Review
Circulating cardiovascular markers and mediators in acute illness: an update

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Abstract

An update is given of the circulating markers and mediators of cardiovascular dysfunction in acute illness. Some of these circulating markers reflect mediator action on the peripheral vasculature, such as endothelium-derived endothelin and nitrite/nitritate, the stable end products of nitric oxide. Other markers mainly reflect actions on the heart, such as the natriuretic peptide family, released from the heart upon dilatation, serving as a marker of congestive heart failure and potentially having negative inotropic effects. Indeed, some factors may be both markers as well as mediators of cardiovascular dysfunction of the acutely ill and bear prognostic significance. Assessing circulating levels may help refine clinical judgment of the cardiovascular derangements encountered at the bedside, together with clinical signs and hemodynamic variables. For instance, assessing natriuretic peptides in patients with pulmonary edema of unclear origin may help to diagnose congestive heart failure and cardiogenic pulmonary edema, when the pulmonary capillary wedge pressure is not measured or inconclusive. Future aligning of hemodynamic abnormalities with patterns of circulating cardiovascular markers/mediators may help to stratify patients for inclusion in studies to assess the causes, response to therapy and prognosis of cardiovascular derangements in the acutely ill.

Introduction

Cardiovascular alterations are common in the acutely ill and are either caused, at least in part, or compensated for by vascular and neurohumoral responses, resulting in endogenous release of a variety of compounds altering vascular tone and cardiac function (Fig. 1). Obviously, the most intensive response is found in patients with shock, either from septic or non-septic origin, so that, for instance, catecholamines are released in the circulation and at nerve endings, following sympathetic stimulation. Conversely, circulating vasoactive markers and mediators not only help to understand the pathophysiology of cardiovascular dysfunction and shock, but may also help to stage syndromes, to judge treatment effects and to predict outcome. In fact, patients may develop organ dysfunction in the course of critical illness, and circulating vasoactive factors may not only play a role but may also help to predict organ failures. Furthermore, understanding the role of these cardiovascular mediators may help in designing future therapeutic studies and inclusion criteria. This could be done through stratification on the basis of circulating cardiovascular markers that bear pathophysiologic and prognostic relevance.

We will collectively review the evidence in the literature of the marker and mediator role of a variety of endogenously released and circulating cardio- and vasoactive substances in the acutely ill. First, we describe the factors, followed by their pathophysiologic and diagnostic role in major conditions in the acutely ill. We will not extensively discuss the animal pathophysiology, nor the contribution of the contact system, complements components or arachidonic acid metabolites to the circulatory alterations of the acutely ill.

Section snippets

Nitric oxide end products: nitrate/nitrite

In healthy humans, endothelial, constitutive nitric oxide synthase (eNOS) is the only origin of nitric oxide (NO) and its metabolic end products nitrite and nitrate, which can be measured in blood with help of the classical Griess reaction by spectrophotometry, fluorometry, colorimetry, liquid chromatography or other techniques [1], [2], [3], [4], [5], [6]. NO released from the vessel wall is first converted to nitrite and subsequently within erythrocytes to nitrate, which is predominant in

Sympathoadrenergic response

Activation of the baroreceptor by hypotension increases sympathetic tone and eventual adrenal release of catecholamines, including norepinephrine and epinephrine, the classic stress hormones. The levels of these substances are elevated in plasma during pump failure or shock, particularly in non-survivors, as measured with help of high performance liquid chromatography, for instance [31], [45], [46].

Endothelin

While there are three forms of endothelin (1, 2 and 3) and proendothelins (big endothelins),

Markers of cardiac injury: troponin

Circulating cardiac isoforms of troponin I and T (cTnI, cTnT), cardiac-specific proteins involved in myosin crossbridging and myocardial contraction and assessed with help of radioimmunoassays, are sensitive and specific markers of myocardial injury [57], [58], [59], [60], [61], [62]. Hence, circulating levels constitute sensitive markers of damage of the myocardial contraction apparatus in coronary syndromes and they appear of prognostic significance, but also in sepsis, shock and allied

Acute coronary syndromes, myocardial infarction and CHF

The neurohumoral response to ventricular dilatation and a relatively low cardiac output in evolving myocardial infarction and CHF includes activation of the RAA system, the sympathetic nervous system, the endothelin system, and the ANP/BNP and l-arginine/NO systems, even before clinical symptoms develop [14], [45], [72]. Circulating (big) endothelin levels and precursors are elevated during CHF, for instance after myocardial infarction and during/after cardiac surgery [34], [43], [45], [73],

Conclusion

There are many markers of mediator actions on the vessel wall and the heart in acute illness. Elucidation of these factors has helped to understand the pathophysiology of cardiovascular dysfunction of the acutely ill. Aligning of hemodynamic abnormalities with patterns of circulating cardiovascular markers/mediators may help to stratify patients with cardiovascular dysfunction for inclusion in studies. This may help to assess the causes, response to therapy and prognosis of cardiovascular

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