The Effects of Exercise on Plaque Volume and Composition in a Mouse Model of Early and Late Life Atherosclerosis

Background: Exercise is associated with a less atherogenic lipid profile; however, there is limited research on the effect of exercise on atherosclerotic plaque composition and markers of plaque stability. Methods: A total of 110 apolipoprotein (apo)E −/− mice were placed on a chow diet and randomly assigned to control or exercise for a period of 10 weeks, commencing either at 12 weeks of age (the early-stage atherosclerosis, EA group) or at 40 weeks of age (the late-stage atherosclerosis, LA group). At the end of the exercise period, blood was assayed for lipids. Histologic analysis of the aortic sinus was undertaken to assess plaque size and composition that includes macrophage content, monocyte chemoattractant protein (MCP)-1, matrix metalloproteinase-2 (MMP-2), and tissue inhibitors of metalloproteinase 1 and 2 (TIMP-1 and 2). Results: A total of 103 mice (38 EA, 65 LA) completed the protocol. In the EA group, exercise reduced plasma total cholesterol (TC) (−16%), free cholesterol (−13%), triglyceride (TG) (−35%), and phospholipid (−27%) levels, when compared to sedentary control mice (p < 0.01). In the EA group, exercise also significantly reduced plaque stenosis (−25%, p < 0.01), and there were higher levels of elastin (3-fold increase, p < 0.0001) and collagen (11-fold increase, p < 0.0001) in plaques, compared to control mice. There was an increase in plaque MMP-2 content in the exercise group (13% increase, p < 0.05) but no significant difference in macrophage or MCP-1 content. In the LA group, exercise reduced plaque stenosis (−18%, p < 0.05), but there was no significant difference in plaque composition. There was no difference in macrophage, MCP-1, or MMP-2 content in the LA groups. TIMP-1 was lower with exercise in both the EA and LA groups (−59%, p < 0.01 and −51%, p < 0.01 respectively); however, there was no difference in TIMP-2 levels. Conclusion: A 10-week exercise period reduces atherosclerotic plaque stenosis when commenced at both early- and late-stage atherosclerosis. Intervening earlier with exercise had a greater beneficial effect on lipids and plaque composition than when starting exercise at a later disease stage.Kelly M. Stanton, Hongjuan Liu, Vivian Kienzle, Christina Bursill, Shisan Bao, and David S. Celermaje

Right ventricular myocardial deoxygenation in patients with pulmonary artery hypertension

Background: In pulmonary arterial hypertension (PAH), progressive right ventricular (RV) dysfunction is believed to be largely secondary to RV ischaemia. A recent pilot study has demonstrated the feasibility of Oxygen-sensitive (OS) cardiovascular magnetic resonance (CMR) to detect in-vivo RV myocardial oxygenation. The aims of the present study therefore, were to assess the prevalence of RV myocardial ischaemia and relationship with RV myocardial interstitial changes in PAH patients with non-obstructive coronaries, and corelate with functional and haemodynamic parameters. Methods: We prospectively recruited 42 patients with right heart catheter (RHC) proven PAH and 11 healthy age matched controls. The CMR examination involved standard functional imaging, OS-CMR imaging and native T1 mapping. An ΔOS-CMR signal intensity (SI) index (stress/rest signal intensity) was acquired at RV anterior, RV free-wall and RV inferior segments. T1 maps were acquired using Shortened Modified Look-Locker Inversion recovery (ShMOLLI) at the inferior RV segment. Results: The inferior RV ΔOS-CMR SI index was significantly lower in PAH patients compared with healthy controls (9.5 (– 7.4–42.8) vs 12.5 (9–24.6)%, p = 0.02). The inferior RV ΔOS-CMR SI had a significant correlation to RV inferior wall thickness (r = – 0.7, p < 0.001) and RHC mean pulmonary artery pressure (mPAP) (r = – 0.4, p = 0.02). Compared to healthy controls, patients with PAH had higher native T1 in the inferior RV wall: 1303 (1107–1612) vs 1232 (1159–1288) ms, p = 0.049. In addition, there was a significant difference in the inferior RV T1 values between the idiopathic PAH and systemic sclerosis associated PAH patients: 1242 (1107–1612) vs 1386 (1219–1552)ms, p = 0.007. Conclusion: Blunted OS-CMR SI suggests the presence of in-vivo microvascular RV dysfunction in PAH patients. The native T1 in the inferior RV segments is significantly increased in the PAH patients, particularly among the systemic sclerosis associated PAH group.Karthigesh Sree Raman, Ranjit Shah, Michael Stokes, Angela Walls, Richard J. Woodman, Rebecca Perry, Jennifer G. Walker, Susanna Proudman, Carmine G. De Pasquale, David S. Celermajer, and Joseph B. Selvanayaga

Therapeutic approaches in adults with congenital heart disease-associated pulmonary arterial hypertension

Pulmonary arterial hypertension is a major contributor to reduced functional capacity in patients with congenital heart disease. Expert care is essential. Whilst careful supportive management has traditionally been the mainstay for these patients, in recent times significant improvements in exercise capacity and even survival have been observed with the use of disease-targeted therapy, including endothelin receptor antagonists, phosphodiesterase inhibitors and prostanoids. In this review we will discuss current therapeutic options and summarise the recent literature on disease-targeted therapy

The emerging role of the contractile and vascular reserves in pulmonary arterial hypertension: From the authors

SCOPUS: le.jinfo:eu-repo/semantics/publishe

Diastolic dysfunction and mortality in 436 360 men and women: the National Echo Database Australia (NEDA).

Aims To examine the characteristics/prognostic impact of diastolic dysfunction (DD) according to 2016 American Society of Echocardiography (ASE) and European Society of Cardiovascular Imaging (ESCVI) guidelines, and individual parameters of DD. Methods and Results Data were derived from a large multicentre mortality-linked echocardiographic registry comprising 436 360 adults with ≥ 1 diastolic function measurement linked to 100 597 deaths during 2.2 million person-years follow-up. ASE/European Association of Cardiovascular Imaging (EACVI) algorithms could be applied in 392 009 (89.8%) cases; comprising 11.4% of cases with ‘reduced’ left ventricular ejection fraction (LVEF < 50%) and 88.6% with ‘preserved’ LVEF (≥50%). Diastolic function was indeterminate in 21.5% and 62.2% of ‘preserved’ and ‘reduced’ LVEF cases, respectively. Among preserved LVEF cases, the risk of adjusted 5-year cardiovascular-related mortality was elevated in both DD [odds ratio (OR) 1.31, 95% confidence interval (CI) 1.22–1.42; P < 0.001] and indeterminate status cases (OR 1.11, 95% CI 1.04–1.18; P < 0.001) vs. no DD. Among impaired LVEF cases, the equivalent risk of cardiovascular-related mortality was 1.51 (95% CI 1.15–1.98, P < 0.001) for increased filling pressure vs. 1.25 (95% CI 0.96–1.64, P = 0.06) for indeterminate status. Mitral E velocity, septal e’ velocity, E:e’ ratio, and LAVi all correlated with mortality. On adjusted basis, pivot-points of increased risk for cardiovascular-related mortality occurred at 90 cm/s for E wave velocity, 9 cm/s for septal e’ velocity, an E:e’ ratio of 9, and an LAVi of 32 mL/m2. Conclusion ASE/EACVI-classified DD is correlated with increased mortality. However, many cases remain ‘indeterminate’. Importantly, when analysed individually, mitral E velocity, septal e’ velocity, E:e’ ratio, and LAVi revealed clear pivot-points of increased risk of cardiovascular-related mortality.David Playford, Geoff Strange, David S Celermajer, Geoffrey Evans, Gregory M Scalia, Simon Stewart ... et al

Probucol inhibits in-stent thrombosis and neointimal hyperplasia by promoting re-endothelialization

BACKGROUND: Evidence suggests that delayed re-endothelialization is responsible for in-stent thrombosis. Probucol inhibits neointimal thickening in animals via enhanced re-endothelialization and is the only oral drug that consistently inhibits restenosis after coronary angioplasty in humans. Here, we examined the effects of probucol on re-endothelialization and neointimal formation in a stent model. METHODS AND RESULTS: New Zealand White rabbits were fed a hypercholesterolemic diet with probucol (1%) or without (control) (n=11 each) for 6 weeks. At 2 weeks, endothelial denudation and stenting of the iliac artery was performed. Iliac arteries were harvested at week 6, and stented segments sectioned and analyzed. Compared with control, probucol increased in-stent re-endothelialization (74+/-6% in controls versus 93+/-3% in probucol-treated; P=0.008), and decreased average luminal stenosis (58+/-27 versus 31+/-16%; P=0.01) and stent depth (619+/-310 versus 314+/-158mum; P=0.009). Compared with control, probucol also decreased accumulation of macrophages in the neointima. Furthermore, none of the probucol-treated rabbits had in-stent thrombosis, whereas four of eleven control rabbits showed thrombosis (P=0.04). CONCLUSIONS: Probucol demonstrates anti-restenotic and appears to have anti-thrombotic properties that are likely related to its ability to promote in-stent re-endothelialization

Effect of a periodontal intervention on pulse wave velocity in Indigenous Australians with periodontal disease: the PerioCardio randomized controlled trial

Abstract O162Introduction: Indigenous Australians have high rates of premature cardiovascular disease and high prevalence of periodontitis, an inflammatory disease of the tissues surrounding teeth. Periodontitis has been associated with arterial stiffening and incident cardiovascular events and. periodontal bacteria have been isolated from atheromatous plaques. If periodontitis contributes causally to cardiovascular disease, periodontal treatment may confer important benefits to the health of Indigenous Australians. Objectives: To determine if a single episode of periodontal treatment improved arterial stiffness in otherwise healthy Indigenous Australian adults. Methods: Participants were 273 Indigenous Australian adults (57% male; age 40.3years [SD 10.2]) with moderate or severe periodontal disease in the Northern Territory, Australia. Participants were randomized into intervention (n¼138) or control (n¼135) groups. The intervention involved removal of sub- and supra-gingival calculus and plaque biofilm by scaling and root-planing once, at randomization. Pulse wave velocity (PWV) was assessed by applanation tonometry (SphygmoCor- PVMx device, AtCor Medical, Sydney, Australia) between the carotid and dorsalis pedis arteries, at baseline and again 3-months (n¼169) and 12-months (n¼171) post randomization. Comparison of randomized groups was by complete case analysis using ANCOVA adjusted for baseline measures. Results: At baseline, the average carotid-dorsalis pedis PWV was 8.34 m/s (SD 1.25). The mean reduction in periodontal pocketing from enrollment to 3-months was 0.14 mm greater [95% CI 0.24 to 0.05] in the intervention group compared to control, P¼0.004). This was less marked at 12-months, mean reduction in periodontal pocketing 0.09 mm greater [95% CI -0.01 to 0.18] in the intervention versus control, P¼0.08). In contrast, the intervention did not affect PWV at 3-months [the primary endpoint] (between-group difference in means +0.06 m/s [95% CI -0.17 to 0.29] intervention vs. control, P ¼ 0.59), although there was some evidence that the intervention increased PWV at 12-months, this was not statistically significant (between-group difference in means +0.21 m/s [95% CI -0.01 to 0.43] intervention vs. control, P¼0.06). Conclusion: A single episode periodontal intervention in Indigenous Australians with periodontal disease provides short-term improvement in periodontal health, but did not significantly influence arterial stiffness as measured by pulse wave velocity. Disclosure of Interest: None DeclaredKostas Kapellas, Louise J. Maple-Brown, Peter M. Bartold, Alex Brown, Kerin O, Dea, Gary D. Slade, David S. Celermajer, Lisa M. Jamieson, Michael R. Skilton, on behalf of PerioCardio Stud