C-REACTIVE PROTEIN AS A MARKER OF CARDIOVASCULAR …



Biophysical-Semeiotic Evaluation of Acute Phase Proteins.

Technical and Practical Aspects.

“I acknowledge the valuable scientific advice provided to me by Prof. Lars Retterstol, Institute of Medical Genetics, University of Oslo, by his paper C-REACTIVE PROTEIN AS A MARKER OF CARDIOVASCULAR DISEASE”

Introduction.

Bed-side evaluating Acute Phase Proteins (APP), including C Reactive Protein (CRP), is nowadays possible by means of Biophysical Semeiotics. APP are numerous proteins, synthesized by the liver; their bed-side evaluation has proved to be useful, from both diagnostic and prognostic view-point, as allows me to state a long well-established “clinical experience. In addition, such as original assessement represents an useful tool in research, and permits doctor to perform therapeutic monitoring in a new, remarkable, and reliable way.

Acute Phase Proteins.

Acute Phase Proteins (APP), and primarily C Reactive Protein (CRP) are tremendous valuable markers of disease activity (and responses to therapy) in tissue damaging, inflammatory, infective, or neoplastic conditions (1). Automated CRP measurements were introduced in the early 1980s, but there was limited sensitivity and poor precision in the low range of CRP values, and concentrations below 5-10 mg/L could not be detected. However, more sensitive CRP measurements have uncovered new information on the development and progression of coronary heart disease (CHD) (2).

The precise biological function of CRP is not fully understood, but its properties are consistent with an important role in nonspecific defense mechanisms . It binds to a variety of substances, including phosphocholin and thus recognizes several pathogens as well as phospholipid constituents of damaged cells (3, 4). It activates, moreover, the classical complement system and enhances the activity to phagocytic cells (1). CRP may initiate the elimination of targeted cells by its interaction with both the cellular and humoral effector systems [6]. CRP may also induce synthesis of cytokines and tissue factor in monocytes. It seems plausible that CRP has many pathophysiologic roles in the inflammatory response (3), as allows to state Biophysical Semeiotics.

Median CRP values are typically 1-2 mg/L in healthy persons, double with age from 30 to 60 years, and tend to be higher in females than in males. It has long been known that CRP levels are elevated in the presence of risk factors of CHD, including smoking, diabetes, obesity, and elevated blood pressure (5-9) (See later on).

Among patients in stable phase after premature myocardial infarction (MI), CRP level was the strongest predictor of both total and cardiac mortality. The effect of CRP is graded, and remains over a long time of follow-up. In fact, CRP appears to be an even stronger predictor of cardiac and total death than ejection fraction (10), which previously has shown to be the most significant indicator of prognosis (11). CRP also predicts prognosis in patients with acute coronary syndromes. Thus, CRP is associated with prognosis in patients in different stages of cardiovascular disease and in healthy persons.

However, the underlying mechanisms that enhance low-grade inflammation are essentially unknown, and several mechanisms are possible, according to numerous authors (12, 13, 14).

In my opinion, inflammatory event in pathogenesis of artheriosclerosis, in general, is not primitive, but, if present, secondary, as I demonstrated in my site, HONCode, N° 233637, semeioticabiofisica.it: “Biophysical-Semeiotic Arteriosclerotic Constitution” and “Microcirculatory Theory of Arteriosclerosis”. (See later on).

As states Lars Rettersol, there is agreement among authors on some possible action mechanisms, like the following:

(1) CRP may be a circulating marker of atherosclerosis. However, in a recent study no association between angiographic findings and CRP was observed (14), but another and larger study concluded otherwise (15). It was reported long ago that another marker of inflammation, erythrocyte sedimentation rate, was associated to extend of coronary atherosclerosis (16).

(2) High levels of CRP may also indicate plaque-instability, reflecting activity of macrophages within the plaque eroding the fibrous cap. CRP is a complement activator, and activated complement may attack cells within the plaque, and thereby establish a self-sustaining autotoxic mechanism leading to plaque instability and cardiac events (17)

(3) There are indications that CRP may promote larger cardiac injury in acute MI, perhaps through activation through the complement system (18) implicating that high levels of CRP before the acute MI worsen the outcome.

(4) CRP may promote blood clotting, possibly mediated through tissue factor [9] or other thrombogenic proteins (19).

(5) Possibly, the effect of CRP on CHD may reflect infections, since CRP may be elevated by viral and bacterial pathogens (20, 21) (See later on). Really, Biophysical Semeiotics, often but not in all cases, as regards “only” the CAD, allowed me to corroborate these data, indicating surely that elevated APP are a secondary, and not primitive facts, as other author demonstrated in according to my results (20, 22).

6) CRP is elevated in acute MI, probably as a response to myocardial injury. In post-MI patients, CRP may reflect infarction size, or long-term repair mechanisms or repair activity in the myocardium, which may, or may not, be dependent of MI size (24).

(7) CRP may be a marker of an overall burden of risk factors or an unhealthy lifestyle.

Combinations of all these explanations are also possible.

Since CRP appears to be a strong predictor of prognosis, one might question whether CRP should be used to screen the general population or be used as a tool for risk stratification of cardiovascular patients in clinical settings (24). CRP has been reported to improve risk prediction in general population screening (24) and special algorithms have now been proposed for such a purpose, based on quintiles of CRP and TC: HDLC ratio.

Physicians may use CRP not only to evaluate prognosis, but also to evaluate the effects of e.g. smoking and advocate smoking cessation. Furthermore, we have to remember the role played by the assessment of CRP in the evaluation of smooking damages and beneficial effects due to cessation, as well as in therapeutic monitoring, e.g., of some drugs, such as statins, which are also antiinflammatory ones.

To summarize, to-day, although diagnostic and prognostic value of APP, briefly illustrated above, we can not consider their high value neither in screening on large population, i.e., in the war against CAD, nor in prognosis (e.g. of AMI), according to other authors (26), analogously to what happened over last years as regards fibrinogen; both are markers of a low-grade inflammation, but CRP is a more sensitive marker of inflammation and thus a better predictor of prognosis.

I agree completely with Lars Rettersol, who suggested me by its cited paper to write present article, when states: “In addition, it has been observed that established risk factors represent different risks in different persons as some individuals remain healthy despite the presence of hypercholesterolemia, hypertension, and even smoking, whereas the same risk factors cause premature cardiovascular disease in others”.

In addition, the author states that “One is tempted to speculate whether inflammation represents the key to this apparent paradox”, concluding as follows: “In some (most) patients, these risk factors may cause an increased inflammatory process and progress of atherosclerosis and predisposition of thrombosis, while in a few patients, only minor changes in the inflammatory response due to modifying genetic or environmental factors. If so, the more than 300 "risk factors" of cardiovascular disease available today can be reduced to only one risk factor: inflammation”.

As I wrote in the cited site (“Biophysical Semeiotic Constitutions”) all possible “risk factors”, by different pathogenetic action mechanisms, must necessarily act on a particular “constitutional terrain” in order to provoke one or more of the most common and serious human diseases, since genetic alterations, both “parenchymal” and “microcirculatory”, well located in a precise biological system, represent the base of different constitutions, conditio sine qua non of the deleterious effectes caused by “risk factors”, sometimes by means of inflammations.

I am going to demonstrate, from biophysical-semeiotic view-point, that the genetic abnormality to produce APP, including CRP, more than normally, i.e. in healthy, takes part of different “constitutions” , which predispose to DM, dyslipidaemia, arterial hypertension, rheumatic diseases, arteriosclerosis, and malignancies.

In a few words, inflammation, revealed by increased production of APP and particularly CRP in CAD, indicates exclusively the presence of one or more of some remarkable biophysical-semeiotic constitutions, predisposing to diverse human disorders, which are most common and serious. Abnormality of inflammatory response shows “clinically” the presence of one (or more) of these constitutions, beeng a sign of them.

Acute Phase Proteins Synthesis: Biophysical-Semeiotic Work Hypotesis.

The synthesis of Acute Phase Proteins (APP), including CRP, takes place in the liver and is stimulated by numerous products of damaged cells during infection, inflammation, malignancies, a.s.o.

APP production increases rapidly in the course of infectious diseases, bacterial and viral in origin, and, then, decreases slowly. Notoriously such substanses act as opsonine and activate both synthesis of numerous cytochines and inflammation cells, taking a part of aspeciific antiinflammatory response.

Hepatic production of APP is necessarily correlated with local microcirculatory modifications, like associated microcirculatory activation, type I (See the site semeioticabiofisica.it/microangiologia). In addition, as work hypotesis, I suspected the presence, in the site of their production, of a “particular” stimulation of local hepatic receptors, inflammatory in origin, analogously to the events of whatever inflammatory process: for example, in case of rheumatic arthritis. In fact, under such as pathological conditions, Biophysical Semeiotics allows to evaluate in “quantitative “ way APP synthesis.

As a consequence, I utilized the same stimulation, i.e., ungueal pressure, applied on cutaneous hepatic dermathomeres (= cutaneous projection area of the liver), in healthy individual without DM, hypertension, arteriosclerosis, rheumatic disorders, malignancies in their family history, in supine position and psycho-physically relaxed, and assessed, at rest, “basal” behaviour of hepatic-aspecific gastric reflex, type II, namely provoked by ungueal pressure (Fig. 1).

[pic]

Fig. 1

Gastric aspecific reflex: in the stomach, both fundus and body are dilated, while antral-pyloric region contracts, caused by ungueal pressure, applied upon lever cutaneous projection area.

In healthy, after a latency time (lt) of 10 sec., appears the gastric aspecific reflex of 1-2 cm in intensity, showing a duration > 3 sec. < 4 sec. and disappearing duration or differential latency time, which preceeds the subsequent reflex, > 3 sec. < 4 sec., which parallells the fractal dimension, when calculated in a sophysticated way (fractal dimension = 3,81), as now known (Fig. 2).

Fig. 2 indicates clearly the significances of reflex various parameters, in the reader’s interest.

[pic]

Fig. 2

Interestingly, in healthy, during “dynamic” evaluation, e.g., Restano’s manoeuvre (apnea test, lasting only 5 sec., combined with boxer’s test) (See Glossary), lt lowers to 9 sec.: non significant value from statistical view-point (Tab. 1).

By contrast, in every infectious diseases, both bacterial and viral, in rheumatic disorders, and in malignancies, doctor observes early and characteristic modifications of parameter values: reduced lt, < 5 sec., prolonged reflex duration > 4 sec. and shorter disappearing duration < 3 sec., in relation to the seriousness of underlying disease, proving to be a reliable tool even in therapeutic monitoring, as RESHS, antibody synthesis, diagram of tissue microvascular unit, simulated sucking test, a.s.o. (See semeioticabiofisica.it).

Without discussing patho-physiological mechanisms of this reflex, wich are surely fascinating, but they do not take any part of this paper, I emphasize the rigorous consideration of Henle-Kock’s three parameters:

1) the presence of whatever disease, which stimulates APP synthesis, is always associated, since early stage, with “pathological” parameter values of hepato-aspecific gastric reflex, type II;

2) reflex intensity parallels always disease seriousness;

3) therapeutic interventios, which favourably modify APP synthesis, contemporaneously modify parametre values of type II hepato-aspecific gastric reflex.

At this point, I conjectured that APP synthesis, assessed with “ungueal” stimulation of cutaneous lever-related receptors, could be in relation to subject’s constitution, in the sense that , besides a physiological response, described above (Tab. 1), I could observe, in apparently “health” individuals, which really are involved by one (or more) biophysical-semeiotic constitution of different seriousness, described in above-mentioned site, starting from the first two life decades, an abnormal response of APP production, in the same way different in degree, at least during “dynamic” manoeuvres.

On the other hand, it is well-known since a long time that diabetic react to a dangerous infectious agents in a different way from what happens in non-diabetic patient, althoug the abnormlities are different from case to case, as diabetic constitution itself.

A 45-year-long clinical experience allows me to state that the presence of “diabetic”, ”rheumatic”, “dislipidaemic”, “arteriosclerotic”, “hypertensive”, “oncological”, biophysical-semeiotic constitution, either alone or associated with other(s), is always combined with abnormalities of type II hepatic-aspecific gastric reflex, more or less intense: “basal” lt ( 9 sec. (NN = 10 sec.) which lowers to < 5 sec. during Restano’s manoeuvre.

It follows that body response to the agents stimulating APP production in the lever, shows a precise genetic component, always correlated with one (or more) particular biophysical-semeiotic constitution, conditio sine qua non of disease onset, e.g., CAD, indicating clearly the real role played by inflammation in arteriosclerosis pathogenesis, that is surely important, but secondary as well as related to a special biophysical-semeiotic constitution, to which is linked in dependent way.

In other words, the altered, intense APP synthesis, under a large variety of pathological conditions, is part of a (or more) singular “constitution” , and a sign of it.

From this original clinical view-point, Lars Rettersol’s compelling intuitions, referred above, are corroborated and, moreover, enlightened by clinical evidence. Inflammation plays surely an important and decisive role in disease onset, for example CAD, in many cases, because it is always dependent by patient’s constitution, which defines both seriousness and type of disease.

|BIOPHYSICAL-SEMEIOTIC EVALUATION OF ACUTE PHASE PROTEINS. HEPATIC-ASPECIFIC GASTRIC REFLEX, TYPE II. |

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|IN HEALTHY |

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|BASAL VALUES: LT 10 SEC.; INTENSITY 1-2 CM.; DURATION > 3 < 4 SEC.; DIFFERENTIAL LT >3 < 4 SEC. (fD 3,81) |

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|DURING RESTANO’S MANOEUVRE: LT 9 SEC.; INTENSITY > 2 < 3 CM.; DURATA > 3 < 4 SEC.; TL DIFFERENTIAL >3 < 4 SEC. (fD < 3,81) |

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|IN CASE OF ACUTE DISEASE: LT 3 SEC.; INTENSITY > 2 CM. |

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|IN INDIVIDUALS WITH DIABETIC, RHUMATIC, HYPERTENSIVE, ARTERIOSCLEROTIC, ONCOLOGICAL, A.S.O. |

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|BASAL VALUES: LT < 10 > 5 SEC.; INTENSITY 2-2,5 CM.; DURATION ( 4 SEC.; DIFFERENTIAL LT ( 3 SEC. (fD ( 3) |

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|DURING RESTANO’S MANOEUVRE: TL ( 5; INTENSITY > 2 CM.; DURATION ( 4 SEC.; DIFFERENTIAL LT( 3 SEC. (fD ( 3) |

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