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Procollagen type III amino terminal peptide (PIIIP) is associated with left ventricular diastolic dysfunction in obstructive sleep apnoea
Letters to the Editor
References [1] Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007;357:2482–94. [2] Giugliano RP, White JA, Bode C, et al. Early versus delayed, provisional eptifibatide in acute coronary syndromes. N Engl J Med 2009;360:2176–90. [3] Gaglia Jr MA, Manoukian SV, Waksman R. Novel antiplatelet therapy. Am Heart J 2010;160:595–604. [4] Steinhubl SR, Badimon JJ, Bhatt DL, Herbert JM, Luscher TF. Clinical evidence for anti-inflammatory effects of antiplatelet therapy in patients with atherothrombotic disease. Vasc Med 2007;12:113–22.
387
[5] Mazaev AA, Naimushin YA, Masenko VP, Ruda MY, Mazurov AV. Eptifibatide does not suppress the increase of inflammatory markers in patients with non-ST-segment elevation acute coronary syndrome. J Thromb Thrombolysis 2009;27:146–53. [6] Breland UM, Halvorsen B, Hol J, et al. A potential role of the CXC chemokine GROalpha in atherosclerosis and plaque destabilization: downregulatory effects of statins. Arterioscler Thromb Vasc Biol 2008;28:1005–11. [7] von HP, Koenen RR, Sack M, et al. Heterophilic interactions of platelet factor 4 and RANTES promote monocyte arrest on endothelium. Blood 2005;105:924–30. [8] Ueland T, Otterdal K, Lekva T, et al. Dickkopf-1 enhances inflammatory interaction between platelets and endothelial cells and shows increased expression in atherosclerosis. Arterioscler Thromb Vasc Biol 2009;29:1228–34.
0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2011.06.117
Procollagen type III amino terminal peptide (PIIIP) is associated with left ventricular diastolic dysfunction in obstructive sleep apnoea Estelle Vautrin a, Jean-Louis Pépin b,c, Patrice Faure d, Gilles Barone-Rochette a,e, Renaud Tamisier b,c, Olivier Ormezzano a,e, Anne-Sophie Gauchez d,e, Patrick Levy b,c, Jean-Philippe Baguet a,e,⁎ a
Department of Cardiology, University Hospital, Grenoble, France HP2 Laboratory (Hypoxia: Pathophysiology), INSERM ERI17, Joseph Fourier University, Grenoble, France Sleep Laboratory, EFCR, University Hospital, Grenoble, France d Department of Biochemistry, Toxicology and Pharmacology, University Hospital, Grenoble, France e Bioclinic Radiopharmaceutics Laboratory, INSERM 1039, Joseph Fourier University, Grenoble, France b c
a r t i c l e
i n f o
Article history: Received 29 April 2011 Revised 7 June 2011 Accepted 25 June 2011 Available online 23 July 2011 Keywords: Procollagen type III Diastolic dysfunction Sleep apnoea
Obstructive sleep apnoea (OSA) is a common pathology associated with the collapse of the upper airways. From a physiopathological point of view, OSA is associated, among other things, with sympathetic hyperactivity. This in turn is responsible for increased blood pressure (BP), particularly increased nocturnal BP, as well as pressure overload in the left ventricle (LV) [1]. These mechanisms encourage the development of LV hypertrophy (LVH) due to myocyte hypertrophy and myocardial fibrosis, both conditions encouraging the appearance of LV diastolic dysfunction. The aim of our study was to analyse the relationships between the plasma level of procollagen type III amino terminal peptide (PIIIP) – a marker of type III collagen synthesis – on the one hand, and respiratory and LV diastolic function parameters on the other hand, in patients with newly diagnosed and untreated OSA, without any vasoactive treatment. No patients had known coronary artery disease, hypertrophic cardiomyopathy or aortic stenosis, and none of them presented any condition associated with alterations to plasma levels of PIIIP (e.g. alcoholic liver disease, metabolic bone disease, hyperthyroidism or renal insufficiency). Ethical approval was Abbreviations: BMI, Body Mass Index; BP, Blood pressure; DT, Mitral deceleration time; LV, Left ventricle; LVH, Left Ventricular Hypertrophy; LVM, Left Ventricular Mass; OSA, Obstructive sleep apnoea; PIIIP, Procollagen type III amino terminal peptide; RDI, Respiratory disturbance index. ⁎ Corresponding author at: Clinique de Cardiologie, CHU de Grenoble, BP 217, 38043, Grenoble Cedex 09, France. Tel.: +33 4 76 76 84 80; fax: +33 4 76 76 55 59. E-mail address: [email protected] (J.-P. Baguet).
obtained from the local ethics committee and all of the participants gave their informed consent. The registration (ClinicalTrials.gov) trial number for this study is: NCT00764218. We diagnosed OSA using a polysomnography, and set a respiratory disturbance index (RDI) threshold of ≥15 per hour of recording in order to confirm the OSA diagnosis. The 57 apnoeic patients included consecutively in the study underwent 24-hour ambulatory BP monitoring (Spacelabs 90207®), laboratory examinations (including serum PIIIP using radioimmunoassay, normal range: 2.3–6.4 μg/L) and cardiac ultrasound. We measured LV mass (LVM) according to the Penn convention using the Devereux formula, and we assessed LV diastolic function using transmitral Doppler as previously described (pulsed Doppler technique with 2D guidance in apical four-chamber view) [2]. We measured or calculated the following diastolic parameters: E/A ratio, mitral deceleration time (DT) and isovolumic relaxation time. We used SPSS software® (SPSS Inc, Chicago, IL, USA) to perform our statistical analyses. We have expressed continuous data as means ± SD and non continuous variables as percentages. We assessed the relationships between the continuous variables using Pearson's or Spearman's correlation analysis, and we compared non-continuous variables using a Chi-square test. We used a student's T test to compare continuous variables between groups and we performed a multivariate analysis by means of a stepwise regression using variables significantly (pb 0.05) associated with the explained variable in the univariate analysis. Forty-eight of the 57 patients (84%) were men, mean age = 50.9 ± 9.3 years, mean BMI = 26.4 ±3.7 kg/m² and mean RDI= 40.2 ± 15.7/h. Seventeen (30%) of the subjects had LV diastolic dysfunction (type 1, i.e. impaired LV relaxation). These patients were older (55.9 ± 9.2 vs 48.7 ± 8.7 years, p = 0.01) and had higher BP levels (118 ± 7 vs 111 ± 13 mm Hg for nocturnal systolic BP, p = 0.038) and a higher PIIIP level (3.97 ± 0.61 vs 3.50 ± 0.92 μg/L, p = 0.028,) (Fig. 1). In the univariate analysis, the PIIIP level was significantly correlated with the RDI (r = 0.38, p = 0.004), the BMI (r = 0.30, p = 0.025), systolic and diastolic BP in clinic (r = 0.34, p = 0.009 and r = 0.26, p = 0.05 respectively) and during the night (r = 0.50, p b 0.001 and r = 0.30, p = 0.025 respectively) and with DT (r = 0.29, p = 0.037),
388
Letters to the Editor
Fig. 1. LV diastolic dysfunction and plasma procollagen type III amino terminal peptide (PIIIP). Graph (mean ± 2 standard errors) showing the level of plasma PIIIP in patients without diastolic dysfunction (n = 40) and in patients with diastolic dysfunction (n = 17). The PIIIP level was significantly higher in patients with LV diastolic dysfunction than in those without LV diastolic dysfunction (3.97 ± 0.61 μg/L vs. 3.50 ± 0.92 μg/L, p = 0.028).
but not with LVM or age. PIIIP level tended to be correlated with the E/A ratio (p = 0.14). In the multivariate analysis performed on the entire group, the PIIIP level was independently correlated with nocturnal systolic BP (beta = 0.56, p b 0.001) and with DT (beta = 0.27, p = 0.018). Histological studies have shown that fibrillar collagen molecules, including mainly type I and type III collagens, accumulate in the interstitial space in the myocardium of hypertensive animals and patients, as an adaptive response initiated by myocardial fibroblasts [3]. These changes appear to result from alterations in the balance between collagen synthesis and degradation. Closely correlated with
0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2011.06.118
myocardial collagen content is the concentration of serum collagen markers, which reflect collagen turnover [4]. It has been shown that in hypertensive patients, the circulating level of PIIIP – a sensitive indicator of type III collagen synthesis – is increased [5]. In this same study, an inverse correlation was found between plasma PIIIP and the E/A ratio [5]. Consequently, measuring type III collagen marker may be a non-invasive way of detecting myocardial fibrosis changes in patients. Plasma PIIIP is also related to reduced LV longitudinal contractility [6]. OSA is associated with LV diastolic dysfunction and LVH [2]. To our knowledge, no study has yet analysed collagen synthesis in OSA. We found a positive correlation between PIIIP and OSA severity, and this suggests that OSA has a harmful effect on collagen synthesis. Moreover, PIIIP is independently correlated with nocturnal BP but not with daytime BP. This result may be explained by the fact that hypertension is predominantly nocturnal in OSA and by the harmful effect this increased BP has on the myocardium. Finally, the PIIIP level is significantly higher in OSA patients with LV diastolic dysfunction and this level is independently related to one of the parameters of LV diastolic function (i.e. DT). All of these data point to the harmful effect that OSA has on the myocardium through LV diastolic dysfunction. Plasma PIIIP can be put forward as a potential marker of LV remodelling and of LV diastolic dysfunction in newly diagnosed OSA patients, partly through nocturnal hypertension frequently present in this condition. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology (Shewan and Coats 2010;144:1–2).
References [1] Lattimore JD, Celermajer DS, Wilcox I. Obstructive sleep apnea and cardiovascular disease. J Am Coll Cardiol 2003;41:1429–37. [2] Baguet JP, Barone-Rochette G, Lévy P, et al. Left ventricular diastolic dysfunction is linked to severity of obstructive sleep apnea. Eur Respir J 2010;36:1323–9. [3] Weber KT, Sun Y, Guarda E, et al. Myocardial fibrosis in hypertensive heart disease: an overview of potential regulatory mechanisms. Eur Heart J 1995;16(Suppl C):24–8. [4] Laviades C, Varo N, Fernandez J, et al. Abnormalities of the extracellular degradation of collagen type I in essential hypertension. Circulation 1998;98:535–40. [5] Díez J, Laviades C, Mayor G, Gil MJ, Monreal I. Increased serum concentrations of procollagen peptides in essential hypertension. Relation to cardiac alterations. Circulation 1995;91:1450–6. [6] Poulsen SH, Andersen NH, Heickendorff L, Mogensen CE. Relation between plasma amino-terminal propeptide of procollagen type III and left ventricular longitudinal strain in essential hypertension. Heart 2005;91:624–9.
References [1] Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007;357:2482–94. [2] Giugliano RP, White JA, Bode C, et al. Early versus delayed, provisional eptifibatide in acute coronary syndromes. N Engl J Med 2009;360:2176–90. [3] Gaglia Jr MA, Manoukian SV, Waksman R. Novel antiplatelet therapy. Am Heart J 2010;160:595–604. [4] Steinhubl SR, Badimon JJ, Bhatt DL, Herbert JM, Luscher TF. Clinical evidence for anti-inflammatory effects of antiplatelet therapy in patients with atherothrombotic disease. Vasc Med 2007;12:113–22.
387
[5] Mazaev AA, Naimushin YA, Masenko VP, Ruda MY, Mazurov AV. Eptifibatide does not suppress the increase of inflammatory markers in patients with non-ST-segment elevation acute coronary syndrome. J Thromb Thrombolysis 2009;27:146–53. [6] Breland UM, Halvorsen B, Hol J, et al. A potential role of the CXC chemokine GROalpha in atherosclerosis and plaque destabilization: downregulatory effects of statins. Arterioscler Thromb Vasc Biol 2008;28:1005–11. [7] von HP, Koenen RR, Sack M, et al. Heterophilic interactions of platelet factor 4 and RANTES promote monocyte arrest on endothelium. Blood 2005;105:924–30. [8] Ueland T, Otterdal K, Lekva T, et al. Dickkopf-1 enhances inflammatory interaction between platelets and endothelial cells and shows increased expression in atherosclerosis. Arterioscler Thromb Vasc Biol 2009;29:1228–34.
0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2011.06.117
Procollagen type III amino terminal peptide (PIIIP) is associated with left ventricular diastolic dysfunction in obstructive sleep apnoea Estelle Vautrin a, Jean-Louis Pépin b,c, Patrice Faure d, Gilles Barone-Rochette a,e, Renaud Tamisier b,c, Olivier Ormezzano a,e, Anne-Sophie Gauchez d,e, Patrick Levy b,c, Jean-Philippe Baguet a,e,⁎ a
Department of Cardiology, University Hospital, Grenoble, France HP2 Laboratory (Hypoxia: Pathophysiology), INSERM ERI17, Joseph Fourier University, Grenoble, France Sleep Laboratory, EFCR, University Hospital, Grenoble, France d Department of Biochemistry, Toxicology and Pharmacology, University Hospital, Grenoble, France e Bioclinic Radiopharmaceutics Laboratory, INSERM 1039, Joseph Fourier University, Grenoble, France b c
a r t i c l e
i n f o
Article history: Received 29 April 2011 Revised 7 June 2011 Accepted 25 June 2011 Available online 23 July 2011 Keywords: Procollagen type III Diastolic dysfunction Sleep apnoea
Obstructive sleep apnoea (OSA) is a common pathology associated with the collapse of the upper airways. From a physiopathological point of view, OSA is associated, among other things, with sympathetic hyperactivity. This in turn is responsible for increased blood pressure (BP), particularly increased nocturnal BP, as well as pressure overload in the left ventricle (LV) [1]. These mechanisms encourage the development of LV hypertrophy (LVH) due to myocyte hypertrophy and myocardial fibrosis, both conditions encouraging the appearance of LV diastolic dysfunction. The aim of our study was to analyse the relationships between the plasma level of procollagen type III amino terminal peptide (PIIIP) – a marker of type III collagen synthesis – on the one hand, and respiratory and LV diastolic function parameters on the other hand, in patients with newly diagnosed and untreated OSA, without any vasoactive treatment. No patients had known coronary artery disease, hypertrophic cardiomyopathy or aortic stenosis, and none of them presented any condition associated with alterations to plasma levels of PIIIP (e.g. alcoholic liver disease, metabolic bone disease, hyperthyroidism or renal insufficiency). Ethical approval was Abbreviations: BMI, Body Mass Index; BP, Blood pressure; DT, Mitral deceleration time; LV, Left ventricle; LVH, Left Ventricular Hypertrophy; LVM, Left Ventricular Mass; OSA, Obstructive sleep apnoea; PIIIP, Procollagen type III amino terminal peptide; RDI, Respiratory disturbance index. ⁎ Corresponding author at: Clinique de Cardiologie, CHU de Grenoble, BP 217, 38043, Grenoble Cedex 09, France. Tel.: +33 4 76 76 84 80; fax: +33 4 76 76 55 59. E-mail address: [email protected] (J.-P. Baguet).
obtained from the local ethics committee and all of the participants gave their informed consent. The registration (ClinicalTrials.gov) trial number for this study is: NCT00764218. We diagnosed OSA using a polysomnography, and set a respiratory disturbance index (RDI) threshold of ≥15 per hour of recording in order to confirm the OSA diagnosis. The 57 apnoeic patients included consecutively in the study underwent 24-hour ambulatory BP monitoring (Spacelabs 90207®), laboratory examinations (including serum PIIIP using radioimmunoassay, normal range: 2.3–6.4 μg/L) and cardiac ultrasound. We measured LV mass (LVM) according to the Penn convention using the Devereux formula, and we assessed LV diastolic function using transmitral Doppler as previously described (pulsed Doppler technique with 2D guidance in apical four-chamber view) [2]. We measured or calculated the following diastolic parameters: E/A ratio, mitral deceleration time (DT) and isovolumic relaxation time. We used SPSS software® (SPSS Inc, Chicago, IL, USA) to perform our statistical analyses. We have expressed continuous data as means ± SD and non continuous variables as percentages. We assessed the relationships between the continuous variables using Pearson's or Spearman's correlation analysis, and we compared non-continuous variables using a Chi-square test. We used a student's T test to compare continuous variables between groups and we performed a multivariate analysis by means of a stepwise regression using variables significantly (pb 0.05) associated with the explained variable in the univariate analysis. Forty-eight of the 57 patients (84%) were men, mean age = 50.9 ± 9.3 years, mean BMI = 26.4 ±3.7 kg/m² and mean RDI= 40.2 ± 15.7/h. Seventeen (30%) of the subjects had LV diastolic dysfunction (type 1, i.e. impaired LV relaxation). These patients were older (55.9 ± 9.2 vs 48.7 ± 8.7 years, p = 0.01) and had higher BP levels (118 ± 7 vs 111 ± 13 mm Hg for nocturnal systolic BP, p = 0.038) and a higher PIIIP level (3.97 ± 0.61 vs 3.50 ± 0.92 μg/L, p = 0.028,) (Fig. 1). In the univariate analysis, the PIIIP level was significantly correlated with the RDI (r = 0.38, p = 0.004), the BMI (r = 0.30, p = 0.025), systolic and diastolic BP in clinic (r = 0.34, p = 0.009 and r = 0.26, p = 0.05 respectively) and during the night (r = 0.50, p b 0.001 and r = 0.30, p = 0.025 respectively) and with DT (r = 0.29, p = 0.037),
388
Letters to the Editor
Fig. 1. LV diastolic dysfunction and plasma procollagen type III amino terminal peptide (PIIIP). Graph (mean ± 2 standard errors) showing the level of plasma PIIIP in patients without diastolic dysfunction (n = 40) and in patients with diastolic dysfunction (n = 17). The PIIIP level was significantly higher in patients with LV diastolic dysfunction than in those without LV diastolic dysfunction (3.97 ± 0.61 μg/L vs. 3.50 ± 0.92 μg/L, p = 0.028).
but not with LVM or age. PIIIP level tended to be correlated with the E/A ratio (p = 0.14). In the multivariate analysis performed on the entire group, the PIIIP level was independently correlated with nocturnal systolic BP (beta = 0.56, p b 0.001) and with DT (beta = 0.27, p = 0.018). Histological studies have shown that fibrillar collagen molecules, including mainly type I and type III collagens, accumulate in the interstitial space in the myocardium of hypertensive animals and patients, as an adaptive response initiated by myocardial fibroblasts [3]. These changes appear to result from alterations in the balance between collagen synthesis and degradation. Closely correlated with
0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2011.06.118
myocardial collagen content is the concentration of serum collagen markers, which reflect collagen turnover [4]. It has been shown that in hypertensive patients, the circulating level of PIIIP – a sensitive indicator of type III collagen synthesis – is increased [5]. In this same study, an inverse correlation was found between plasma PIIIP and the E/A ratio [5]. Consequently, measuring type III collagen marker may be a non-invasive way of detecting myocardial fibrosis changes in patients. Plasma PIIIP is also related to reduced LV longitudinal contractility [6]. OSA is associated with LV diastolic dysfunction and LVH [2]. To our knowledge, no study has yet analysed collagen synthesis in OSA. We found a positive correlation between PIIIP and OSA severity, and this suggests that OSA has a harmful effect on collagen synthesis. Moreover, PIIIP is independently correlated with nocturnal BP but not with daytime BP. This result may be explained by the fact that hypertension is predominantly nocturnal in OSA and by the harmful effect this increased BP has on the myocardium. Finally, the PIIIP level is significantly higher in OSA patients with LV diastolic dysfunction and this level is independently related to one of the parameters of LV diastolic function (i.e. DT). All of these data point to the harmful effect that OSA has on the myocardium through LV diastolic dysfunction. Plasma PIIIP can be put forward as a potential marker of LV remodelling and of LV diastolic dysfunction in newly diagnosed OSA patients, partly through nocturnal hypertension frequently present in this condition. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology (Shewan and Coats 2010;144:1–2).
References [1] Lattimore JD, Celermajer DS, Wilcox I. Obstructive sleep apnea and cardiovascular disease. J Am Coll Cardiol 2003;41:1429–37. [2] Baguet JP, Barone-Rochette G, Lévy P, et al. Left ventricular diastolic dysfunction is linked to severity of obstructive sleep apnea. Eur Respir J 2010;36:1323–9. [3] Weber KT, Sun Y, Guarda E, et al. Myocardial fibrosis in hypertensive heart disease: an overview of potential regulatory mechanisms. Eur Heart J 1995;16(Suppl C):24–8. [4] Laviades C, Varo N, Fernandez J, et al. Abnormalities of the extracellular degradation of collagen type I in essential hypertension. Circulation 1998;98:535–40. [5] Díez J, Laviades C, Mayor G, Gil MJ, Monreal I. Increased serum concentrations of procollagen peptides in essential hypertension. Relation to cardiac alterations. Circulation 1995;91:1450–6. [6] Poulsen SH, Andersen NH, Heickendorff L, Mogensen CE. Relation between plasma amino-terminal propeptide of procollagen type III and left ventricular longitudinal strain in essential hypertension. Heart 2005;91:624–9.