Lately we have come to understand that some of the phenomena involved in the development of various chronic diseases, like atherosclerosis, can be evidenced by following a path opposite to the one traditionally used in research. From the secondary prevention of a chronic disease we can learn about some of the mechanisms that originate it. This unusual, but ethical, approach even makes it possible to clarify models developed in laboratories and improve them to reproduce the process under study.

For the last 30 years and up to the present, the acute thrombotic phenomenon that is mainly responsible for what are now known as the coronary syndromes dominated the attention of most practicing physicians.

From the original trials of antiplatelet and antithrombotic therapy1-4 to the megastudies that confirm the effectiveness and safety of these agents, enough time has passed to understand, at least in part, why the recurrence of cardiovascular accidents is far from negligible in the atherosclerotic population in spite of early and effective treatment.

A new myocardial infarction or death occurs in approximately 6 of 100 patients per month To these cases must be added another 6 non-fatal infarctions or deaths for every 100 subjects a year, and revascularization rates rise to 9% from the time that the patient leaves the hospital in an apparently good state of health after suffering a first coronary event and in the next 12 months of follow-up.5

The first assumption about the pathological mechanism involved in this overly high rate of reiterative episodes of ischemia was that the same thrombotic phenomenon remains active and capable of inducing thrombin formation days after the initial accident involving the atherosclerotic plaque.6,7

Nevertheless, the prolongation of antithrombotic therapy beyond the first days has so far produced inconsistent results.8 An apparent benefit has been observed with certain drugs, in addition to a high cost in terms of loss of safety.9

Even aggressive trials combining antithrombotic therapy and early revascularization procedures, particularly in patients with a suspected high clinical risk,10 entail an equally high incidence of subsequent events.11

If the incidence of cardiovascular accidents obtained from medical records is added to the results of clinical trials, it results in a fair amount of information.

Certain intriguing associations have been found in the epidemiology of coronary artery disease, suggesting that other mechanisms are involved. An example of this is the incidence of myocardial infarction and cardiovascular death observed in winter and during flu epidemics.12,13

More recently, Naghavi et al14 found this association in an observational study of coronary patients seen at the University of Texas during the winter season from October 1997 to March 1998. These investigators found that patients who were vaccinated against flu had a significantly lower risk of a new adverse event than those who were not vaccinated. Similarly, Lavallee et al15 found that the patients vaccinated with this aim during the epidemiological campaign had lower rates of cerebrovascular accident in the winter of 1999 to 2000 in Paris, France.

This information can be combined with that obtained in models developed at the same time.

An interesting viral theory can explain some of the mechanisms that lead to restenosis and the development of coronary artery disease.16,17 In immunocompetent subjects, virosis is rarely reactivated with such an aggressive replication rate. In any case, this subject is in a state of «aborted infection» where certain genetic viral products can be regenerated and converted, under certain circumstances, into triggers for viral replication, as in the case of endothelial injury caused by an angioplasty balloon in infected individuals.

These findings make lymphocytic cells of the B line relevant.

It is well known that a large percentage of T lymphocytes in atherosclerotic plaques are «preactivated» in relation to other circulating T cells. In addition, a small proportion of these lymphocytes express certain antigens of cell proliferation or receptor co-stimulation, indicating that they are responding to the presence of other antigenic stimuli.18 The origin of this stimulation is unknown and not even very clear, although it is evident that the immunological process and infectious process coincide.

In contrast with this cell line, few B lymphocytes are found in the same atherosclerotic plaques. B lymphocytes are activated in the usual way against specific antigens, but rarely spontaneously. This makes it likely that a rapid humoral response, either specific or non-specific, occurs after vaccination, reflecting an immediate migration of subpopulations of these cells that can respond to the stimulus induced.19 Influenza antibodies are found in peripheral blood one week after the flu vaccination.20

In the case of atherosclerosis, the first conception of this phenomenon was indirectly analyzed in an animal model. In 1978, Fabricant et al21 infected hens with herpes virus, which quickly developed atherosclerotic injuries similar to those seen in humans. Minick et al22 immediately verified that immunizing them with an attenuated viral load prevented the development of atherosclerosis.

In our original study with macrolide antibiotics,23 we found that the effect of these medications persisted up to 60 days after therapy stopped.24

This phenomenon is commonly observed in any situation in which an immunosuppressive therapy is applied. When this therapy ceases abruptly, a residual effect persists that benefits the subject, indicating the appearance of immunocompetent states and deficiencies.

This was the rationale for the first trial of a flu vaccine in 200 acute coronary patients (myocardial infarction with or without deviation of the ST segment) and an additional group of 100 symptomatic subjects with angina who were scheduled for transluminal coronary angioplasty but did not have any sort of previous atherosclerotic evidence, in order to avoid reactivating a potentially infectious viral load in subjects undergoing «scheduled endothelial injury.»

The initial results of the Flu Vaccination in Acute Coronary Syndromes (FLUVACS) study25 were obtained 6 months after a single dose of the strain recommended by the World Health Organization in the southern hemisphere for the winter of 2001,26 0.5 ml of the A/Moscow/10/99, A/New Caledonia/20/99 (H1N1) and AB/Sichuan/379/99. The results are shown in Tables 1 to 3.

In the trial, the benefit was confined mainly to the group with myocardial infarction (Table 2; Figure 1). Preliminary speculations on this topic arose from the idea that the nonspecific activation of the B lymphocyte line, beyond a limited number of patients and given the role of probability, acts in an independent way in a frankly unstable clinical situation with probable endothelial injury, as opposed to the circumstances where the absence of clinical instability suggests different state of immunocompetence a priori.

Fig. 1. Patients free of events (%).

Concomitantly with this clinical study, Dimayuga et al27 investigated the effects of reconstitution with B cells in immunodeficient mice subjected to an endothelial insult. They found that these cells could modulate tissue aggression.

In Sweden, Caligiuri and Hansson28 found that splenectomy in hypercholesterolemic apo-E deficient mice aggravated the development of atherosclerosis. They later transferred cells from the spleen of these mice to themselves, significantly reducing disease progression.

Bacterial and viral infections can evidently stimulate an immunological reaction through specific and non-specific mechanisms that recall and simulate well-known molecular structures for the maintenance over time of a chronic disease with a strong inflammatory component, as is the case of atherosclerosis.29

The conditions that determine how the innate and acquired immunological system finally contributes to the pathogenesis of these conditions have still not been resolved.

Although the administration of a single dose of flu vaccine, as suggested by health-care organizations, is practically innocuous, the modification of health-care policies for this indication during hospitalization for a cardiovascular event probably merits further study.

Correspondence: Dr. E. Gurfinkel.
Jefe de la Unidad Coronaria. Fundación Favaloro.
Avda. Belgrano, 1746. 1093 Buenos Aires. Argentina.
E-mail: epgurfinkel@ffavaloro.org