High-resolution transthoracic echocardiography accurately detects pulmonary arterial pressure and decreased right ventricular contractility in a mouse model of pulmonary fibrosis and secondary pulmonary hypertension

BACKGROUND: To date, assessment of right ventricular (RV) function in mice has relied extensively on invasive measurements. Echocardiographic advances have allowed adaptation of measures used in humans for serial, noninvasive RV functional assessment in mice. We evaluated the diagnostic performance of tricuspid annular plane systolic excursion (TAPSE), RV peak systolic myocardial velocity (s'), RV myocardial performance index (MPI), and RV fractional area change (FAC) in a mouse model of pulmonary hypertension. METHODS AND RESULTS: Echocardiography was performed on mice at baseline and 3 weeks after induction of pulmonary hypertension using inhaled bleomycin or saline, including adapted measures of TAPSE, s', MPI, and FAC. RV systolic pressure was measured by invasive catheterization, and RV contractility was measured as the peak slope of the RV systolic pressure recording (maximum change pressure/change time). Postmortem morphological assessment of RV hypertrophy was performed. RV systolic pressure was elevated and maximum change pressure/change time was reduced in bleomycin versus control (n=8; P=0.002). Compared with controls, bleomycin mice had reduced TAPSE (0.79±0.05 versus 1.06±0.04 mm; P=0.003), s' (21.3±1.2 versus 29.2±1.3 mm/s; P<0.001), and FAC (20.3±0.7% versus 31.0±1.3%; P<0.001), whereas MPI was increased (0.51±0.03 versus 0.37±0.01; P=0.006). All measures correlated with RV systolic pressure and maximum change pressure/change time. Intraobserver and interobserver variability were minimal. Receiver operating characteristic curves demonstrated that TAPSE (<0.84 mm), s'(<23.3 mm/s), MPI (0.42), and FAC (<23.3%) identified maximum change pressure/change time ≤2100 mm Hg/s with high accuracy. CONSLUSIONS: TAPSE, s', MPI, and FAC are measurable consistently using high-resolution echocardiography in mice, and are sensitive and specific measures of pulmonary pressure and RV function. This validation opens the opportunity for serial noninvasive measures in mouse models of pulmonary hypertension, enhancing the statistical power of preclinical studies of novel therapeutics

Association of global coagulation profiles with cardiovascular risk factors and atherosclerosis: A sex disaggregated analysis from the BioHEART-CT study

Background: Although the association between dysregulated coagulation and atherosclerosis is well recognized, individual assays have been of minimal value in understanding disease susceptibility. Here we investigated the association of global coagulation profiles with coronary artery disease with consideration of sex differences. Methods and Results: The study included patients from the BioHEART-CT (The BioHEART Study: Assessing Patients With Suspected Cardiovascular Disease for New Disease Markers and Risk Factors) biobank who had computed tomography coronary angiograms scored for coronary artery calcium score (CACS) and Gensini score. The cohort included 206 adult patients who were referred for clinically indicated computed tomography coronary angiography and had a median of 2 major cardiac risk factors; 50% were women and the average age was 62.6 years (±9.9 years). The overall hemostatic potential (OHP) and calibrated automated thrombography generation assays were performed on platelet-poor plasma. CACS and Gensini score in men were significantly correlated in bivariate analysis with measures from the OHP assay, and regression models predicting disease severity by CACS or Gensini score were improved by adding the OHP assay variables in men but not in women. The calibrated automated thrombography generation assay demonstrated a more hypercoagulable profile in women than in men. The OHP assay showed hypercoagulable profiles in women with hyperlipidemia and men with obesity. Conclusions: The OHP assay identified hypercoagulable profiles associated with different risk factors for each sex and was associated with CACS and Gensini score severity in men, emphasizing the associations between increased fibrin generation and reduced fibrinolysis with cardiac risk factors and early atherosclerosis. Registration Information: www.anzctr.org.au. Identifier: ACTRN12618001322224.Katharine A. Kott, Marie-Christine Morel-Kopp, Stephen T. Vernon, Yuki Takagi, Belinda A. Di Bartolo, Karlheinz Peter, Jean Y. Yang, Stuart M. Grieve, Christopher Ward, Gemma A. Figtre

Endothelial cell dysfunction: Implications for the pathogenesis of peripheral artery disease

Peripheral artery disease (PAD) is caused by occluded or narrowed arteries that reduce blood flow to the lower limbs. The treatment focuses on lifestyle changes, management of modifiable risk factors and vascular surgery. In this review we focus on how Endothelial Cell (EC) dysfunction contributes to PAD pathophysiology and describe the largely untapped potential of correcting endothelial dysfunction. Moreover, we describe current treatments and clinical trials which improve EC dysfunction and offer insights into where future research efforts could be made. Endothelial dysfunction could represent a target for PAD therapy.Mary M. Kavurma, Christina Bursill, Christopher P. Stanley, Freda Passam, Siân P. Cartland, Sanjay Patel, Jacky Loa, Gemma A. Figtree, Jonathan Golledge, Sarah Aitken, and David A. Robinso

Patient endothelial colony-forming cells to model coronary artery disease susceptibility and unravel the role of dysregulated mitochondrial redox signalling

Mechanisms involved in the individual susceptibility to atherosclerotic coronary artery disease (CAD) beyond traditional risk factors are poorly understood. Here, we describe the utility of cultured patient-derived endothelial colony-forming cells (ECFCs) in examining novel mechanisms of CAD susceptibility, particularly the role of dysregulated redox signalling. ECFCs were selectively cultured from peripheral blood mononuclear cells from 828 patients from the BioHEART-CT cohort, each with corresponding demographic, clinical and CT coronary angiographic imaging data. Spontaneous growth occurred in 178 (21.5%) patients and was more common in patients with hypertension (OR 1.45 (95% CI 1.03–2.02), p = 0.031), and less likely in patients with obesity (OR 0.62 [95% CI 0.40–0.95], p = 0.027) or obstructive CAD (stenosis > 50%) (OR 0.60 [95% CI 0.38–0.95], p = 0.027). ECFCs from patients with CAD had higher mitochondrial production of superoxide (O2 −–MitoSOX assay). The latter was strongly correlated with the severity of CAD as measured by either coronary artery calcium score (R2 = 0.46; p = 0.0051) or Gensini Score (R2 = 0.67; p = 0.0002). Patient-derived ECFCs were successfully cultured in 3D culture pulsatile mini-vessels. Patient-derived ECFCs can provide a novel resource for discovering mechanisms of CAD disease susceptibility, particularly in relation to mitochondrial redox signalling.Marie Besnier, Meghan Finemore, Christine Yu, Katharine A. Kott, Stephen T. Vernon, Nicole A. Seebacher, Elijah Genetzakis, Anamarija Furman, Owen Tang, Ryan L. Davis, Thomas Hansen, Peter J. Psaltis, Kristen J. Bubb, Steven G. Wise, Stuart M. Grieve, Belinda A. Di Bartolo, and Gemma A. Figtre

Incorporating a polygenic risk score-triaged coronary calcium score into cardiovascular disease examinations to identify subclinical coronary artery disease (ESCALATE): Protocol for a prospective, nonrandomized implementation trial

Background: Identifying and targeting established modifiable risk factors has been a successful strategy for reducing the burden of coronary artery disease (CAD) at the population-level. However, up to 1-in-4 patients who present with ST elevation myocardial infarction do so in the absence of such risk factors. Polygenic risk scores (PRS) have demonstrated an ability to improve risk prediction models independent of traditional risk factors and self-reported family history, but a pathway for implementation has yet to be clearly identified. The aim of this study is to examine the utility of a CAD PRS to identify individuals with subclinical CAD via a novel clinical pathway, triaging low or intermediate absolute risk individuals for noninvasive coronary imaging, and examining the impact on shared treatment decisions and participant experience. Trial Design: The ESCALATE study is a 12-month, prospective, multicenter implementation study incorporating PRS into otherwise standard primary care CVD risk assessments, to identify patients at increased lifetime CAD risk for noninvasive coronary imaging. One-thousand eligible participants aged 45 to 65 years old will enter the study, which applies PRS to those considered low or moderate 5-year absolute CVD risk and triages those with CAD PRS ≥80% for a coronary calcium scan. The primary outcome will be the identification of subclinical CAD, defined as a coronary artery calcium score (CACS) >0 Agatston units (AU). Multiple secondary outcomes will be assessed, including baseline CACS ≥100 AU or ≥75th age-/sexmatched percentile, the use and intensity of lipid- and blood pressure-lowering therapeutics, cholesterol and blood pressure levels, and health-related quality of life (HRQOL). Conclusion: This novel trial will generate evidence on the ability of a PRS-triaged CACS to identify subclinical CAD, as well as subsequent differences in traditional risk factor medical management, pharmacotherapy utilization, and participant experience.Michael P. Gray, Yemima Berman, Giordano Bottà, Stuart M. Grieve, Amy Ho, Jessica Hu, Karice Hyun, Jodie Ingles, Garry Jennings, Gary Kilov, Jean-Frederic Levesque, Peter Meikle, Julie Redfern, Tim Usherwood, Stephen T. Vernon, Stephen J. Nicholls, and Gemma A. Figtree, On behalf of the PPP-CAD Collaborator

Taking the next steps to implement polygenic risk scoring for improved risk stratification and primary prevention of coronary artery disease

Coronary artery disease (CAD) remains the leading cause of death worldwide. The role of hypertension, cholesterol, diabetes mellitus, and smoking in driving disease has been well recognized at a population level and has been the target of primary prevention strategies for over 50 years with substantial impact. However, in many cases, these factors alone do not provide enough precision at the individual level to allow physicians and patients to take appropriate preventive measures and many patients continue to suffer acute coronary syndromes in the absence of these risk factors. Recent advances in user-friendly chip designs, high speed throughput, and economic efficiency of genome-wide association studies complemented by advances in statistical analytical approaches have facilitated the rapid development of polygenic risk scores (PRSs). The latest PRSs combine data regarding hundreds of thousands of single-nucleotide polymorphisms to predict chronic diseases including CAD. Novel CAD PRSs are strong predictors of risk and may have application, in a complementary manner with existing risk prediction algorithms. However, there remain substantial controversies, and ultimately, we need to move forward from observational studies to prospectively and rigorously assess the potential impact if widespread implementation is to be aspired to. Consideration needs to be made of ethnicity, sex, as well as age, and risk estimate based on existing non-genomic algorithms. We provide an overview and commentary on the important advances in deriving and validating PRSs, as well as pragmatic considerations that will be required for implementation of the new knowledge into clinical practice.Gemma Alexandra Figtree, Stephen Thomas Vernon, and Stephen James Nicholl

Truncated estrogen receptor alpha 46-kDa isoform in human endothelial cells: relationship to acute activation of nitric oxide synthase.

BACKGROUND: Estrogen acutely activates endothelial nitric oxide synthase (eNOS). However, the identity of the receptors involved in this rapid response remains unclear. METHODS AND RESULTS: We detected an estrogen receptor alpha (ERalpha) transcript in human endothelial cells that encodes a truncated 46-kDa ERalpha (Delta1a-hERalpha-46). A corresponding 46-kDa ERalpha protein was identified in endothelial cell lysates. Transfection of cDNAs encoding the full-length ERalpha (ERalpha-66) and Delta1a-hERalpha-46 resulted in appropriately sized recombinant proteins identified by anti-ERalpha antibodies. Confocal microscopy revealed that a proportion of both ERalpha-66 and hERalpha-46 was localized outside the nucleus and mediated specific cell-surface binding of estrogen as assessed by FITC-conjugated, BSA-estrogen binding studies. Both ERalpha isoforms colocalized with eNOS and mediated acute activation of eNOS in response to estrogen stimulation. However, estrogen-stimulated transcriptional activation mediated by Delta1a-hERalpha-46 was much less than with ERalpha-66. Furthermore, Delta1a-hERalpha-46 inhibited classical hERalpha-66-mediated transcriptional activation in a dominant-negative fashion. CONCLUSIONS: These findings suggest that expression of an alternatively spliced, truncated ERalpha isoform in human endothelial cells confers a unique ability to mediate acute but not transcriptional responses to estrogen

Comparison of two dimensional quantitative coronary angiography (2D-QCA) with optical coherence tomography (OCT) in the assessment of coronary artery lesion dimensions

There is limited data on how well 2D-QCA and OCT agree with each other for measurement of coronary artery lumen dimensions. We aimed to assess the agreement between the two modalities. Patients undergoing OCT for assessment of coronary artery lesions were reviewed. Minimum luminal diameter (MLD), proximal reference diameter and distal reference diameter were measured for each lesion prior to stenting. OCT was performed in 64 patients and 40 lesions were suitable for analysis. There was a good correlation for proximal and distal reference diameters (r = 0.86, p < 0.0001 and r = 0.92, p < 0.0001 respectively). There was good agreement on Bland–Altman analysis, the proximal and distal reference diameters measured by QCA were on average 0.09 mm (95% CI, − 0.52 to 0.53 mm) and 0.1 mm (95% CI, − 0.59 to 0.6 mm) smaller than OCT respectively. There was a satisfactory correlation (r = 0.63, p = < 0.0001) between QCA and OCT for MLD. However, the MLD by QCA was 0.49 mm (95% CI, − 1.57 to 0.59 mm) smaller than OCT, suggesting a poor agreement for MLD. There is a good correlation and agreement between QCA and OCT for measurement of proximal and distal reference diameters. However, the MLD was underestimated by QCA

Comparison of two dimensional quantitative coronary angiography (2D-QCA) with optical coherence tomography (OCT) in the assessment of coronary artery lesion dimensions

AbstractObjectivesThere is limited data on how well 2D-QCA and OCT agree with each other for measurement of coronary artery lumen dimensions. We aimed to assess the agreement between the two modalities.MethodsPatients undergoing OCT for assessment of coronary artery lesions were reviewed. Minimum luminal diameter (MLD), proximal reference diameter and distal reference diameter were measured for each lesion prior to stenting.ResultsOCT was performed in 64 patients and 40 lesions were suitable for analysis. There was a good correlation for proximal and distal reference diameters (r=0.86, p<0.0001 and r=0.92, p<0.0001 respectively). There was good agreement on Bland–Altman analysis; the proximal and distal reference diameters measured by QCA were on average 0.09mm (95% CI, −0.52 to 0.53mm) and 0.1mm (95% CI, −0.59 to 0.6mm) smaller than OCT respectively. There was a satisfactory correlation (r=0.63, p=<0.0001) between QCA and OCT for MLD. However, the MLD by QCA was 0.49mm (95% CI, −1.57 to 0.59mm) smaller than OCT, suggesting a poor agreement for MLD.ConclusionsThere is a good correlation and agreement between QCA and OCT for measurement of proximal and distal reference diameters. However, the MLD was underestimated by QCA