Unplanned readmissions to hospital after percutaneous coronary intervention (PCI) pose a signific... more Unplanned readmissions to hospital after percutaneous coronary intervention (PCI) pose a significant burden to the healthcare system and are potentially preventable. In this study, we sought to determine the incidence of, and risk factors for, unplanned hospital readmissions within 30 days following PCI. We prospectively collected data on 28,488 patients undergoing PCI between 2013 and 2019, who were enrolled in the state-wide multi-centre Victorian Cardiac Outcomes Registry. Patients’ data were then linked to data from the Victorian Department of Health administrative database that records statewide hospital admissions. Disease diagnosis codes were used to identify cause of readmission. Patients who had an unplanned readmission were further divided into those who had a cardiac vs. non-cardiac cause for readmission. Overall, 3059 patients (10.7%) had an unplanned hospital readmission within 30 days of PCI, of which 1848 patients (60.4%) were readmitted for primarily cardiac diagnose...
Aims: To review the complications, mortality and destination therapy of patients undergoing ballo... more Aims: To review the complications, mortality and destination therapy of patients undergoing balloon aortic valvuloplasty (BAV) in the era of transcatheter aortic valve implantation (TAVI). Methods: A systematic literature search identified journal articles reporting the outcomes of adult patients undergoing BAV procedures. Cohorts of 50 or more patients undergoing BAV between January 2002 and May 2018 were included in the review. Patient baseline characteristics, surgical risk scores, complications, short-and long-term mortality and reported destination therapy were extracted and aggregated, with estimated mean and standard deviation weighted by cohort size. Results: A total of 29 papers were included, describing the outcomes of 9,602 patients. The mean age of the patient cohorts was 82.3 ± 1.3 years. 51.6% of the patients were female and the mean STS score was 12.3 ± 3.2. The rates of stroke, myocardial infarction, major vascular complications and greater than BARC 2 bleeding post-BAV were 1.2% ± 0.7, 1.2% ± 1.5, 2.4% ± 1.1 and 8.9% ± 2.2 respectively. Periprocedural and intrahospital mortality rates were 1.7% ± 2.8 and 7.0% ± 4.2. Mortality rates at 30 days and 12 months were 7.7% ± 6.0 and 34.4% ± 12.7. Reported rates of patients undergoing TAVI, surgical aortic valve replacement or medical management post-BAV were 17.2% ± 12.1, 4.9% ± 4.0 and 77.0% ± 14.0. Conclusions: Short and medium-term outcomes following BAV are similar to contemporary cohorts undergoing TAVI. The vast majority of patients do not proceed to further intervention, with BAV being their destination therapy. The clinical and economic impact of such practice in the era of TAVI requires further study.
Abstracts S73 median (IQR) (66 min, 43-79 vs. 67 min, 44-96, p = 0.9), leading to shorter symptom... more Abstracts S73 median (IQR) (66 min, 43-79 vs. 67 min, 44-96, p = 0.9), leading to shorter symptom-to-balloon time, median (IQR) (184 min, 132-239 vs. 194 min, 141-291, p = 0.051). There were no significant differences between outcomes for in-hospital, 30-day, 12-months and (NDI-linked) long-term mortality between the two groups. ST was not an independent predictor of 30-day MACE on multivariate analysis (HR 0.8, CI 0.4-1.8, p = 0.75). Patients presenting with STEMI caused by definite ST had similar outcomes to those caused by de novo lesions. A shorter STDT may represent earlier recognition of symptoms in the ST group and possibly contributed to their similar outcome with the de novo group.
Background: Trans-radial access for percutaneous coronary intervention (PCI) has been associated ... more Background: Trans-radial access for percutaneous coronary intervention (PCI) has been associated with lower vascular complication rates and improved outcomes. We assessed the current uptake of trans-radial PCI in Victoria, Australia, and evaluated if patients were selected according to baseline bleeding risk in contemporary clinical practise, and compared selected clinical outcomes. Methods: PCI data of all patients between 1st January 2013 and 31st December 2014 were analysed using The Victorian Cardiac Outcomes Registry (VCOR). Propensity-matched analysis was performed to compare the clinical outcomes. Results: 11,711 procedures were analysed. The femoral route was the predominant access site (66%). Patients undergoing trans-radial access PCI were younger (63.9 ± 11.6 vs. 67.2 ± 11.8; p b 0.001), had a higher BMI (28.9 ± 5.5 vs. 28.5 ± 5.2; p b 0.001), more likely to be male (80.0 vs. 74.9%;p b 0.001), less likely to have presented with cardiogenic shock (0.9 vs. 2.8%; p b 0.001) or have the following comorbidities: diabetes (19.8 vs. 23.1%; p b 0.001), peripheral vascular disease (2.9 vs. 4.3%; p = 0.005) or renal impairment (13.6 vs. 22.1%; p b 0.001). The radial group had less bleeding events (3.2 vs. 4.6%; p b 0.001) and shorter hospital length of stay (3.1 ± 4.7 vs. 3.3 ± 3.9; p = 0.006). There was no significant difference in mortality (1.0 vs. 1.4%; p = 0.095). Conclusions: Trans-femoral approach remains the dominant access site for PCI in Victoria. The choice of route does not appear to be selected by consideration of bleeding risk. The radial route is associated with improved clinical outcomes of reduced bleeding and length of stay consistent with previous findings, and this supports the efficacy and safety of trans-radial PCI in real-world clinical practise.
The cellular localisation and expression of angiotensin AT 4 receptors was examined in the normal... more The cellular localisation and expression of angiotensin AT 4 receptors was examined in the normal human prostate and benign prostatic hyperplasia (BPH) by quantitative in vitro autoradiography using [ 125 I]-Ang IV. In the normal human prostate, AT 4 receptors were localised to the glandular epithelium. Interestingly, specific AT 4 receptor binding was significantly reduced in BPH compared to the normal prostate, as quantitated macroscopically (normal: 5038 9 476 dpm/mm 2 , n=6 vs BPH: 27019176 dpm/mm 2 , n=6, P B0.001) and microscopically (normal: 7.28 9 0.36 grains/mm 2 , n= 6 vs BPH: 2.509 0.47 grains/mm 2 , n =6, P B0.001). The findings of the present study demonstrate the presence of AT 4 receptors in the human prostate, being localised to the glandular epithelium, which suggest that the Ang IV/AT 4 system may play a role in the regulation of ionic transport and glandular secretion in the human prostate. The observation that AT 4 receptors appear reduced in BPH suggests that the AT 4 receptor may undergo agonist-induced receptor internalisation, possibly due to increased local tissue levels of Ang IV in BPH.
The present study examined the in vivo effects of candesartan cilexetil compared with losartan on... more The present study examined the in vivo effects of candesartan cilexetil compared with losartan on angiotensin II (Ang II) receptor binding in the rat kidney after oral administration. Male Sprague-Dawley rats (250 to 300 g) were gavaged with candesartan cilexetil or losartan in doses of 0.1, 0.3, 1, 3, 10, or 30 mg/kg, or corresponding vehicle. Rats were killed at 0, 1, 2, 8, or 24 h after drug administration, trunk blood collected, and kidneys removed. The effects of candesartan cilexetil and losartan on Ang II receptor binding were determined by quantitative in vitro autoradiography using the radioligand [ 125 I]-[Sar 1 ,Ile 8 ] Ang II. Ang II receptor binding in the kidney was mainly due to AT 1 receptors with high levels of binding localized to the inner stripe of the outer medulla and glomeruli in cortical regions. Candesartan cilexetil (0.1 to 30 mg/kg) inhibited Ang II receptor binding to all anatomical sites of the kidney, in a dose-dependent manner. Losartan (0.1 to 30 mg/kg) also produced dosedependent inhibition of Ang II receptor binding but was approximately 10-to 30-fold less potent than candesartan cilexetil. Inhibition of Ang II receptor binding was near maximal about 1 h after administration of candesartan cilexetil (10 mg/kg) or losartan (10 mg/kg), with both drugs producing persistent blockade at 24 h despite plasma renin activity and plasma drug concentrations returning to near normal levels. In vitro, candesartan, losartan, and EXP3174 (1 ؋ ؋ 10 ؊ ؊10 to 1 ؋ ؋ 10 ؊ ؊5 mol/L) displaced [ 125 I]-[Sar 1 ,Ile 8 ] Ang II binding from AT 1 receptors in the kidney in a concentration-dependent manner with a rank order of potency of candesartan > > EXP3174 > > losartan. The concentration required to displace 50% of radioligand binding (IC 50 ) by candesartan, EXP3174, and losartan was 0.9 ؎ ؎ 0.1 nmol/L, 3.4 ؎ ؎ 0.4 nmol/L, and 8.9 ؎ ؎ 1.1 nmol/L, respectively. In conclusion, the findings of the present study suggest that candesartan cilexetil is more potent than losartan in antagonizing AT 1 receptors in the kidney in vivo. Nonetheless, both candesartan cilexetil and losartan produce rapid, complete, and sustained blockade of AT 1 receptors in the rat kidney. Tissue blockade of Ang II receptors in target organs, such as the kidney, may contribute to the beneficial effects of Ang II receptor antagonists as antihypertensive agents.
To evaluate the impact of preoperative atrial fibrillation (pre-op AF) on early and late mortalit... more To evaluate the impact of preoperative atrial fibrillation (pre-op AF) on early and late mortality after isolated coronary artery bypass graft (CABG) surgery. Data obtained prospectively between June 2001 and December 2009 by the Australasian Society of Cardiac and Thoracic Surgeons National Cardiac Surgery Database Program were retrospectively analyzed. Patients who underwent concomitant atrial arrhythmia surgery/ablation were excluded. Demographic and operative data were compared between patients with and without pre-op AF. The independent association of pre-op AF on early mortality, perioperative complications, and late mortality was determined. Isolated CABG surgery was performed in 21,534 patients; 1312 (6.1%) presented with pre-op AF. Pre-op AF patients were older (mean age, 71 years vs. 65 years, p<0.001) and had more comorbidities reflected in a higher additive EuroSCORE (8.4±3.5 vs. 6.5±3.2, p=0.001). Even after accounting for confounding factors, however, pre-op AF was ...
h-Arrestins play a role in AT 1 endocytosis by binding the cytoplasmic, C-terminus region T332 -S... more h-Arrestins play a role in AT 1 endocytosis by binding the cytoplasmic, C-terminus region T332 -S338, the major site of angiotensin II (Ang II)-induced phosphorylation. However, the processes responsible for recruiting h-arrestin to the activated receptor are poorly defined. In this study, we used CHO-K1 and HEK 293 cells expressing wild-type or mutant AT 1 to investigate two possibilities: activated AT 1 induces global relocation of h-arrestins to the plasma membrane or the phosphorylated C-terminus acts as bait to attract h-arrestins. Results obtained using high osmolarity and dominant-negative h-arrestin confirmed that internalization of AT 1 in both CHO-K1 and HEK 293 cells is predominately via clathrin-mediated endocytosis involving h-arrestin, and substitution of T332, S335, T336 and S338 with alanine to preclude phosphorylation markedly attenuated AT 1 internalization. Confocal microscopy revealed that wild-type AT 1 induced a timedependent translocation of GFP-tagged h-arrestins 1 and 2 to the cell surface. In contrast, the TSTS/A mutant did not traffic h-arrestin 1 at all, and only trafficked h-arrestin 2 weakly. Results of rescue-type experiments were consistent with the idea that both h-arrestins are able to interact with the non-phosphorylated receptor, albeit with much lower affinity and h-arrestin 1 less so than h-arrestin 2. In conclusion, this study shows that the high affinity binding of h-arrestins to the phosphorylated C-terminus is the predominant mechanism of agonist-induced h-arrestin recruitment to the cell surface and AT 1 receptor.
β-arrestins bind to phosphorylated, seven-transmembrane-spanning, G protein-coupled receptors (GP... more β-arrestins bind to phosphorylated, seven-transmembrane-spanning, G protein-coupled receptors (GPCRs), including the type 1 angiotensin II receptor (AT 1 R), to promote receptor desensitization and internalization. The AT 1 R is a class B GPCR that recruits both β-arrestin1 and β-arrestin2, forming stable complexes that co-traffic to deep-core endocytic vesicles. β-arrestins contain one amphipathic and potentially amphitropic (membrane-targeting) α-helix (helix I) that may promote translocation to the membrane or influence receptor internalization or trafficking. Here, we have investigated the trafficking and function of β-arrestin1 and β-arrestin2 mutants bearing substitutions in both the hydrophobic and positively-charged faces of helix I. The level of expression of these mutants and their cytoplasmic localization (in the absence of receptor activation) was similar to wild type β-arrestins. Following angiotensin II stimulation, both wild type and β-arrestin mutants translocated to the cell membrane, although recruitment was weaker for mutants of the hydrophobic face of helix I. For all β-arrestin mutants, the formation of deep-core vesicles was less observed compared to wild type β-arrestins. Furthermore, helix I conjugated to green fluorescent protein is not membranelocalized, suggesting that helix I, in isolation, is not amphitropic. BRET analysis revealed that both wild type and β-arrestin mutants retained a capacity to interact with the AT 1 R, although the interaction with the mutants was less stable. Finally, wild type and mutant β-arrestins fully supported receptor internalization in human embryonic kidney cells and mouse embryonic fibroblasts deficient in β-arrestin1 and 2. Thus, helix I is implicated in post-membrane trafficking, but is not strongly amphitropic.
The expression and cellular localization of angiotensin II (Ang II) and AT1 receptor proteins wer... more The expression and cellular localization of angiotensin II (Ang II) and AT1 receptor proteins were examined in the normal human prostate and benign prostatic hyperplasia (BPH) by immunohistochemistry. In the normal prostate, Ang II immunoreactivity was localized to the basal layer of the epithelium and AT1 receptor immunostaining was found predominantly on stromal smooth muscle and also on vascular smooth muscle of prostatic blood vessels. Ang II immunoreactivity was markedly increased in hyperplastic acini in BPH compared with acini in the normal prostate (normal: 7.4±0.2%, n=5 vs. BPH: 22.7±1.9%, n=5, p<0.001). However, AT1 receptor immunoreactivity was significantly decreased in BPH compared with the normal prostate [normal: 16.4±2.2%, n=4 vs. BPH: 9.4±1.3%, n=5, p<0.05 (p=0.025)]. The present study demonstrates the presence of Ang II peptide in the basal layer of the epithelium and AT1 receptors on stromal smooth muscle, suggesting that Ang II may mediate paracrine functio...
Journal of Cardiothoracic and Vascular Anesthesia, 2009
The purpose of this study was to determine the incidence of injury associated with transesophagea... more The purpose of this study was to determine the incidence of injury associated with transesophageal echocardiography (TEE injuries) in cardiac surgery. Design: Retrospective. Setting: University-affiliated hospitals. Participants: Four thousand seven hundred eighty-four patients, 89% of all public hospital cardiac surgery patients in Victoria, from the Australasian Society of Cardiac and Thoracic Surgeons (ASCTS) database undergoing cardiac surgery with
Background: The objective of the study was to compare the demographic data and intensive care sta... more Background: The objective of the study was to compare the demographic data and intensive care stay of patients undergone CABG and aortic valve surgery combined between June to September 2003 and 2008 at Auckland. Methods: We retrospectively reviewed the medical records, operative notes and intensive care data of patients who had CABG and CABG&AVR during that period. Results: 185 patients had CABG in 2003 and 119 in 2008 with mean age of 65.0 ± 9.8 and 63.2 ± 11.4, respectively. 73.5% were males and 26.5% females in 2003 and 81.5% males and 18.5% females in 2008. The mortality rate was 2.2% in 2003 and 1.7% in 2008. 31 patients had CABG&AVR in 2003 and 23 in 2008 with mean age of 67.4 ± 9.1 and 73.1 ± 7.5 respectively. 64.5% were male and 35.5% female in 2003 and 78.3% male and 21.7% female patients had in 2008. The mortality rate was 12.9% in 2003 and 4.4% in 2008. The dialysis rate during ICU stay was 3.2% in 2003 and 8.7% in 2008. The median stay in intensive care was 1.08 (0.93-2.13) days in 2003 and 1.96 (1.02-3.85) days in 2008. 2 patients had stroke in 2008 and none in 2003. Conclusion: There was increasing trend of male in 50s and female in the 70+ group getting CABG in 2008. The patients undergoing CABG&AVR in 2008 were elderly and stayed longer in ICU requiring more resources. There was an increase in rate of neurological event in this group. The overall mortality rate declined in both group indicating better skills and technology.
Since the call for a National Cardiac Procedures Database in 2001, much work has been accomplishe... more Since the call for a National Cardiac Procedures Database in 2001, much work has been accomplished in both cardiac surgery and interventional cardiology in an attempt to establish a unified, systematic approach to data collection, defining a common minimum dataset pertinent to the Australian context, and instituting quality control measures to ensure integrity and privacy of data. In this paper we outline the aims of the Australasian Society of Cardiac and Thoracic Surgeons (ASCTS) and the Melbourne Interventional Group (MIG) registries, and propose a comprehensive set of standardised data elements and their definitions to facilitate transparency in data collection, consistency between these and other data sets, and encourage ongoing peer-review. The aims are to improve outcomes for patients by determining key performance indicators and standards of performance for hospital units, to allow estimation of procedural risks and likelihood of outcomes for patients, and to report outcomes to relevant stake-holders and the public.
Unplanned readmissions to hospital after percutaneous coronary intervention (PCI) pose a signific... more Unplanned readmissions to hospital after percutaneous coronary intervention (PCI) pose a significant burden to the healthcare system and are potentially preventable. In this study, we sought to determine the incidence of, and risk factors for, unplanned hospital readmissions within 30 days following PCI. We prospectively collected data on 28,488 patients undergoing PCI between 2013 and 2019, who were enrolled in the state-wide multi-centre Victorian Cardiac Outcomes Registry. Patients’ data were then linked to data from the Victorian Department of Health administrative database that records statewide hospital admissions. Disease diagnosis codes were used to identify cause of readmission. Patients who had an unplanned readmission were further divided into those who had a cardiac vs. non-cardiac cause for readmission. Overall, 3059 patients (10.7%) had an unplanned hospital readmission within 30 days of PCI, of which 1848 patients (60.4%) were readmitted for primarily cardiac diagnose...
Aims: To review the complications, mortality and destination therapy of patients undergoing ballo... more Aims: To review the complications, mortality and destination therapy of patients undergoing balloon aortic valvuloplasty (BAV) in the era of transcatheter aortic valve implantation (TAVI). Methods: A systematic literature search identified journal articles reporting the outcomes of adult patients undergoing BAV procedures. Cohorts of 50 or more patients undergoing BAV between January 2002 and May 2018 were included in the review. Patient baseline characteristics, surgical risk scores, complications, short-and long-term mortality and reported destination therapy were extracted and aggregated, with estimated mean and standard deviation weighted by cohort size. Results: A total of 29 papers were included, describing the outcomes of 9,602 patients. The mean age of the patient cohorts was 82.3 ± 1.3 years. 51.6% of the patients were female and the mean STS score was 12.3 ± 3.2. The rates of stroke, myocardial infarction, major vascular complications and greater than BARC 2 bleeding post-BAV were 1.2% ± 0.7, 1.2% ± 1.5, 2.4% ± 1.1 and 8.9% ± 2.2 respectively. Periprocedural and intrahospital mortality rates were 1.7% ± 2.8 and 7.0% ± 4.2. Mortality rates at 30 days and 12 months were 7.7% ± 6.0 and 34.4% ± 12.7. Reported rates of patients undergoing TAVI, surgical aortic valve replacement or medical management post-BAV were 17.2% ± 12.1, 4.9% ± 4.0 and 77.0% ± 14.0. Conclusions: Short and medium-term outcomes following BAV are similar to contemporary cohorts undergoing TAVI. The vast majority of patients do not proceed to further intervention, with BAV being their destination therapy. The clinical and economic impact of such practice in the era of TAVI requires further study.
Abstracts S73 median (IQR) (66 min, 43-79 vs. 67 min, 44-96, p = 0.9), leading to shorter symptom... more Abstracts S73 median (IQR) (66 min, 43-79 vs. 67 min, 44-96, p = 0.9), leading to shorter symptom-to-balloon time, median (IQR) (184 min, 132-239 vs. 194 min, 141-291, p = 0.051). There were no significant differences between outcomes for in-hospital, 30-day, 12-months and (NDI-linked) long-term mortality between the two groups. ST was not an independent predictor of 30-day MACE on multivariate analysis (HR 0.8, CI 0.4-1.8, p = 0.75). Patients presenting with STEMI caused by definite ST had similar outcomes to those caused by de novo lesions. A shorter STDT may represent earlier recognition of symptoms in the ST group and possibly contributed to their similar outcome with the de novo group.
Background: Trans-radial access for percutaneous coronary intervention (PCI) has been associated ... more Background: Trans-radial access for percutaneous coronary intervention (PCI) has been associated with lower vascular complication rates and improved outcomes. We assessed the current uptake of trans-radial PCI in Victoria, Australia, and evaluated if patients were selected according to baseline bleeding risk in contemporary clinical practise, and compared selected clinical outcomes. Methods: PCI data of all patients between 1st January 2013 and 31st December 2014 were analysed using The Victorian Cardiac Outcomes Registry (VCOR). Propensity-matched analysis was performed to compare the clinical outcomes. Results: 11,711 procedures were analysed. The femoral route was the predominant access site (66%). Patients undergoing trans-radial access PCI were younger (63.9 ± 11.6 vs. 67.2 ± 11.8; p b 0.001), had a higher BMI (28.9 ± 5.5 vs. 28.5 ± 5.2; p b 0.001), more likely to be male (80.0 vs. 74.9%;p b 0.001), less likely to have presented with cardiogenic shock (0.9 vs. 2.8%; p b 0.001) or have the following comorbidities: diabetes (19.8 vs. 23.1%; p b 0.001), peripheral vascular disease (2.9 vs. 4.3%; p = 0.005) or renal impairment (13.6 vs. 22.1%; p b 0.001). The radial group had less bleeding events (3.2 vs. 4.6%; p b 0.001) and shorter hospital length of stay (3.1 ± 4.7 vs. 3.3 ± 3.9; p = 0.006). There was no significant difference in mortality (1.0 vs. 1.4%; p = 0.095). Conclusions: Trans-femoral approach remains the dominant access site for PCI in Victoria. The choice of route does not appear to be selected by consideration of bleeding risk. The radial route is associated with improved clinical outcomes of reduced bleeding and length of stay consistent with previous findings, and this supports the efficacy and safety of trans-radial PCI in real-world clinical practise.
The cellular localisation and expression of angiotensin AT 4 receptors was examined in the normal... more The cellular localisation and expression of angiotensin AT 4 receptors was examined in the normal human prostate and benign prostatic hyperplasia (BPH) by quantitative in vitro autoradiography using [ 125 I]-Ang IV. In the normal human prostate, AT 4 receptors were localised to the glandular epithelium. Interestingly, specific AT 4 receptor binding was significantly reduced in BPH compared to the normal prostate, as quantitated macroscopically (normal: 5038 9 476 dpm/mm 2 , n=6 vs BPH: 27019176 dpm/mm 2 , n=6, P B0.001) and microscopically (normal: 7.28 9 0.36 grains/mm 2 , n= 6 vs BPH: 2.509 0.47 grains/mm 2 , n =6, P B0.001). The findings of the present study demonstrate the presence of AT 4 receptors in the human prostate, being localised to the glandular epithelium, which suggest that the Ang IV/AT 4 system may play a role in the regulation of ionic transport and glandular secretion in the human prostate. The observation that AT 4 receptors appear reduced in BPH suggests that the AT 4 receptor may undergo agonist-induced receptor internalisation, possibly due to increased local tissue levels of Ang IV in BPH.
The present study examined the in vivo effects of candesartan cilexetil compared with losartan on... more The present study examined the in vivo effects of candesartan cilexetil compared with losartan on angiotensin II (Ang II) receptor binding in the rat kidney after oral administration. Male Sprague-Dawley rats (250 to 300 g) were gavaged with candesartan cilexetil or losartan in doses of 0.1, 0.3, 1, 3, 10, or 30 mg/kg, or corresponding vehicle. Rats were killed at 0, 1, 2, 8, or 24 h after drug administration, trunk blood collected, and kidneys removed. The effects of candesartan cilexetil and losartan on Ang II receptor binding were determined by quantitative in vitro autoradiography using the radioligand [ 125 I]-[Sar 1 ,Ile 8 ] Ang II. Ang II receptor binding in the kidney was mainly due to AT 1 receptors with high levels of binding localized to the inner stripe of the outer medulla and glomeruli in cortical regions. Candesartan cilexetil (0.1 to 30 mg/kg) inhibited Ang II receptor binding to all anatomical sites of the kidney, in a dose-dependent manner. Losartan (0.1 to 30 mg/kg) also produced dosedependent inhibition of Ang II receptor binding but was approximately 10-to 30-fold less potent than candesartan cilexetil. Inhibition of Ang II receptor binding was near maximal about 1 h after administration of candesartan cilexetil (10 mg/kg) or losartan (10 mg/kg), with both drugs producing persistent blockade at 24 h despite plasma renin activity and plasma drug concentrations returning to near normal levels. In vitro, candesartan, losartan, and EXP3174 (1 ؋ ؋ 10 ؊ ؊10 to 1 ؋ ؋ 10 ؊ ؊5 mol/L) displaced [ 125 I]-[Sar 1 ,Ile 8 ] Ang II binding from AT 1 receptors in the kidney in a concentration-dependent manner with a rank order of potency of candesartan > > EXP3174 > > losartan. The concentration required to displace 50% of radioligand binding (IC 50 ) by candesartan, EXP3174, and losartan was 0.9 ؎ ؎ 0.1 nmol/L, 3.4 ؎ ؎ 0.4 nmol/L, and 8.9 ؎ ؎ 1.1 nmol/L, respectively. In conclusion, the findings of the present study suggest that candesartan cilexetil is more potent than losartan in antagonizing AT 1 receptors in the kidney in vivo. Nonetheless, both candesartan cilexetil and losartan produce rapid, complete, and sustained blockade of AT 1 receptors in the rat kidney. Tissue blockade of Ang II receptors in target organs, such as the kidney, may contribute to the beneficial effects of Ang II receptor antagonists as antihypertensive agents.
To evaluate the impact of preoperative atrial fibrillation (pre-op AF) on early and late mortalit... more To evaluate the impact of preoperative atrial fibrillation (pre-op AF) on early and late mortality after isolated coronary artery bypass graft (CABG) surgery. Data obtained prospectively between June 2001 and December 2009 by the Australasian Society of Cardiac and Thoracic Surgeons National Cardiac Surgery Database Program were retrospectively analyzed. Patients who underwent concomitant atrial arrhythmia surgery/ablation were excluded. Demographic and operative data were compared between patients with and without pre-op AF. The independent association of pre-op AF on early mortality, perioperative complications, and late mortality was determined. Isolated CABG surgery was performed in 21,534 patients; 1312 (6.1%) presented with pre-op AF. Pre-op AF patients were older (mean age, 71 years vs. 65 years, p<0.001) and had more comorbidities reflected in a higher additive EuroSCORE (8.4±3.5 vs. 6.5±3.2, p=0.001). Even after accounting for confounding factors, however, pre-op AF was ...
h-Arrestins play a role in AT 1 endocytosis by binding the cytoplasmic, C-terminus region T332 -S... more h-Arrestins play a role in AT 1 endocytosis by binding the cytoplasmic, C-terminus region T332 -S338, the major site of angiotensin II (Ang II)-induced phosphorylation. However, the processes responsible for recruiting h-arrestin to the activated receptor are poorly defined. In this study, we used CHO-K1 and HEK 293 cells expressing wild-type or mutant AT 1 to investigate two possibilities: activated AT 1 induces global relocation of h-arrestins to the plasma membrane or the phosphorylated C-terminus acts as bait to attract h-arrestins. Results obtained using high osmolarity and dominant-negative h-arrestin confirmed that internalization of AT 1 in both CHO-K1 and HEK 293 cells is predominately via clathrin-mediated endocytosis involving h-arrestin, and substitution of T332, S335, T336 and S338 with alanine to preclude phosphorylation markedly attenuated AT 1 internalization. Confocal microscopy revealed that wild-type AT 1 induced a timedependent translocation of GFP-tagged h-arrestins 1 and 2 to the cell surface. In contrast, the TSTS/A mutant did not traffic h-arrestin 1 at all, and only trafficked h-arrestin 2 weakly. Results of rescue-type experiments were consistent with the idea that both h-arrestins are able to interact with the non-phosphorylated receptor, albeit with much lower affinity and h-arrestin 1 less so than h-arrestin 2. In conclusion, this study shows that the high affinity binding of h-arrestins to the phosphorylated C-terminus is the predominant mechanism of agonist-induced h-arrestin recruitment to the cell surface and AT 1 receptor.
β-arrestins bind to phosphorylated, seven-transmembrane-spanning, G protein-coupled receptors (GP... more β-arrestins bind to phosphorylated, seven-transmembrane-spanning, G protein-coupled receptors (GPCRs), including the type 1 angiotensin II receptor (AT 1 R), to promote receptor desensitization and internalization. The AT 1 R is a class B GPCR that recruits both β-arrestin1 and β-arrestin2, forming stable complexes that co-traffic to deep-core endocytic vesicles. β-arrestins contain one amphipathic and potentially amphitropic (membrane-targeting) α-helix (helix I) that may promote translocation to the membrane or influence receptor internalization or trafficking. Here, we have investigated the trafficking and function of β-arrestin1 and β-arrestin2 mutants bearing substitutions in both the hydrophobic and positively-charged faces of helix I. The level of expression of these mutants and their cytoplasmic localization (in the absence of receptor activation) was similar to wild type β-arrestins. Following angiotensin II stimulation, both wild type and β-arrestin mutants translocated to the cell membrane, although recruitment was weaker for mutants of the hydrophobic face of helix I. For all β-arrestin mutants, the formation of deep-core vesicles was less observed compared to wild type β-arrestins. Furthermore, helix I conjugated to green fluorescent protein is not membranelocalized, suggesting that helix I, in isolation, is not amphitropic. BRET analysis revealed that both wild type and β-arrestin mutants retained a capacity to interact with the AT 1 R, although the interaction with the mutants was less stable. Finally, wild type and mutant β-arrestins fully supported receptor internalization in human embryonic kidney cells and mouse embryonic fibroblasts deficient in β-arrestin1 and 2. Thus, helix I is implicated in post-membrane trafficking, but is not strongly amphitropic.
The expression and cellular localization of angiotensin II (Ang II) and AT1 receptor proteins wer... more The expression and cellular localization of angiotensin II (Ang II) and AT1 receptor proteins were examined in the normal human prostate and benign prostatic hyperplasia (BPH) by immunohistochemistry. In the normal prostate, Ang II immunoreactivity was localized to the basal layer of the epithelium and AT1 receptor immunostaining was found predominantly on stromal smooth muscle and also on vascular smooth muscle of prostatic blood vessels. Ang II immunoreactivity was markedly increased in hyperplastic acini in BPH compared with acini in the normal prostate (normal: 7.4±0.2%, n=5 vs. BPH: 22.7±1.9%, n=5, p<0.001). However, AT1 receptor immunoreactivity was significantly decreased in BPH compared with the normal prostate [normal: 16.4±2.2%, n=4 vs. BPH: 9.4±1.3%, n=5, p<0.05 (p=0.025)]. The present study demonstrates the presence of Ang II peptide in the basal layer of the epithelium and AT1 receptors on stromal smooth muscle, suggesting that Ang II may mediate paracrine functio...
Journal of Cardiothoracic and Vascular Anesthesia, 2009
The purpose of this study was to determine the incidence of injury associated with transesophagea... more The purpose of this study was to determine the incidence of injury associated with transesophageal echocardiography (TEE injuries) in cardiac surgery. Design: Retrospective. Setting: University-affiliated hospitals. Participants: Four thousand seven hundred eighty-four patients, 89% of all public hospital cardiac surgery patients in Victoria, from the Australasian Society of Cardiac and Thoracic Surgeons (ASCTS) database undergoing cardiac surgery with
Background: The objective of the study was to compare the demographic data and intensive care sta... more Background: The objective of the study was to compare the demographic data and intensive care stay of patients undergone CABG and aortic valve surgery combined between June to September 2003 and 2008 at Auckland. Methods: We retrospectively reviewed the medical records, operative notes and intensive care data of patients who had CABG and CABG&AVR during that period. Results: 185 patients had CABG in 2003 and 119 in 2008 with mean age of 65.0 ± 9.8 and 63.2 ± 11.4, respectively. 73.5% were males and 26.5% females in 2003 and 81.5% males and 18.5% females in 2008. The mortality rate was 2.2% in 2003 and 1.7% in 2008. 31 patients had CABG&AVR in 2003 and 23 in 2008 with mean age of 67.4 ± 9.1 and 73.1 ± 7.5 respectively. 64.5% were male and 35.5% female in 2003 and 78.3% male and 21.7% female patients had in 2008. The mortality rate was 12.9% in 2003 and 4.4% in 2008. The dialysis rate during ICU stay was 3.2% in 2003 and 8.7% in 2008. The median stay in intensive care was 1.08 (0.93-2.13) days in 2003 and 1.96 (1.02-3.85) days in 2008. 2 patients had stroke in 2008 and none in 2003. Conclusion: There was increasing trend of male in 50s and female in the 70+ group getting CABG in 2008. The patients undergoing CABG&AVR in 2008 were elderly and stayed longer in ICU requiring more resources. There was an increase in rate of neurological event in this group. The overall mortality rate declined in both group indicating better skills and technology.
Since the call for a National Cardiac Procedures Database in 2001, much work has been accomplishe... more Since the call for a National Cardiac Procedures Database in 2001, much work has been accomplished in both cardiac surgery and interventional cardiology in an attempt to establish a unified, systematic approach to data collection, defining a common minimum dataset pertinent to the Australian context, and instituting quality control measures to ensure integrity and privacy of data. In this paper we outline the aims of the Australasian Society of Cardiac and Thoracic Surgeons (ASCTS) and the Melbourne Interventional Group (MIG) registries, and propose a comprehensive set of standardised data elements and their definitions to facilitate transparency in data collection, consistency between these and other data sets, and encourage ongoing peer-review. The aims are to improve outcomes for patients by determining key performance indicators and standards of performance for hospital units, to allow estimation of procedural risks and likelihood of outcomes for patients, and to report outcomes to relevant stake-holders and the public.
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