Sympathetic activation and sub-clinical inflammation: a new combination to identify high risk subjects

Federico Lombardi*

Cardiologia Dipartimento di Medicina, Chirurgia e Odontoiatria, Ospedale San Paolo, University of Milan, Milan, Italy

* Correspondence: Tel.: +39-289127828; fax: +39-02-50323145
E-mail address: federico.lombardi{at}unimi.it

Received 31 December 2003; accepted 13 January 2004

This editorial refers to "Increased heart rate and reduced heart-rate variability are associated with subclinical inflammation in middle-aged and elderly subjects with no apparent heart disease"1. by Ahmad Sajadieh et al. on page 363

In the last 20 years, in spite of a larger utilization of arrhythmic risk markers, identification of sudden death victims has remained far from being satisfactory. It seems that we are unable to move out from a situation where the availability of effective devices to target ventricular tachycardia or fibrillation in selected populations only marginally affects sudden death incidence in the larger group of apparently healthy subjects.1

The extent of coronary artery disease and depression of left ventricular function have long been recognized as factors associated with an increased total cardiac and arrhythmic mortality. The possibility of assessing autonomic modulation by means of time and frequency domain analysis of heart-rate variability or baroreflex sensitivity has finally made it possible to characterize the autonomic profile of patients with a variety of cardiovascular diseases and to extend to the clinical setting most of the information derived from the experimental evidence indicating a pro-arrhythmic role of sympathetic activation and reduced vagal activity.2 The combination of a reduced left ventricular ejection fraction and one of the different autonomic risk markers has been proven effective in identifying subgroups of post-myocardial infarction or heart failure patients with an increased arrhythmic mortality. Nevertheless, the complexity and the variability of factors responsible of sudden cardiac death account for the limited and unsatisfactory positive predictive value of the above parameters in the identification of patients at risk particularly when the screening involves less selected patient's population.1,2

The risk identification approach mainly based on extent of pump dysfunction and presence of autonomic or arrhythmic markers, has, in my opinion, to take into consideration recent epidemiological observations, which have indicated that genetics factors, thrombosis and inflammation may play a critical role in favoring the occurrence of sudden cardiac death.1,3,4 Fibrinogen levels, platelet activation and inhibition of endogenous fibrinolysis may all contribute to thrombus formation. In this context, sympathetic activation may not only promote coronary artery occlusion but also negatively affect cardiac electrical properties leading to sudden cardiac death as an initial manifestation of coronary artery disease.3

Moreover, measures of inflammation such as, for example, C-reactive protein or interleukine-6 have been proven as risk factors for cardiovascular mortality in both apparently healthy subjects and patients with different cardiovascular diseases. Growing experimental and clinical evidence indicates that inflammation plays a determinant role in the pathogenesis and progression of atherosclerosis: a finding that may well explain the strong epidemiological association between inflammation and cardiovascular morbidity and mortality.4

It may be of interest to note that in most of clinical conditions characterized by an increase of inflammatory markers such as, for example, diabetes or acute coronary syndromes, a reduction in heart-rate variability parameters is consistently observed in high risk patients, thus making the connection between inflammation and autonomic dysfunction more tightened than it was till now appreciated.

The paper of Sajadieh and co-workers 5 describes for the first time the association between heart rate, heart-rate variability and sub-clinical inflammation in subjects with no apparent heart disease. Six hundred and forty-three subjects aged 55–75 years were studied. Mean RR interval and SDNN (standard deviation of normal RR intervals), i.e., the two most simple heart-rate variability parameters were calculated from Holter recording; C-reactive protein and white blood cell count were the selected markers of inflammation. Heart rate and SDNN were negatively associated with inflammation markers as well as with smoking, blood sugar, triglyceride concentration, female gender and diabetes. In multivariate regression analysis both increase heart rate and reduced heart-rate variability were associated with laboratory evidence of sub-clinical inflammation.

The results of this study are of relevant clinical interest and can be considered at two different levels: The first of a simple association, the second one of an initial evidence of a cause-effect relationship.

The negative association between increased heart rate (or reduced SDNN) and either C-reactive protein or white cell blood count indicates that signs of an increase sympathetic modulation of sinus node characterized patients with laboratory evidence of sub-clinical inflammation. Although heart-rate variability analysis does not allow a proper identification of the individual role of one of the two branches of the autonomic nervous system, the absence of a robust correlation between markers of inflammation and heart rate or SDNN measured during night time, when vagal modulation is prevailing, supports a critical role of sympathetic activation.6 As both sympathetic activation and sub-clinical inflammation have been independently associated with an increased cardiac mortality and, in particular, sudden cardiac death, we may expect that, in a near future, C-reactive protein levels will be combined with ejection fraction (and/or brain natriuretic peptide) and heart rate (and/or SDNN), to provide a more accurate noninvasive risk stratification of patients with coronary artery disease, heart failure or hypertension. The combination of heart rate and C-reactive protein could also be utilized for identification of subject at risk for faster progression of atherosclerosis in larger cohorts of apparently healthy subjects in conjunction with more traditional risk factors.

The second level of interpretation is related to the fact that the association of increased heart rate (or a reduced SDNN) with markers of sub-clinical inflammation might reflect an interaction between the autonomic nervous system and inflammation. As appropriately discussed by Sajadieh and co-workers5, autonomic imbalance leading to sympathetic predominance may promote activation of inflammation, which, in turn, could further alter autonomic balance. This hypothesis could explain the presence of signs of sub-clinical inflammation in clinical conditions such as diabetes, hypertension and coronary artery disease where signs of enhanced sympathetic modulation and reduced vagal activity are well evident since the initial manifestations of the disease. What causes this alteration in autonomic control mechanisms remains uncertain, although recent evidence suggests that genetic and environmental factors are likely to play a key role.

Two major limitations of the study must be considered. First of all, there is no clinical follow-up of subjects enrolled in the study. The description of an association between cardiovascular events and combination of autonomic and inflammatory markers would have been of great interest in order to validate Authors' hypothesis and to promote a clinical utilization of such a combination in the clinical setting. Second, the study was restricted to subjects aged 55–75 thus excluding relatively younger persons who also suffer from sudden cardiac death. Moreover, by considering subjects characteristics, it is evident that almost one third of the subjects were classified as hypertensives, whereas diabetes was present in about 10% of cases, thus making the definition of "no apparent heart disease" questionable.

Nevertheless, the study provides two important suggestions: (i) the increased cardiovascular mortality in patients with increased heart rate (or reduced SDNN) and elevated levels of C-reactive protein could reflect the negative effects of the interaction between sympathetic activation and sub-clinical inflammation on atherosclerosis progression; (ii) the combination of autonomic and inflammatory markers could facilitate the noninvasive identification of subjects at risk for an increased cardiovascular mortality.

Footnotes

1 10.1016/j.ehj.2003.12.003 Back

References

  1. Huikuri HV, Mäkikallio TH, Raatikainen MJP, Perkiömäky J, Castellanos A, Myerburg R. Prediction of cardiac sudden death: appraisal of the studies and methods assessing the risk of sudden arrhythmic death. Circulation. 2003;108:110–115.[Free Full Text]
  2. Lombardi F, Mäkikallio TH, Myerburg RJ, Huikuri HV. Sudden cardiac death: role of heart rate variability to identify patients at risk. Cardiovasc. Res. 2001;50:210–217.[CrossRef][Medline]
  3. Hamaad A, Lip GHY, MacFadyen RJ. Unheralded sudden cardiac death: do autonomic tone and thrombosis interacts key factors in aetiology. Ann. Med. 2003;:592–604.
  4. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105:1135–1143.[Abstract/Free Full Text]
  5. Sajadieh A, Wendelboe Nilsen O, Rasmussen V, Hein HO, Abedini S, Jorgen FH. Increased heart rate and reduced heart rate variability are associated with subclinical inflammation in middle-aged and elderly subjects with no apparent heart disease. Eur Heart J. 2004;25:363–370.[Abstract/Free Full Text]
  6. Lombardi F. Clinical implications of present physiological understanding of HRV components. Cardiac Electrophysiol. Rev. 2002;6:245–249.[CrossRef][Medline]

Related articles in EHJ:

Increased heart rate and reduced heart-rate variability are associated with subclinical inflammation in middle-aged and elderly subjects with no apparent heart disease
Ahmad Sajadieh, Olav Wendelboe Nielsen, Verner Rasmussen, Hans Ole Hein, Sadollah Abedini, and Jørgen Fischer Hansen
EHJ 2004 25: 363-370. [Abstract] [Full Text]  




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