognize that with increased testosterone levels, the risk of prostate cancer also increases.
Basics of DHEA: comes from the adrenal glands and of course makes testosterone and estrogen. The DHEA reduces fat mass and insulin resistance and improves endothelial function and decreases oxidative stress and decreases inflammation.
Bottom line: Consideration should be given to measuring either DHEA levels and or testosterone levels in older men.
Myeloperoxidase: Plasma Myeloperoxidase Concentrations is Inversely Associated with Brachial Flow Mediated Vasodilation in Subjects with Abnormal Glucose Metabolism. P. Scheffer (Amsterdam, The Netherlands)
MPO is inversely associated with brachial artery flow. MPO levels increase with rising blood glucose levels – this can occur within hours. The authors did show that in approximately 380 male and female subjects, age 55-70 years that for those with adverse glucose metabolism there was also an increased MPO and also altered flow mediated dilatation as compared to the control group with normal glucose metabolism. There appears to be a relationship with increased MPO and decreased flow mediated dilatation.
Bottom line: We must consider drawing MPO levels in fasting subjects – needs to be discussed and investigated further – will discuss with Prognostix.
Niacin: Effects of Niacin on Plasma Liporptiens – MI. Kashyap
Dr. Kashyap gave a very well informed lecture on Niacin – as time marches on, the functionality of Niacin continues to define itself.
Niacin and TG lowering: Niacin inhibits the enzyme diacylgylercerol acyl transferase (DGAT-2). This enzyme is necessary to synthesize triglycerides from free fatty acids and glycerol. Niacin also inhibits free fatty acid release from adipose tissue –
Niacin and ApoB lowering: This is done by its ability to lower TG (TG get metabolized by microzomal triglyceride protein (MTP) into Apo B particles.
Niacin and HDL: It has been known for some time that Niacin increases HDL levels by decreasing the catabolism of HDL and Apo A1. The mechanism for this is by reducing the expression of myocondrial hepatic ATP expression. ATP is necessary for the breakdown of HDL. Niacin decreased surface expression of ATP synthase B chain in HepG2 cells (Qhang LD et al. J lipid Res. 49:1195, 2008).
Niacin and inflammation: Niacin increases the redox state of human aortic endothelial cells resulting in decreased LDL oxidation and expression of redox sensitive genes and inhibition of monocy
Niacin and Adipose Tissue – cell is adipocyte – receptor GPR 109A (niacin receptor) – primary effects – decreased lipolysis, and decreased FFA and clinically – decreased VLDL- TG
Niacin and fatty liver: – cell is hepatocyte – receptors decreases DGAT2 which decreased TG synthesis, apoB asecretion leading to decreased VLDL-TG, apoB and Increase LDL size. Anoth receptors Beta-chain ATP synthase and ABCA1 Transporter these lead to kecreased HDL and increased chol efflux from liver increasing the biogenesis of HDL from the liver.
Niacin and Artery – endothelium – increase HAD, decreased Redox sensitive genes – decreased LDL, MCP1 VCAM1 and increase Prostaglandin J2 and Increased PPAR and decreases MPO.
Niacin’s Non lipid effects include lowering of plasma fibrinogen, plasminogen activator inhibitor 1 and increases in prostaglandin D2, E2 PGJ2 and angiogenesis and adiponectin.
Effects of the Statin/Niacin Combination for Heart Disease Prevention: Dr. Greg Brown (Seattle, WA)
AIM-HIGH – double blind, placebo-controlled for niacin – ER Niacin 2 gm plus simvastatin 20-80 mg versus simvastatin alone – treatment goal for LDL <80mg/dL Open label ezetimibe added if needed. Greg Brown, MD, is the Primary Investigator
Study design: CHD pts with HDL <40 for men and <50 women AND TG >150
Primary endpt: composite of nonfatal MI, CHD death, stroke, hospitalization for acute coronary syndrome
HPS2-Thrive Study Design – double blind, placebo-controlled for MK-0524A (niacin/laropiprant) – no specific lipid entry criteria for HDL or TG – Primary endpoint: nonfatal MI, CHD death, stroke , or arterial revascularization.
Dr. Brown discussed a formula: Take the % change in HDL and multiply it by 1.3 and the % change in LDL and multiply it by 1 and add these two together = this will give the event relative risk reduction. This is not agent specific (therefore not study specific but rather independent HDL and LDL response specific).
Of interesting note: we tried this with VA-HIT [no change in LDL, 6% increase in HDL = 24% event reduction]….this formula did not work with this trial. VA-HIT: Rubins HB, et al.N Engl J Med. 1999:341:410-418.
Take home: this lends to the fact that the BaleDoneen Method’s focus for LDL, HDL, TG reduction goals lend to the evaluation of TC/HDL rather than the independence of each variable % change. It is well documented with several articles that the most predictive lipid parameter for prediction is ApoB/ApoA1 – basically TC/HDL – the total cholesterol impact yields the benefit. Also keep in mind, that lipids are one aspect of this very complex disease of atherosclerosis. Any efforts to achieve 100% risk reduction must go well beyond simply controlling the lipids.
Discussion – Dr. Alan Tayor – Washington DC
Do you have a personal HDL target? Kashyap: Better to look at function.
What are the key questions that exist to compare changes or benefit? Kashyap: By the time we get results of AIM HIGH we will also get info on the CETP inhibitors – future of drug trials will be influenced by this – is the way in which you raise HDL (the function of HDL) important. Brown: we have a combination of treatments that affect both LDL and HDL. This will become a public health issue to know how low or how high to go with both lipid parameter. Dose response studies will become very helpful. McGovern: We have now reached the limit of what we can do with LDL – the future will be…what else can we do?? Exploring the dose/effect response with niacin will also be helpful.
Should we have data in Primary Prevention cohort? Brown: the link between primary or secondary effect – atherosclerosis goes on whether you have had a cardiovascular event or not – we will value the effectiveness of treatment on the atherosclerotic process. Better stratification of risk because atherosclerosis is a continuum – rather than waiting for an event to place peole into one bin or the other.
Statin/fibrate or statin/niacin? Go to niacin after second line therapy before fibrate.
Interesting comment during discussion: Kashyap said that Niacin lowers MPO in the leukocyte but no reference was provided.
As one would expect there have been many more presentations regarding genetics and cardiovascular disease in 2009 compared to 2006. This is the most rapidly evolving field in medicine and there are many more questions than answers at this point. Some of the general concepts are worthy of attention.
CV genetics will allow for more accurate assessment of risk in the individual patient. This will allow the clinician to offer therapies at an earlier stage of the disease process. As the biological effects of the genetic influences are unraveled, new precise therapies will emerge. At this time we are a long way from understanding all of the biological effects which will have multiple layers of interactions between numerous genes. It will be similar to trying to elucidate all of the pathways within our brain. It will require the utilization of sophisticated computer systems and numerous bits of genetic knowledge. The complexity is really staggering. For example, one genetic variant that influences the risk of developing type 2 diabetes is very gender specific; if you inherit the gene from your father, this gene increases the risk of becoming diabetic 1.5 times; if you inherit the gene from your mother, this gene reduces the risk of becoming diabetic 0.8 times. The other factor to keep in mind was brought up by Kari Steffanson: “man is still being chiseled out; there is no finished product yet; we are in a constant state of evolution.” So, not only are we a long way from discovering all the genetic variants, but the genes themselves are in a constant state of change. This plays into Kari’s belief that there are probably very significant contributions being made by rare genetic variants within an individual subject and this makes for a much more complex genetic modeling. Given all of this, we can still start applying genetic knowledge clinically couched in the understanding that we are in the infancy stage with this field of medicine. One example of this is the 9p21 gene which is associated with increased risk of heart attack, abdominal aortic and cerebral aneurysm. If a Caucasian patient is homozygous for this gene, they are at 50% greater likelihood of developing premature coronary artery disease. This is a patient that should be counseled early in life about lifestyle issues known to effect cardiovascular risk. They would also be candidates for early aggressive pharmaceutical management if necessary to maintain optimal control of risk factors. If they become diabetic, we now also know they will get significant risk reduction from very tight control of their blood glucose levels. If they developed a puzzling persistent headache, a brain scan should be considered earlier than one might consider otherwise. Screening for abdominal aortic aneurysm should be considered at age 50yo as opposed to 60yo. Bottom line: the genetic knowledge we possess now, even though tiny, can have clinical impact. This field of medicine will, in the end, play a very dominate role in cardiovascular disease prevention.
Monday morning – June 15
A few updates from various sessions –
Statins: Pleotrophic effect of statins – it is not necessary to reduce LDL to get the pleiotrophic effects of statins. Statins have many effects beyond the lipids – which include anti-inflammatory, anti-thrombotic, anti-oxidant effects, improving angiogenesis, and improving endothelial function.
Data relating oxidized phospholipids, lipo(a) – studies have shown that OxPhospholipids are only found on Lp(a). Some of the OxPhospholipids are in the LDL base of Lp(a) and others are covaliently attached to Lp(a) kringles, in particular kringle 5. OxPhos are very soluble so they can escape from the intima more rapidly with reverse cholesterol transport. Paradoxically, Ox Phos as well as Lp(a) serum levels rise with regression. Interestingly, PLAC-2 preferentially is bound by Lp(a). OxPhos are pro-inflammatory but what is measured is the amount in the serum and that can be influenced by reverse cholesterol transport.
Sweetened Beverages – 1.6 billion overweight humans on the planet. Obesity has accelerated over the past 20 years as we have shifted away from water, milk, tea, coffee to more sweetened beverages. 75% of our foods now have sweeteners added. It has been documented that all of the increased calories consumed in the United States diet are in beverages such as fruit drinks and sodas. Interesting concept – if you take away water, you will die in 3-4 days. If you take away food – it will take a month or more to die. For thousands of years – all we had for beverages was water and breast milk. More than 400 calories/day in the US are from beverages and people do not compensate by decreasing other intake. Some of the problems with the beverages are called, “globalization” which happens extremely quickly – it took Coke Cola 70 years to penetrate the world market – it has taken Red Bull only 5 years. Measures being taken to correct this issue are: Mexico removing all whole milk from the grocery stores and replacing it with skim milk. Mexico is also introducing safe water in all schools and removing all caloric beverages from schools and taxing all sweetened beverages. Other measures being considered – label amount of calories in drinks and ban vending machines and advertising for sweetened beverages. There are some interesting differences between fructose and glucose….fructose is more thermogenic so it takes more oxygen to consume fructose and increases TG more as well as BP, HR, weight gain, respiratory rate, increased visceral fat and increases amount of small dense LDL. Amount of sugar in a 12 ounce coke is the same amount used in an oral glucose tolerance test. One sweetened soda per day over 8 years will increase a person’s weight about 20 pounds and increases risk of going on to diabetes by 40% and increases risk of gestational diabetes by 25%. It has now been documented that the consumption of soft drinks and sweetened drinks do increase risk of coronary disease in women.
Hello from Boston and the International Symposium on Atherosclerosis (ISA) meeting.
We are excited to be here with a program packed with wonderful information regarding the World’s number one cause of death and disability. It is also fun to see our names listed for three presentations. Amy will deliver her oral presentation tomorrow afternoon at 5 pm Eastern in the workshop titled, ‘Epidemiology of Cardiovascular Disease: Global Risk Assessment’. She will present right after Dr. Amato from Italy presents data from work he and Baldassarre have done. This is especially nice as we were with them in Washington, DC last year at a very small all day international meeting regarding CIMT. Amy will present orally the abstract titled, ‘Patients With Atherosclerosis Missed By Framingham 10-Year Risk Scoring’. We went by the room today where she will be speaking and it holds over 750 people. Then on Wednesday we present two posters on abstracts titled, ‘Insulin Resistance In Non-Diabetic Subjects Predicts Coronary Artery Disease Or Coronary Artery Disease Equivalence’ and ‘Framingham Risk Scoring Underestimates Cardiovascular Risk Associated With Insulin Resistance’.
Today there were afternoon talks regarding women and CVD. There were no huge revelations, but reinforcement of previous information. The paucity of women in CV studies continues in the US as well as internationally. This is despite the fact more women suffer from CV disease than men. In 2005 the Europeans started the ‘Women at Heart Program’; one of the purposes of this program is to insure females get better representation in CV studies.
One presentation was focused on African-American (AA) female risk. One interesting statistic is that AA females are two and a half times more likely to suffer a heart attack in the prime years of their lives which is 45-55 years old. It was also interesting that AA females have lower obstructive CAD, but a higher mortality rate with CAD. One thought is that they have higher arterial inflammation; it is known they run higher hsCRPs. AA females overall have more hypertension, obesity and elevated lipo (a) levels. The data tells us AA females derive the same benefit from treatments as other ethnicities. Despite this knowledge, they receive less treatment.
Another presentation was on non-US female data. Again it was reported that females have more strokes and heart attacks. There is poor representation in studies. They are under treated. They have less obstructive disease, but again higher mortality. The Interheart data indicates that lifestyle is more important in women than men. Women have more trouble with weight, smoking and lipids. Aspirin significantly reduces stroke risk, but not heart attack risk. It is becoming apparent that females need different guidelines than males.
A talk was given on secondary prevention in females in the US. It is frightening that CV death in females is not declining and in young women it is actually increasing. Again women are under treated: only 12% of these high risk women were found to be a guideline goals for all the lipids. In general women are more likely to be insulin resistant, overweight, hypertensive and hyperlipidemic. Non-fasting triglycerides are very predictive of risk in women. The residual risk in mono-statin therapy trials is very similar to men’s. The AHA has established specific guidelines for females; some of the unique features are: use niacin or fibrate for low HDL or high non-HDL; focus on lifetime risk; high risk patients get LDL <70; do not use HRT or SERMS; do not use anti-oxidants; do not use folic acid; use low dose aspirin for high risk females. In general the FRS in females is poor due to age and not taking into account insulin resistance.
Ridker commented that Jupiter included 6,801 women. That study actually showed women did better with risk reduction than men with Crestor. The number needed to treat for females > 60yo with elevated hsCRP was lower than the NNT for men. The median FRS of women in Jupiter was 4% which again goes along with the need to look at lifetime risk and not FRS.
It was also pointed out by another responder that women who benefit from aspirin therapy are usually insulin resistant, hypertensive and have increased hsCRP. Aspirin use in females for primary prevention is indicated when the risk of stroke is greater than the risk of harm from the aspirin.
The issue of younger women experiencing a rising CV mortality curve was re-addressed. Some other reasons proposed for this were; higher incidence of smoking and obesity along with poorer access to care.
Some of our thoughts after these presentations:
The observation that less obstructing CAD is associated with higher mortality fits very well with the atherothrombotic process. It backs up the fact that most events are from a clot obstructing the flow of blood and not cholesterol build up.
All these presentations point out how risk factor assessment fails to identify many women at risk. This supports our position for a disease based model of CV prevention. This is the ‘heart’ of Amy’s presentation tomorrow!
We do recommend low dose aspirin for all patients with CVD. A lot of our patients are identified as having ASVD via CIMT testing. If a female has plaque in her carotids, she certainly has risk for a stroke. The data showing significant stroke risk reduction in females supports our recommendation of low dose aspirin therapy.
Tonight we attended the Key Note address by Brown and Goldstein. It was fabulous! Their work defining cholesterol metabolism is phenomenal. This was a very in depth scientific discussion of their genetic and molecular research. There is absolutely no way to summarize this presentation other than to say it has taken 37 years of very intricate amazing work to find out the genetic defect of Familial Hypercholesterolemia is due to a few angstroms where there is a failure of six amino acids to be inserted into one chain of a protein involved in the transfer of material from the endothelial reticulum to the Golgia body with in a cell. They started their work in the early 1970’s. They brought the house down!
This first day was a great start to phenomenal five days of information. For those who want to join us at the next ISA meeting, it will be in Sydney, Australia March 25-29th, 2012. We certainly plan to have presence there.
Brad and Amy
ISA 2009 Opening Ceremonies:
The opening ceremony for this year’s International Symposium of Atherosclerosis set the stage for an exciting week of stimulating discussion and networking opportunities with some of the greatest medical scientists of this era. The keynote speakers for this opening session humbly and profoundly presented their life’s work. Dr. Michael Brown and Dr. Joseph Goldstein were presented with a clinical situation in the late 1960’s that shaped their careers. Little did they realize that the introduction of a little 12 year old girl who presented with a unique clinical situation that required inquisitive minds and passionate scientific research quickly carved out a unique window of research. Brown and Goldstein’s journey started to formalize in 1973 when they examined the HMG CoA Reductase Activity in Fibroblasts. Twenty years later, in 1993, they discovered the SREBP, which was the first membrane bound transcription factor. Another ten years of continued research led to the discovery in 2003 of how this SREBP transcription factor undergoes synthesis into the cells. After a 37 year journey of combined research, Drs. Brown and Goldstein have demonstrated the delicate balance of cholesterol homeostasis. They humbly conclude that a lifetime of dedicated research and many accolades allows them to simply say that they now “know the process well enough that (they) know what questions to ask next”. At the end of the day, they both agree – it was this little 12 year old girl with familial heterogeneous hyperlipidemia that launched them into a career of discovery and insight.
So starts the week…..we will keep you posted. Amy and Brad…
Monday June 15 –
Today I will highlight the session entitled:
Epidemiology of Cardiovascular Disease: Global Risk Assessment.
Moderators: Dr. D’Agostino from Boston, MA and Dr. Assmann from Munster, Germany
This session was held from 3:30 to 5:30 pm in Ballroom C – holding approximately 750 people – one of the larger ballrooms for these sessions. I must admit to all of you that I was a bit taken a back upon first viewing the room – due to its size and formal seating arrangement, I felt the twinge of nerves begin to develop prior to my presentation.
The title of this session suggests a complex question with a very simple answer. For years it has been debated how to properly assess an individual’s risk for a cardiovascular event – matter of fact, the moderator, Dr. D’Agostino candidly stated that he has dedicated his life’s work to try and determine who is “at risk” and who needs therapeutic intervention for that risk. Much debate has entwined itself around the idea that certain risk factors, such as age, smoking, cholesterol and blood pressure somehow hold the key in determining who should get treatment and who shouldn’t receive treatment.
Our premise, the Bale/Doneen Method challenges this very concept. Our Method is focused on a disease treatment paradigm. It is quite simple really – find out who has disease (atherosclerosis) and then determine the inflammation of that disease and then go after what caused it to be there and lastly, monitor that disease over time. The very premise of our work revolves around the simple idea that risk does not always equate to disease and vice-versa.
The first lecture was entitled: Evaluating the Impact of New Markers on Risk Prediction by Dr. Cook from Harvard. Dr. Cook and Dr. Ridker designed the Reynold’s Risk Score for women. As you know, Dr. Ridker was the P.I. for the Jupitor Trial. Dr. Cook’s lecture revolved around an epidemiological focus on risk – simply do a risk calculation and treat accordingly. The premise of her talk suggested that adding hsCRP to standard risk screening will reclassify an individual (male or female) into a proper risk category. As you can imagine – not a mention of “disease” in her lecture.
Dr. D’Agostino from Boston was next to present – CVD Global Risk Models: The Framingham Experience. Dr. D’Agostino did a wonderful job highlighting the historical perspective of Framingham Risk Scoring and, in a subtle but impactful way (albeit unknowingly) began to pave the way for my upcoming presentation. He respectively pointed out some of the limitations with FRS, including time frame limitations and relative vs.absolute risk.
Dr. Wilson from Atlanta Georgia was next with his presentation entitled; Global Risk Assessment for Cardiovascular Disease in 2009.
(By now I was beginning to get a bit nervous because the tone of the room was focused on “risk” vs “disease”. I certainly did not intend to propose an inflammatory response to risk factor analysis. Rather, my intent was to suggest a disease paradigm rather than a risk factor paradigm in isolation.)
Dr. Wilson’s talk began to put me at ease – for the first time during this session – the idea was proposed……subtly suggesting the idea that augmenting risk factors with other tests, such as coronary calcification “might” be something to consider.
Dr. Wood from London U.K. was next up – his talk was entitled, Vascular Risk Assessment and Management. He made the eloquent statement of: “Don’t look at risk factors in isolation – for it is the company for which they keep”. He went on to say that we must place “qualifiers” on our risk assessments so that we can recognize and account for asymptomatic disease.
(O.K. – yes – he said it!! The stage was now beginning to set for my upcoming lecture….calling for a paradigm shift to disease rather than risk)
Dr. Wood mentioned structural tests for disease identification, including CACS and CIMT.
Dr. Assmann from Munster, Germany was next – The Patient at Risk for Myocardial Infarction and Stroke: New PROCAM Data. Dr. Assmann’s talk was music to our ears…..he stressed the importance of individualizing and personalizing medicine. The PROCAM data revolves around three areas of assessment – imaging, genes and biomarkers. He also pointed out that in the PROCAM data set – the <10% FRS had an event rate that equaled the >20% group – a clear call out that something better must be out there. He also said, “it would take a lot of imagination to think that one marker such as hsCRP could make that dramatic of a change. He went on to discuss the value of Lp(a), among others. At this point, Dr. Ridker got up and walked out of the room….
Dr. Amato from Milan, Italy was next. Common Carotid Artery Diameter as a Marker of Cardiovascular Risk: Preliminary Results of the IMPROVE Study. Brad and I had the fortunate opportunity to meet and continue to work with Dr. Amato and his colleague, Dr. Baldassarre, on the international panel discussing the clinical utility of CIMT, along with Dr. Gene Bond and Dr. Mark Oldendorf. Dr. Amato gave an eloquent presentation on the preliminary results of the IMPROVE study – interestingly looking at the lumen diameter with CIMT, among other findings.
Well – now it was my turn. Fortunately the speakers before me had laid the ground work for our data – I felt the audience was ready to hear our message, albeit certainly to provoke some controversy and thought.
The title of my talk was: Patients with Atherosclerosis Missed by Framingham 10-year Risk Scoring. So, I took a deep breath and headed to the podium – now or never!
I will try to summarize the talk as succinctly as possible – basically we took our data set (576 patients) and calculated FRS and performed structural testing on all of them to find the presence or absence of disease using well validated clinical tools such as CIMT, CACS, AAA, ABI. The question is quite simple…… What was the predictive value of FRS detecting disease? I started stating the facts – Cardiovascular disease is the leading cause of death in all developing countries and is intended to remain so for many years to come. Unfortunately, up to one half of all deaths are sudden and unexpected, due to atherosclerotic events in previously asymptomatic individuals. After covering the background, methods and demographics, the results clinched our message. I would like to point out the bottom line – “The relationship between the three FRS categories and the presence or absence of atherosclerosis highlights some important clinical findings. Instructively and surprisingly, it is important to note that 79% of patients with documented atherosclerosis had a FRS score of <10%. Also – a FRS of <20% substantially and significantly leads to false negatives which and will have an effect on therapeutic strategies, leading to potentially detrimental clinical outcomes. Similarly – what is the predictive value of a high risk FRS of >20%? Basically, FRS >20% has a great specificity but has a very weak negative predictive value – actually the data shows that if your FRS is NOT high risk, you only have a 16% chance of NOT having disease!! In closing I asked for a paradigm shift in clinical medicine – a shift that moves away from the sole practice of using a risk factor model to one that incorporates disease identification and treatment and monitoring of disease.
I did get some good questions during the Q&A. The moderator, Dr. D’Agostino found it hard to believe that so many people had disease and didn’t know it? As we all know – you do not feel this disease unless you get a thrombus that alters the flow of blood enough that symptoms develop. Dr. Assmann from Germany was very complimentary and came up afterwards to visit about our data – he has my card and I would like to see our data compared to the PROCAM data set – he sounded intrigued.
Lastly – the final presentation of the session was entitled: Carotid Plaque and IMT in the Population Based Refine Reykjavik Study in Context with the SHAPE Guidelines by Dr. Gudnason from Kopavogar, Iceland. His research certainly backed up our belief in a diease treatment paradigm – great ending to the session!
On a more candid note – Yes, I was nervously excited to give this presentation and yes, I did take a sigh of relief upon the day’s completion.
Monday afternoon Amy Doneen did a marvelous job orally presenting the abstract which essentially argues cardiovascular prevention needs to be rooted in identifying the presence of atherosclerotic disease as opposed to simply looking at risk factors. She adeptly showed data from the Spokane cohort reveals risk factor assessment as per Framingham misses approximately 85% of the patients who actually have subclinical atherosclerosis. It is becoming well accepted that subclinical atherosclerosis is extremely valuable information and places a patient into a high lifetime risk for heart attack and stroke. These individuals need to be targeted for optimal control of global CV risk factors. Framingham only calls for optimal control in 15% of the Spokane patients who actually were proven to have atherosclerosis. This clearly is a gross failure of uncovering those in need of aggressive management. She also made the point very effectively that we have clinical tools available to find atherosclerosis in patients and these tools are not expensive or harmful. She had a huge impact on the audience that it is time for a paradigm change in CV risk assessment. There is a need to look beyond risk factors and anchor our advice for treatment of the individual patient based on the actual disease of atherosclerosis. Her presentation was in a large ballroom. The room could seat up to 750 people and there were several hundred present. Her composure was remarkable in front of world experts. She received more questions than any of the speakers. Her answers were clear and succinct; they left no doubt that she was responding from a platform of confident clinical knowledge. At the end of the session, Amy was swamped with people complimenting her position and wanting more information. There were two world expert moderators and neither one could get to her before others. Therefore, one came up to me and extolled positive comments regarding her talk. This older physician has spent his whole career trying to figure out which risk factors to assess in order to identify those who should be treated aggressively. He is well published and an established authority on risk factor analysis. He was obviously blown away by Amy’s message and struggling to accept the obvious, that it does make sense to base management on the actual presence or absence of atherosclerosis and not on a set of risk factors. To his credit he gave her voice very serious attention and probably is having a few sleepless nights. The other moderator managed to get Amy’s attention to alert her that he wants to establish an ongoing dialogue because he was so excited about her information.
Following her call for a shift in risk assessment from one rooted in risk factors like, blood pressure and cholesterol, to one rooted in the actual disease of atherosclerosis, numerous comments by many people have been made to support this contention. One of the most remarkable was Christie Ballentyne today at the large plenary session. He repeatedly brought up concepts like lifetime risk; actual atherosclerosis in an individual patient; the value of carotid IMT screening with identifying and monitoring subclinical atherosclerosis. His message, along with numerous others, provides reinforcement for our BaleDoneen Method. It is so refreshing to be present at a meeting where many healthcare providers from around the world are truly interested in the prevention of devastating events like heart attacks and strokes. It is not an easy task to stand before such an audience and call for a significant change in the technique of evaluating an individual’s CV risk. Amy accomplished this with great composure and expertise. On June 15th , Amy Doneen significantly impacted the world of CV medicine in a very positive manner. It was a pleasure and honor to witness her presentation.
I will share some thoughts on a lecture by Dr. JoAnn Manson – Hormone Therapy – where are we now?
Lessons learned from WHI –
Role of age, time since menopause and other risk factors in modifying outcomes associated with HRT
Observational research – 40+ studies of HRT and CHD
Randomized trials –
Secondary prevention – NO cardioprotection found HERS, ERA, HRT, WEST, ESPRIT, WAVE – No benefit and perhaps precipitation of MII
Primary Prevention WHI – Estrogen+Progestin Trial, Estrogen-Alone Trial
WHI: Estrogen +Progestin trial – x 5 years – risk outweighed the benefits and it was stopped early – mean age was 63 (talking about women over a decade past menopause – increase of CHD and stroke – 40% increase and PE increase 113%, Breast Cancer increase 26% – problem thought that it was age at the time of HRT initiation among other things.
WHI: Estrogen alone: stroke increased 39% – neutral: CHD, PE, Breast AA, colorectal cancer, total mortality, benefits – hip fracture reduced 39%……..stopped 1 year early
Observational study – Nurses Health Study (NHS)–
NHS: average age 52 – very close to onset of menopause – within 1-3 yrs of onset of menopause
Differences b/t WHI and observational (NHS) –
Age of HT initiation: 63 vs 52,
Time since menopause : >12 year vs 1-3 years
BMI:28-30, vs 24-25
Duration of HT use: short vs long
HT formulation: CEE+MPA vs Diverse
WHI: E+P trial –
Women <10 yrs since menopause: RR=.89
Women 10-19 since menopause: RR=1.22
Women 20++ years since menopause: RR=1.71
HT still has clinical role in tx of moderate to severe hot flashes and other menopausal symptoms – use lowest effective dose for the shortest duration necessary. Postmenopausal HRT should NOT be initiated or continue for the primary or secondary prevention of CVD or other chronic diseases. When prescribing solely for urogenital symptoms, use topical.
Prevention of postmenopausal osteoporosis – only after non-estrogen meds have been tried
KEEPS, ELITE studies pending.
Sunday – June 14th, 2009