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A Novel Relationship Between Circulating RAGE and Pulmonary Hypertension
S10
Heart, Lung and Circulation 2013;22:S1–S125
CSANZ 2013 Abstracts
ABSTRACTS
Vascular/Hypertension 19 A Novel Relationship Between Circulating RAGE and Pulmonary Hypertension T. Lancefield 1,2,∗ , S. Patel 1 , M. Freeman 1 , E. Velkoska 1 , L. Oliver 2 , O. Farouque 1,2 , M. Horrigan 2 , L. Burrell 1,2 1 The
University of Melbourne, Department of Medicine, Melbourne, Australia 2 Department of Cardiology, Austin Health, Melbourne, Australia Background: Inflammation and adverse remodelling in the pulmonary vasculature is an important cause of pulmonary hypertension (PH). The receptor for advanced glycation end products (RAGE) amplifies inflammation and endothelial dysfunction. We sought to identify the relationship between circulating RAGE and PH. Methods: We recruited 68 subjects undergoing right heart catheterisation. PH was diagnosed as a mean pulmonary artery pressure (mPAP) ≥ 25 mmHg (n = 25) and was subdivided as pre-capillary (n = 10) and post-capillary (n = 15) PH according to pulmonary capillary wedge pressure (PCWP) < 15 or >15 mmHg respectively. Circulating sRAGE and the splice variant esRAGE were measured in serum using an ELISA. Analysis included spearman correlation coefficient, one-way ANOVA and general linear model. Results: Mean age was 68 ± 9 y in subjects with PH and 63 ± 11 y in subjects without PH (p = 0.08). Almost 2/3rds in each group were men (p = 0.6). Prevalence of diabetes, coronary disease, chronic kidney disease and lung disease were similar. mPAP significantly correlated with sRAGE (r = 0.41, p = 0.001) and esRAGE (r = 0.47, p < 0.001). Pulmonary vascular resistance correlated with circulating RAGE (p ≤ 0.01) while PCWP did not (p = 0.3). Circulating RAGE was significantly higher in subjects with PH compared to no PH (p < 0.001) even after correction for age, gender, eGFR and PCWP (p = 0.003). Circulating RAGE was higher in pre-capillary PH compared with postcapillary PH and no PH (Figs. 1 and 2).
Figure 1. One-way ANOVA: mean sRAGE and PH type.
Figure 2. One-way ANOVA: mean esRAGE and PH type.
Conclusion: Circulating RAGE is a novel marker of PH. Further study is needed to assess its usefulness in distinguishing PH type and potential as a treatment target. http://dx.doi.org/10.1016/j.hlc.2013.05.020 20 Acute Serelaxin Treatment Causes Rapid and Sustained Bradykinin-mediated Vasodilation through Endothelium-derived Hyperpolarising Factor and Prostacyclin Pathways C. Leo 1,∗ , M. Jelinic 1 , M. Tare 2 , L. Parry 1 1 The
University of Melbourne, Australia University, Australia
2 Monash
A recent phase III clinical trial (RELAX-AHF) demonstrated that 48 h chronic intravenous infusion of recombinant human relaxin, serelaxin (sRLX) to patients with acute heart failure reduced cardiovascular mortality at 180 days. Clinical studies suggest that sRLX causes rapid nitric oxide (NO)-dependent vasodilation. No studies have investigated the contribution of prostacyclin and endothelium-derived hyperpolarising factor (EDHF) to the vasodilatory actions of sRLX. Furthermore, neither the effects nor the duration of the response to a single bolus intravenous injection of sRLX have been assessed. This study aimed to investigate sRLX-mediated vasodilation in mesenteric arteries after intravenous sRLX injection and if these effects are prolonged for 24 h in the absence of circulating sRLX. Male Wistar rats were injected with 13.3 g/kg sRLX into the tail vein; mesenteric arteries were assessed 3 h and 24 h after treatment using wiremyography. Plasma sRLX levels were 2.33 ng/ml after 3 h but were undetected after 24 h. The sensitivity but not maximum relaxation to bradykinin (BK) was significantly increased after 3 h (pEC50 , 8.25 ± 0.10, p < 0.001) and 24 h (pEC50 , 8.39 ± 0.15, p < 0.001) in sRLX-treated rats compared to controls (pEC50 , 7.60 ± 0.11). When the contribution of NO was inhibited by L-NAME, the sensitivity to BK was significantly increased at both time points. However, the combination of L-NAME and the cyclooxygenase inhibitor, indomethacin only attenuated the sensitivity to BK 24 h after sRLX treatment. In summary, our data show that a bolus intravenous injection of sRLX causes rapid BK-mediated vasodilation through EDHF. Importantly, we also demonstrated a sustained vasodilatory response to sRLX that is mediated by prostacyclin. http://dx.doi.org/10.1016/j.hlc.2013.05.021
Heart, Lung and Circulation 2013;22:S1–S125
CSANZ 2013 Abstracts
ABSTRACTS
Vascular/Hypertension 19 A Novel Relationship Between Circulating RAGE and Pulmonary Hypertension T. Lancefield 1,2,∗ , S. Patel 1 , M. Freeman 1 , E. Velkoska 1 , L. Oliver 2 , O. Farouque 1,2 , M. Horrigan 2 , L. Burrell 1,2 1 The
University of Melbourne, Department of Medicine, Melbourne, Australia 2 Department of Cardiology, Austin Health, Melbourne, Australia Background: Inflammation and adverse remodelling in the pulmonary vasculature is an important cause of pulmonary hypertension (PH). The receptor for advanced glycation end products (RAGE) amplifies inflammation and endothelial dysfunction. We sought to identify the relationship between circulating RAGE and PH. Methods: We recruited 68 subjects undergoing right heart catheterisation. PH was diagnosed as a mean pulmonary artery pressure (mPAP) ≥ 25 mmHg (n = 25) and was subdivided as pre-capillary (n = 10) and post-capillary (n = 15) PH according to pulmonary capillary wedge pressure (PCWP) < 15 or >15 mmHg respectively. Circulating sRAGE and the splice variant esRAGE were measured in serum using an ELISA. Analysis included spearman correlation coefficient, one-way ANOVA and general linear model. Results: Mean age was 68 ± 9 y in subjects with PH and 63 ± 11 y in subjects without PH (p = 0.08). Almost 2/3rds in each group were men (p = 0.6). Prevalence of diabetes, coronary disease, chronic kidney disease and lung disease were similar. mPAP significantly correlated with sRAGE (r = 0.41, p = 0.001) and esRAGE (r = 0.47, p < 0.001). Pulmonary vascular resistance correlated with circulating RAGE (p ≤ 0.01) while PCWP did not (p = 0.3). Circulating RAGE was significantly higher in subjects with PH compared to no PH (p < 0.001) even after correction for age, gender, eGFR and PCWP (p = 0.003). Circulating RAGE was higher in pre-capillary PH compared with postcapillary PH and no PH (Figs. 1 and 2).
Figure 1. One-way ANOVA: mean sRAGE and PH type.
Figure 2. One-way ANOVA: mean esRAGE and PH type.
Conclusion: Circulating RAGE is a novel marker of PH. Further study is needed to assess its usefulness in distinguishing PH type and potential as a treatment target. http://dx.doi.org/10.1016/j.hlc.2013.05.020 20 Acute Serelaxin Treatment Causes Rapid and Sustained Bradykinin-mediated Vasodilation through Endothelium-derived Hyperpolarising Factor and Prostacyclin Pathways C. Leo 1,∗ , M. Jelinic 1 , M. Tare 2 , L. Parry 1 1 The
University of Melbourne, Australia University, Australia
2 Monash
A recent phase III clinical trial (RELAX-AHF) demonstrated that 48 h chronic intravenous infusion of recombinant human relaxin, serelaxin (sRLX) to patients with acute heart failure reduced cardiovascular mortality at 180 days. Clinical studies suggest that sRLX causes rapid nitric oxide (NO)-dependent vasodilation. No studies have investigated the contribution of prostacyclin and endothelium-derived hyperpolarising factor (EDHF) to the vasodilatory actions of sRLX. Furthermore, neither the effects nor the duration of the response to a single bolus intravenous injection of sRLX have been assessed. This study aimed to investigate sRLX-mediated vasodilation in mesenteric arteries after intravenous sRLX injection and if these effects are prolonged for 24 h in the absence of circulating sRLX. Male Wistar rats were injected with 13.3 g/kg sRLX into the tail vein; mesenteric arteries were assessed 3 h and 24 h after treatment using wiremyography. Plasma sRLX levels were 2.33 ng/ml after 3 h but were undetected after 24 h. The sensitivity but not maximum relaxation to bradykinin (BK) was significantly increased after 3 h (pEC50 , 8.25 ± 0.10, p < 0.001) and 24 h (pEC50 , 8.39 ± 0.15, p < 0.001) in sRLX-treated rats compared to controls (pEC50 , 7.60 ± 0.11). When the contribution of NO was inhibited by L-NAME, the sensitivity to BK was significantly increased at both time points. However, the combination of L-NAME and the cyclooxygenase inhibitor, indomethacin only attenuated the sensitivity to BK 24 h after sRLX treatment. In summary, our data show that a bolus intravenous injection of sRLX causes rapid BK-mediated vasodilation through EDHF. Importantly, we also demonstrated a sustained vasodilatory response to sRLX that is mediated by prostacyclin. http://dx.doi.org/10.1016/j.hlc.2013.05.021