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ADV Primary Prevention

Primary Prevention is Life

A Case for Reflections on Our Approach to Cardiovascular Diseases
Authored by Dr. Antonino DiMarco, MD, June 2006

Heart attacks and Stroke are often devastating events. While some occur in patients who have known diseases, most strike individuals who are in apparent good health, often with irreparable consequences for them and their families. We have definite proof that atherosclerosis is the disease which brings on these devastating events. Could they be avoided?

Traditionally, cardiovascular medicine has focused on detecting diseases (in this case atherosclerosis) with the hope of preventing their complications. We look for symptoms, examine for physical abnormalities, and test for abnormal functions and anatomy, with stress tests, MRI, CT, cardiac catherization, and other invasive modalities. This is what we call “secondary prevention”.

In atherosclerosis however secondary prevention, i.e. waiting until significant disease has developed, is clearly inadequate prevention. This simple truth stems from the fact that even the mildest forms of this disease, the smallest non-obstructive plaques, may cause heart attacks and stroke suddenly and without warning.

Even more sobering is the counterintuitive realization that the majority of heart attacks, especially those coming unexpectedly out of a blue sky, strike individuals with the milder forms of disease. In other words, had these individuals gone through a stress test, cardiac catherization, CT or MRI, just before their heart attacks, they would have been found free of disease or with only mild abnormalities, and told that they needed not to worry.

Clearly, when it comes to atherosclerosis, absence of advanced disease is not equivalent with absence of risk. And tests that can only detect disease cannot rule out risk. The assumption or suggestion that a negative test result could or should provide “piece of mind” is therefore a serious mistake.

At an individual level, they distract one from focusing on the real problem, and cause lost of precious opportunities for prevention.

At a societal level, the practice is misinforming and disruptive to effective public policymaking, to communities’ educational activities, and to sound professional care standards: all of which, based on the fundamental knowledge we already possess, would be immensely more effective.

What we need is a strategy to detect predisposition to atherosclerosis well before the disease and its symptoms develop. Since such strategy must work at a time when there are yet no disease or symptoms, it relies on a comprehensive approach to detect the presence of relevant individual risk factors and their combination thereof, and to submit them to critical analysis, and to assign a degree of cardiovascular risk in accordance with that analysis.

The interventional component of the strategy will then match individual degrees and sets of risks with the latest notions from fundamental science and epidemiology, and formulate individual plans, treatments when necessary, that will keep risks from ever becoming disease.

What I just described is “primary prevention”. It defines what is necessary to prevent the very occurrence of disease (i.e. atherosclerosis): a distinguishing concept from the “secondary prevention” discussed above.

I will now outline the scientific base of a strategy of primary prevention of atherosclerosis and its dreadful consequences.

• Atherosclerosis occurs in individuals with predisposing. Traits inevitably come first, and atherosclerosis will follow: in certain individuals the disease appears sooner in life, while in others it may require a lifetime to unfold. The sequence of this process however –traits before disease, has no exceptions.

• And there is a very important corollary: those who carry no predisposing traits, i.e. the vast majority of us, will not develop the disease.

• If we were able to detect the presence of these traits, we could then distinguish their “carriers”, and focus our concerns on them, since they are the ones at risk. A huge amount of tests could thus be avoided, as well as unnecessary anxiety, fears and enormous waste of personal and societal resources.

• Traits do not ordinarily cause symptoms, physical abnormalities, or any thing else which stress-testing, cardiac catherization, CT, or MRI can pick up. Such tests can only detect diseases, not traits.

• Traits are biological markers based on genes, chromosomal arrangements, and their genomic combinations thereof. As genetic entities, traits are parts of our DNA, and tend to cluster in families; we may inherit those of our parents, or we may not –it is a chance process; but we won’t have traits that our parents didn’t have themselves.

• If we knew all the genes and genomic combinations responsible for atherosclerosis we could just run specific tests and see if one carries them or not. But these are among the many things we still don’t know. The completed discovery of the human genome has been a revolution in biology, and tests will presumably be available in the future, which will detect clusters of genes specifically involved in atherosclerosis.

• Till then however, clinicians can still gather very useful information on an individual’s traits for atherosclerosis, from reviewing the experience with this disease in her/his family. Such review, the “family history”, properly taken and interpreted by the experienced clinician, is the single most effective intervention to date, in estimating the risk of a normal individual for developing atherosclerosis.

• And there is strong plausibility to the effectiveness of this tool: the complexity of the genetic base of atherosclerosis, which is not one gene or few, but the interplay of many genes in many different genomic contexts. There is no test, imaging study, invasive procedure that can shed light on the phenotypic expression of such genomic complexity as well as “family” history does: and nothing comes even close. Unfortunately, this most powerful tool remains greatly underestimated.

If family history is the cornerstone of risk assessment, are there any other tools available to us? End what about cholesterol levels?

• We know of several biochemical markers in various ways associated with the predisposition to atherosclerosis. Some bear directly on the disease mechanism. Cholesterol is the most important, homocysteine is another, and yet another marker -- C-reactive protein, may relate to disease activity.

• Biomarkers however are neither sufficient nor necessary in establishing an individual’s risk for atherosclerosis. Take cholesterol for example. There is most compelling evidence and a clear rationale for its direct involvement in atherosclerosis. Nonetheless we all know of individuals with normal or low “bad” cholesterol (LDL), which should make them safe, and yet develop severe atherosclerosis. And we also know of yet others, who have very high level of bad cholesterol, and who nonetheless have normal coronary arteries, and who reach their eighties in excellent shape.

Clearly there is more to the story of atherosclerosis than cholesterol levels can tell. Cholesterol levels do have value, especially in monitoring responses to interventions, but they should not be the initial or sole indicator in assessing individual risks and make decisions on treatments.

As to other known biochemical markers, the evidence behind them is not as compelling as it is for cholesterol, and the rationale in their support is even weaker: frankly such markers are not very useful in primary prevention.

• There is new interest however in the study of some parameters of physiological functions which become altered early in life, in individuals who will later will go on to develop atherosclerosis. The changes are not losses of particular cell functions, of biochemical markers or molecules, nor the appearance of new ones. What become altered early in the life of these individuals are the balances of constitutive vs. inducible, inhibitory vs. facilitating pathways, in particular aspects of cell biology.

The phenomena we are talking about are indeed very subtle, since affected cell lineages must still be able to survive and be competitive for the long time it takes to bring on the disease. Drastic unbalances would result in immediate cell death or cancer.

These very subtle unbalances of functions are by nature difficult to detect, but they are the link between the disease atherosclerosis and its genetic traits. As such they are promising targets of primary prevention.

Primary prevention of atherosclerosis is also concerned with the impact of coexisting conditions and non-genetic factors in modulating the individual genetic risk.

• Diabetes, Hypertension, and Obesity, among others, certainly increase the risk and severity of atherosclerosis (I am not sure if they do so even in individuals without background genetic predisposition). Of course these conditions need to be aggressively treated on their own merit. Emphasizing their relation to atherosclerosis however, may motivate patients and improve compliance with “aggressive” approaches.

The same considerations apply to life-stile-related risk factor: smoking, for example, for which there must be zero tolerance in individual with predisposition to atherosclerosis.

As you may have noticed, there is a corollarium to primary prevention. It must be effective, but also practical, non-invasive and affordable; and it must be applicable to entire communities, not just to patients.

We have at our disposal an armamentarium of interventions for the diagnosis and treatment of atherosclerosis. In the discussion above I dealt with some of these interventions, and offered a reason why they are ineffective and inappropriate for primary prevention.

Nonetheless many such interventions are being used in an ever-increasing fashion for reasons other than treatment, often with the intent to assess risk, or to give reassurance and “peace of mind”. Not only can these objectives not be achieved, but the infatuation with these interventions also imposes a large burden on the limited resources of individuals and society alike, which are unreasonable and unsustainable.

Furthermore, it is not science propelling this practice. It is rather technology at its worst, branching out in a seemingly cancerous growth, loosing connection with the most fundamental postulate of true science, and seeing patients and human beings not as subjects of life and dignity, but as exploitable expedients for its own growth.

However, medicines and lifestyle modifications are a different story. Not only are they extremely important in treating atherosclerosis, but can also be very effective in its primary prevention.

Lets take “statins”, for example, a class of cholesterol-lowering medicines. There is undisputed evidence that “statins” delay progression of atherosclerosis and decrease its complications. Even more importantly, a solid body of fundamental knowledge from basic research tells us that statins given early enough interfere with, and may in fact halt the very first steps in the cellular and metabolic derangements leading to atherosclerosis. This makes this class of medicines a most powerful tool for primary prevention.

CONCLUSIONS

Very effective measures to prevent the disease atherosclerosis and its dreadful consequences are now possible.
Physicians can take these measures today, at individual level in their own practices. They can also try to educate communities, and influence professional organizations in various ways.

This task however is difficult and of limited impact, since individual physicians are up against a pervasive system of disinformation driven by the seemingly unlimited resources of technology and our fascination with, and uncritical acceptance of “the latest” of everything.

It is clearly in society best interest that we develop public policies, which will protect the health of our citizens and educate them on how to best protect themselves. Society cannot be passive and leave unchallenged the self-serving technology that dismantles basic health care structures and devour its resources.