Lavinia Tran

Effects of a Rho kinase inhibitor on pressure overload induced cardiac hypertrophy and associated diastolic dysfunction

The RhoA-Rho kinase (ROCK) signaling pathway has an important role in cardiovascular diseases. However, the effect of Rho kinase inhibition on pressure overload-induced cardiac hypertrophy (POH) and associated diastolic dysfunction has not been evaluated. This study examined the effect of a selective ROCK inhibitor (GSK-576371) in a POH model, induced by suprarenal abdominal aortic constriction. POH rats were divided into the following four groups: 1 (GSK 1, n = 9) or 3 (GSK 3, n = 10) mg/kg bid GSK-576371, 1 mg.kg(-1).day(-1) ramipril (n = 10) or vehicle (n = 11) treatment for 4 wk. Sham animals (n = 11) underwent surgery without banding. Echocardiograms were performed before surgery and posttreatment, and hemodynamic data were obtained at completion of the study. Echocardiography showed an increase in relative wall thickness of the left ventricle (LV) following POH + vehicle treatment compared with sham animals. This was attenuated by both doses of GSK-576371 and ramipril. Vehicle treatment demonstrated abnormal diastolic parameters, including mitral valve (MV) inflow E wave deceleration time, isovolumic relaxation time, and MV annular velocity, which were dose dependently restored toward sham values by GSK-576371. LV end diastolic pressure was increased following POH + vehicle treatment compared with sham (6.9 +/- 0.7 vs. 3.2 +/- 0.7 mmHg, P = 0.008) and was reduced with GSK 3 and ramipril treatment (1.7 +/- 0.7, P < 0.01 and 2.9 +/- 0.6 mmHg, P < 0.01, respectively). Collagen I deposition in the LV was increased following POH + vehicle treatment (32.2%; P < 0.01) compared with sham animals and was significantly attenuated with GSK 1 (21.7%; P < 0.05), GSK 3 (23.8%; P < 0.01), and ramipril (35.5%; P < 0.01) treatment. These results suggest that ROCK inhibition improves LV geometry and reduces collagen deposition accompanied by improved diastolic function in POH.

Chronic urotensin-II infusion induces diastolic dysfunction and enhances collagen production in rats.

The vasoactive peptide urotensin-II (U-II) is likely to play a key causal role in cardiac remodeling that ultimately leads to heart failure. Its contribution, specifically to the development of diastolic dysfunction and the downstream intracellular signaling, however, remains unresolved. This study interrogates the effect of chronic U-II infusion in normal rats on cardiac structure and function. The contribution of Rho kinase (ROCK) signaling to these pathophysiological changes is evaluated in cell culture studies. Chronic high-dose U-II infusion over 4 wk significantly impaired diastolic function in rats on echocardiography-derived Doppler indexes, including E-wave deceleration time (vehicle 56.7 +/- 3.3 ms, U-II 118.0 +/- 21.5 ms; P < 0.01) and mitral valve annulus peak early/late diastolic tissue velocity (vehicle 2.01 +/- 0.19 ms, U-II 1.04 +/- 0.25 ms; P < 0.01). A lower dose of U-II infusion (1 nmol.kg(-1).h(-1)) yielded comparable changes. Diastolic dysfunction was accompanied by molecular [significant increases in procollagen-alpha(1)(I) gene expression on real-time PCR] and morphological (increases in total collagen, P < 0.05, and collagen type-I protein deposition, P < 0.001) evidence of left ventricular (LV) fibrosis following high-dose U-II infusion. The ROCK inhibitor GSK-576371 (10(-7) to 10(-5) M) elicited concentration-dependent inhibition of U-II (10(-7) M)-stimulated cardiac fibroblast collagen synthesis and cardiac myocyte protein synthesis. Chronic U-II infusion causes diastolic dysfunction, caused by fibrosis of the LV. The in vitro data suggest that this may be in part occurring via a ROCK-dependent pathway.

AusSCORE II in predicting 30-day mortality after isolated coronary artery bypass grafting in Australia and New Zealand

OBJECTIVES To update the Australian System for Cardiac Operative Risk Evaluation (AusSCORE) model for operative estimation of 30-day mortality risk after isolated coronary artery bypass grafting in the Australian population. METHODS Data were collected by the Australian and New Zealand Society of Cardiac and Thoracic Surgeons registry from 2001 to 2011 in 25 hospitals. A total of 31,250 patients underwent isolated coronary artery bypass grafting and the outcome was 30-day mortality. A total of 2154 (6.9%) patients had 1 or multiple missing values. Missing values were estimated assuming missing completely at random and logistic regression with a generalized estimating equation was used to address within-hospital variance. Bootstrapping methods were used to construct and validate the updated model (AusSCORE II). Also the model was validated on an out-of-creation sample of 4700 patients who underwent bypass surgery in 2012. RESULTS The average age of the patients was 65.6±12.9 years and 78.6% were male. Thirteen variables were selected in the updated model. The bootstrap discrimination and calibration of the AusSCORE II was very good (receiver operating characteristics [ROC], 82.0%; slope calibration, 0.987). The overall observed/AusSCORE II predicted mortality was 1.63% compared with the original AusSCORE predicted mortality of 1.01%. The validation of the AusSCORE II on the out-of-sample data also showed a high performance of the model (ROC, 84.5%; Hosmer-Lemoshow P value, .7654). CONCLUSIONS The AusSCORE II model provides improved prediction of 30-day mortality and successfully stratifies patient risk. The model will be useful to improve the preoperative consultation regarding risk stratification in terms of 30-day mortality.

Evaluation of the effects of urotensin II and soluble epoxide hydrolase inhibitor on skin microvessel tone in healthy controls and heart failure patients.

INTRODUCTION Urotensin II (UII) is a potent vasoactive peptide that exerts differential effects on heart failure (HF) patients compared to health controls. However, the mechanism of action remains unclear. The role of soluble epoxide hydrolase (sEH) as a mediator of UII in the vasculature has not been explored. AIMS The aim of this study was to examine the effect of UII in the presence and absence of sEH inhibitor AUDA on skin microvessel tone in HF patients and healthy controls using iontophoresis and laser Doppler velocimetry. UII (10(-7) M) and AUDA (10(-10), 10(-7), and 10(-5) M) were administered to the forearm of participants by iontophoresis for 30 seconds. Laser Doppler velocimetry was performed for 5 minutes to measure flux through the subcutaneous blood vessels. Response (flux) was measured for 5 minutes per concentration with 25 continuous scans. RESULTS UII increased flux in healthy controls by 39% (P < 0.05) and increased flux in HF patients by 6% (ns). AUDA (10(-10) and 10(-7) M) administration further decreased flux by 115% (P < 0.05) and 255% (P < 0.0001), respectively in healthy controls. In HF patients, AUDA (10(-10), 10(-7), and 10(-5) M) further increased flux by 77% (P < 0.05), 67% (P < 0.01), and 100% (P < 0.05), respectively. AUDA alone at 10(-7) M increased flux in both groups by 31% (healthy controls, P < 0.05) and 36% (HF, P < 0.01). CONCLUSION Taken together, the presence of HF appeared to abrogate the vasodilator responsiveness of sEH inhibitor. These results suggest an important role for both UII and sEH in vascular regulation and that sEH may be involved in mediating UII effects. Furthermore, the study highlights the therapeutic potential of sEH inhibitors for the treatment of HF.

Acute Risk Change for Cardiothoracic Admissions to Intensive Care (ARCTIC index): A new measure of quality in cardiac surgery

BACKGROUND Quality of cardiac surgical care may vary between institutions. Mortality is low and large numbers are required to discriminate between hospitals. Measures other than mortality may provide better comparisons. OBJECTIVES To develop and assess the Acute Risk Change for Cardiothoracic Admissions to Intensive Care (ARCTIC) index, a new performance measure for cardiothoracic admissions to intensive care units (ICUs). METHODS The Australian and New Zealand Society of Cardiac and Thoracic Surgeons database and Australian and New Zealand Intensive Care Society Adult Patient Database were linked. Logistic regression was used to generate a predicted risk of death first from preoperative data using the previously validated Allprocscore and second on admission to an ICU using Acute Physiology and Chronic Health Evaluation III score. Change in risk as a percentage (ARCTIC) was calculated for each patient. The validity of ARCTIC as a marker of quality was assessed by comparison with intraoperative variables and postoperative morbidity markers. RESULTS Sixteen thousand six hundred eighty-seven patients at 21 hospitals from 2008 to 2011 were matched. An increase in ARCTIC score was associated with prolonged cardiopulmonary bypass time (P = .001), intraoperative blood product transfusion (P < .001), reoperation (P < .0001), postoperative renal failure (P < .0001), prolonged ventilation (P < .0001), and stroke (P = .001). CONCLUSIONS The ARCTIC index is associated with known markers of perioperative performance and postoperative morbidity. It may be used as an overall marker of quality for cardiac surgery. Further work is required to assess ARCTIC as a method to discriminate between cardiac surgical units.

A review of valve surgery for rheumatic heart disease in Australia

BackgroundGlobally, rheumatic heart disease (RHD) remains an important cause of heart disease. In Australia it particularly affects older non-Indigenous Australians and Aboriginal Australians and/or Torres Strait Islander peoples. Factors associated with the choice of treatment for advanced RHD remain variable and poorly understood.MethodsThe Australian and New Zealand Society of Cardiac and Thoracic Surgeons Cardiac Surgery Database was analysed. Demographics, co-morbidities, pre-operative status and valve(s) affected were collated and associations with management assessed.ResultsSurgical management of 1384 RHD and 15843 non-RHD valve procedures was analysed. RHD patients were younger, more likely to be female and Indigenous Australian, to have atrial fibrillation (AF) and previous percutaneous balloon valvuloplasty (PBV). Surgery was performed on one valve in 64.5%, two valves in 30.0% and three valves in 5.5%. Factors associated with receipt of mechanical valves in RHD were AF (OR 2.69) and previous PBV (OR 1.98) and valve surgery (OR 3.12). Predictors of valve repair included being Indigenous (OR 3.84) and having fewer valves requiring surgery (OR 0.10). Overall there was a significant increase in the use of mitral bioprosthetic valves over time.ConclusionsRHD valve surgery is more common in young, female and Indigenous patients. The use of bioprosthetic valves in RHD is increasing. Given many patients are female and younger, the choice of valve surgery and need for anticoagulation has implications for future management of RHD and related morbidity, pregnancy and lifestyle plans.

The association between peri-operative acute risk change (ARC) and long-term survival after cardiac surgery

Acute risk change has been described as the difference in calculated mortality risk between the pre‐operative and postoperative periods of cardiac surgery. We aimed to assess whether this was associated with long‐term survival after cardiac surgery. We retrospectively analysed 22,570 cardiac surgical patients, with minimum and maximum follow‐up of 1.0 and 6.7 years. Acute risk change was calculated as the arithmetic difference between pre‐ and postoperative mortality risk. ‘Rising risk’ represented an increase in risk from pre‐ to postoperative phase. The primary outcome was one‐year mortality. Secondary outcomes included mortality at 3 and 5 years and time to death. Univariable and multivariable analyses were undertaken to examine the relationship between acute risk change and outcomes. Rising risk was associated with higher mortality (5.6% vs. 3.5%, p < 0.001). After adjusting for baseline risk, rising risk was independently associated with increased 1‐year mortality (OR 2.6, 95%CI 2.2–3.0, p < 0.001). The association of rising risk with long‐term survival was greatest in patients with highest baseline risk. Cox regression confirmed rising risk was associated with shorter time to death (HR 1.86, 1.68–2.05, p < 0.001). Acute risk change may represent peri‐operative clinical events in combination with unmeasured patient risk and noise. Measuring risk change could potentially identify patterns of events that may be amenable to investigation and intervention. Further work with case review, and risk scoring with shared variables, may identify mechanisms, including the interaction between miscalibration of risk and true differences in peri‐operative care.

Acute risk change (ARC) identifies outlier institutions in perioperative cardiac surgical care when the standardized mortality ratio cannot

BACKGROUND With improvements in short-term mortality after cardiac surgery, the sensitivity of the standardized mortality ratio (SMR) as a performance-monitoring tool has declined. We assessed acute risk change (ARC) as a new and potentially more sensitive metric to differentiate overall cardiac surgical unit performance. METHODS Retrospective analysis of the Australian and New Zealand Society of Cardiac and Thoracic Surgeons database and Australian and New Zealand Intensive Care Society Adult Patient Database was performed. The 16 656 patients who underwent coronary artery bypass grafting or cardiac valve procedures during a 4 yr period were included. The ARC was generated using the change between preoperative and postoperative probability of death. Outlier institutions were those with higher (outside 99.8% confidence intervals) ARC or SMR on annual and 4 yr funnel plots. Outliers were grouped and compared with non-outliers for baseline characteristics, intraoperative events, and postoperative morbidity. RESULTS No outliers were identified using SMR. Two outliers were identified using ARC. Outliers had higher rates of new renal failure (5.7 vs 4.5%, P=0.017), stroke (1.6 vs 0.9%, P=0.001), reoperation (9 vs 6.0%, P<0.001), and prolonged ventilation (15.3 vs 9.5%, P<0.001). Outliers transfused more blood products (P<0.001) and had longer cardiopulmonary bypass times (P<0.001) and less senior surgeons operating (P<0.001). CONCLUSIONS Acute risk change was able to discriminate between units where SMR could not. Outliers had more adverse events. Acute risk change can be calculated before mortality outcome and identifies outliers with lower patient numbers. This may allow early recognition and investigation of outlier units.

Age and other perioperative risk factors for postoperative systemic inflammatory response syndrome after cardiac surgery

Background The inflammatory response to surgery varies considerably between individual patients. Age might be a substantial factor in this variability. Our objective was to examine the association of patient age and other potential risk factors with the occurrence of a postoperative systemic inflammatory response syndrome, during the first 24 h after cardiac surgery. Methods This was a retrospective cohort study, using linked data from the Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) Database and the Australian and New Zealand Intensive Care Society (ANZICS) Adult Patient Database. Data from patients who underwent coronary artery bypass grafting and/or valve surgery were used. The association between age and postoperative SIRS was analysed using Poisson regression, and corrected for other risk factors. Restricted cubic splines were used to determine relevant age categories. Results are expressed as risk ratios (RR) with 95% confidence intervals (CI). Results Data from 28 513 patients were used. In both univariable and multivariable models, increased patient age was strongly associated with reduced postoperative SIRS prevalence. Using 73-83 yr as the reference category, the RRs (95% CI) for the age categories were 1.38 (1.28-1.49) for ≤43 yr, 1.15 (1.09-1.20) for 44-63 yr, 1.05 (1.00-1.09) for 64-72 yr, and 1.03 (0.94-1.12) for >83 yr, respectively. The predictive value for postoperative SIRS of the final model, however, was moderate (c-statistic: 0.61). Conclusions We have demonstrated that advanced patient age is associated with a decreased risk of postoperative SIRS among cardiac surgery patients, where patients aged over 72 yr had the lowest risk.

Case load and valve surgery outcome in Australia

BACKGROUND In Australia it has been suggested that heart valve surgery, particularly for rheumatic heart disease (RHD), should be consolidated in higher volume centres. International studies of cardiac surgery suggest large volume centres have superior outcomes. However the effect of site and surgeon case load on longer term outcomes for valve surgery has not been investigated. METHODS The Australian and New Zealand Society of Cardiac and Thoracic Surgeons Cardiac Surgery Database was analysed. The adjusted association between both average annual site and surgeon case load on short term complications and short and long-term survival was determined. RESULTS Outcomes associated with 20,116 valve procedures at 25 surgical sites and by 93 surgeons were analysed. Overall adjusted analysis showed increasing site and surgeon case load was associated with longer ventilation, less reoperation and more anticoagulant complications. Increasing surgeon case load was also associated with less acute kidney injury. Adjusted 30-day mortality was not associated with site or surgeon case load. There was no consistent relationship between increasing site case load and long term survival. The association between surgeon case load and outcome demonstrated poorer adjusted survival in the highest volume surgeon group. CONCLUSIONS In this Australian study, the adjusted association between surgeon and site case load was not simple or consistent. Overall larger volume sites or surgeons did not have superior outcomes. Mandating a particular site case load level for valve surgery or a minimum number of procedures for individual surgeons, in an Australian context, cannot be supported by these findings.