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Low-density lipoprotein-cholesterol lowering effect of a nutraceutical regimen with or without ezetimibe in hypercholesterolaemic patients with statin intolerance.
Ward, NC, Reid, CM, Watts, GF
Frontiers in cardiovascular medicine. 2022;:1060252
Abstract
BACKGROUND Statins are the most widely prescribed medication to lower low-density lipoprotein cholesterol (LDL-c). However, a significant portion of patients are unable to tolerate them due to side effects, most commonly muscle related. Nutraceuticals, natural plant derivatives with lipid-lowering properties, may provide an alternative to lower LDL-c in these patients. AIMS To investigate whether a nutraceutical regimen, either alone or in combination with ezetimibe, can lower LDL-c in patients with hypercholesterolemia who are intolerant to statins. METHODS Participants were recruited into a double-blind, randomized, placebo-controlled intervention study. Treatments were (i) placebo, (ii) nutraceutical (500 mg berberine, 200 mg red yeast rice (RYR), 2 g plant sterols)/daily, (iii) ezetimibe (10 mg)/daily, or (iv) the combination of nutraceutical and ezetimibe/daily. At baseline and week 8, all participants provide a fasting blood sample for assessment of lipid profile and safety bloods. RESULTS Fifty participants were randomized, with 44 completing the treatment period. Following adjustment for baseline levels and compared with placebo, LDL-c was significantly reduced (all p < 0.0001) with ezetimibe (-1.02 mmol/L), nutraceutical (-1.15 mmol/L) and the nutraceutical and ezetimibe combination (-1.92 mmol/L). Non-HDL cholesterol was significantly reduced (all p < 0.0001) with ezetimibe (-1.29 mmol/L), nutraceutical (-1.37 mmol/L) and the nutraceutical and ezetimibe combination (-2.18 mmol/L). Remnant cholesterol and triglycerides was significantly reduced with the nutraceutical and ezetimibe combination (p = 0.018). CONCLUSION A nutraceutical regimen (berberine, RYR and plant sterols) and ezetimibe independently and additively lower LDL-c in patients with hypercholesterolemia who are intolerant to statins.
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A Tale of Two New Targets for Hypertriglyceridaemia: Which Choice of Therapy?
Ward, NC, Chan, DC, Watts, GF
BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy. 2022;(2):121-135
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Abstract
Angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein C-III (apoC-III) are novel metabolic targets for correcting hypertriglyceridaemia (HTG). As a background to their potential clinical use, we review the metabolic aetiology of HTG, particular abnormalities in triglyceride-rich lipoproteins (TRLs) and their role in atherosclerotic cardiovascular disease (ASCVD) and acute pancreatitis. Molecular and cardiometabolic aspects of ANGPTL3 and apoC-III, as well as inhibition of these targets with monoclonal antibody and nucleic acid therapies, are summarized as background information to descriptions and analyses of recent clinical trials. These studies suggest that ANGPTL3 and apoC-III inhibitors are equally potent in lowering elevated plasma triglycerides and TRLs across a wide range of concentrations, with possibly greater efficacy with inhibition of apoC-III. ANGPTL3 inhibition may, however, have the advantage of greater lowering of plasma LDL cholesterol and could specifically address elevated LDL cholesterol in familial hypercholesterolaemia refractory to standard drug therapies. Large clinical outcome trials in relevant populations are still required to confirm the long-term efficacy, safety and cost effectiveness of these potent agents for mitigating the complications of HTG. Beyond targeting severe chylomicronaemia in the prevention of acute pancreatitis, both agents could be useful in addressing residual risk of ASCVD due to TRLs in patients receiving best standard of care, including behavioural modifications, statins, ezetimibe, fibrates and proprotein convertase subtilisin/kexin type 9 inhibitors.
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Anti-inflammatory effect of rosuvastatin in patients with HIV infection: An FDG-PET pilot study.
Boczar, KE, Faller, E, Zeng, W, Wang, J, Small, GR, Corrales-Medina, VF, deKemp, RA, Ward, NC, Beanlands, RSB, MacPherson, P, et al
Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology. 2022;(6):3057-3068
Abstract
AIMS: This study aimed to evaluate markers of systemic as well as imaging markers of inflammation in the ascending aorta, bone marrow, and spleen measured by 18F-FDG PET/CT, in HIV+ patients at baseline and following therapy with rosuvastatin. METHODS AND RESULTS Of the 35 HIV+ patients enrolled, 17 were randomized to treatment with 10 mg/day rosuvastatin and 18 to usual care for 6 months. An HIV- control cohort was selected for baseline comparison of serum inflammatory markers and monocyte markers of inflammation. 18F-FDG-PET/CT imaging of bone marrow, spleen, and thoracic aorta was performed in the HIV+ cohort at baseline and 6 months. While CD14++CD16- and CCR2 expressions were reduced, serum levels of IL-7, IL-8, and MCP-1 were elevated in the HIV+ population compared to the controls. There was a significant drop in FDG uptake in the bone marrow (TBRmax), spleen (SUVmax) and thoracic aortic (TBRmax) in the statin-treated group compared to the control group (bone marrow: - 10.3 ± 16.9% versus 5.0 ± 18.9%, p = .0262; spleen: - 9.8 ± 20.3% versus 11.3 ± 28.8%, p = .0497; thoracic aorta: - 19.1 ± 24.2% versus 4.3 ± 15.4%, p = .003). CONCLUSIONS HIV+ patients had significantly markers of systemic inflammation including monocyte activation. Treatment with low-dose rosuvastatin in the HIV+ cohort significantly reduced bone marrow, spleen and thoracic aortic FDG uptake.
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Quantifying dietary vitamin K and its link to cardiovascular health: a narrative review.
Palmer, CR, Blekkenhorst, LC, Lewis, JR, Ward, NC, Schultz, CJ, Hodgson, JM, Croft, KD, Sim, M
Food & function. 2020;(4):2826-2837
Abstract
Cardiovascular disease is the leading cause of death and disability worldwide. Recent work suggests a link between vitamin K insufficiency and deficiency with vascular calcification, a marker of advanced atherosclerosis. Vitamin K refers to a group of fat-soluble vitamins important for blood coagulation, reducing inflammation, regulating blood calcium metabolism, as well as bone metabolism, all of which may play a role in promoting cardiovascular health. Presently, there is a lack of a comprehensive vitamin K database on individual foods, which are required to accurately calculate vitamin K1 and K2 intake for examination in epidemiological studies. This has likely contributed to ambiguity regarding the recommended daily intake of vitamin K, including whether vitamin K1 and K2 may have separate, partly overlapping functions. This review will discuss the presence of: (i) vitamin K1 and K2 in the diet; (ii) the methods of quantitating vitamin K compounds in foods; and (iii) provide an overview of the evidence for the cardiovascular health benefits of vitamin K in observational and clinical trials.
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The effects of vitamin K-rich green leafy vegetables on bone metabolism: A 4-week randomised controlled trial in middle-aged and older individuals.
Sim, M, Lewis, JR, Prince, RL, Levinger, I, Brennan-Speranza, TC, Palmer, C, Bondonno, CP, Bondonno, NP, Devine, A, Ward, NC, et al
Bone reports. 2020;:100274
Abstract
BACKGROUND High vegetable intake is associated with beneficial effects on bone. However, the mechanisms remain uncertain. Green leafy vegetables are a rich source of vitamin K1, which is known to have large effects on osteoblasts and osteocalcin (OC) metabolism. OBJECTIVE To examine the effects of consumption of two to three extra serves of green leafy vegetables daily on bone metabolism. METHODS Thirty individuals (mean age 61.8 ± 9.9 years, 67% male) completed three experimental phases in a randomised controlled crossover design, each lasting four weeks, with a washout period of four weeks between phases (clinical trial registration: ACTRN12615000194561). The three experimental phases were: (i) increased dietary vitamin K1 by consuming green leafy vegetables (H-K; ~200 g/d containing 164.3 [99.5-384.7] μg/d of vitamin K1); (ii) low vitamin K1 by consuming vitamin K1-poor vegetables (L-K; ~200 g/d containing 9.4 [7.7-11.6] μg/d of vitamin K1); and (iii) control (CON) where participants consumed an energy-matched non-vegetable control. OC forms, total OC (tOC), carboxylated OC (cOC) and undercarboxylated OC (ucOC), were measured in serum pre- and post-intervention for each experimental phase using a sandwich-electrochemiluminescence immunoassay. RESULTS Pre-intervention tOC, ucOC and ucOC:tOC levels were similar between phases (P > .05). Following H-K, but not L-K, tOC, ucOC and ucOC:tOC levels were significantly lower compared to pre-intervention levels (P ≤ .001) and compared to CON (~14%, 31% and 19%, respectively, all P < .05), while cOC remained unchanged. CONCLUSIONS In middle-aged healthy men and women, an easily achieved increase in dietary intake of vitamin K1-rich green leafy vegetables substantially reduces serum tOC and ucOC suggesting increased entry of OC into bone matrix, where it may improve the material property of bone. In conjunction with previous epidemiological and randomised controlled trial data, these findings suggest that interventions to increase vegetable intake over extended periods should include bone end points including fracture risk.
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The effect of regular consumption of lupin-containing foods on glycaemic control and blood pressure in people with type 2 diabetes mellitus.
Ward, NC, Mori, TA, Beilin, LJ, Johnson, S, Williams, C, Gan, SK, Puddey, IB, Woodman, R, Phillips, M, Connolly, E, et al
Food & function. 2020;(1):741-747
Abstract
BACKGROUND Type 2 diabetes mellitus is a metabolic disorder characterized by high glucose and insulin resistance. It is strongly linked to lifestyle, including poor diet and physical inactivity. Lupin is a novel food ingredient, rich in protein and fibre with negligible sugar and starch, which can be incorporated into various foods to reduce glycaemic load. Regular consumption of lupin-enriched foods may be a novel and easily achievable means of reducing overall glycaemic load and improving glycaemic control in diabetes. OBJECTIVE To determine whether regular consumption of lupin-enriched foods can improve glycaemic control and lower blood pressure in people with type 2 diabetes mellitus. DESIGN Fourteen men and 8 women (mean age 58.0 ± 6.6 years and BMI 29.0 ± 3.5 kg m-2) with type 2 diabetes mellitus were recruited from the general population to take part in a double-blind, randomised, controlled cross-over study. Participants consumed lupin or control foods for breakfast and lunch every day, and for dinner at least 3 days per week during the 8-week treatment periods. Lupin-enriched foods consisted of bread, pasta, Weetbix™ cereal and crumbs, with energy-matched control products. Treatments were completed in random order with an 8-week washout period. All participants monitored their blood glucose levels pre- and post-breakfast and lunch, and their blood pressure in the morning and evening, 3 days per week for the duration of each treatment period. RESULTS Seventeen participants completed both treatment arms, with all 22 participants (14 males, 8 females) analysed on an intention-to-treat basis. Eight weeks consumption of lupin-enriched food had no significant effect on mean blood glucose levels (mean difference: -0.08 ± 0.06 mmol L-1, p = 0.214) or post-prandial blood glucose levels (-0.13 ± 0.10 mmol L-1, p = 0.196). There was no effect on home systolic (-0.4 ± 0.4 mmHg, p = 0.33) or diastolic (0.3 ± 0.3 mmHg, p = 0.321) blood pressure and heart rate (0.5 ± 0.3 bpm, p = 0.152), and no effect on body weight throughout the treatment periods. CONCLUSION Regular consumption of lupin-enriched foods had no significant effect on glycaemic control or blood pressure in people with type 2 diabetes mellitus.
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Clinical guidance on the contemporary use of proprotein convertase subtilisin/kexin type 9 monoclonal antibodies.
Ward, NC, Page, MM, Watts, GF
Diabetes, obesity & metabolism. 2019;:52-62
Abstract
There is now significant evidence for the benefits of lowering low-density lipoprotein cholesterol (LDL-c) to reduce the risk of atherosclerotic cardiovascular disease (ASCVD). Although statins are the most widely prescribed lipid-lowering therapy that effectively lower LDL-c, especially in combination with ezetimibe, some patients require adjunctive therapy to further lower LDL-c and mitigate attendant risk of ASCVD. The gap can be filled by proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies whose use is currently supported by two recent cardiovascular outcome studies and new treatment guidelines. We provide an overview of extant studies investigating PCSK9 monoclonal antibodies in various patient populations, an update of the guidelines regarding their use and a case-based discussion.
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Vegetable Nitrate Intakes Are Associated with Reduced Self-Reported Cardiovascular-Related Complications within a Representative Sample of Middle-Aged Australian Women, Prospectively Followed up for 15 Years.
Jackson, JK, Patterson, AJ, MacDonald-Wicks, LK, Forder, PM, Blekkenhorst, LC, Bondonno, CP, Hodgson, JM, Ward, NC, Holder, C, Oldmeadow, C, et al
Nutrients. 2019;(2)
Abstract
Nitric oxide (NO) facilitates anti-atherosclerotic effects. Vegetables are a major source of dietary nitrate. Experimental data indicates that dietary nitrate can significantly reduce major risk factors for atherosclerosis and subsequent cardiovascular disease (CVD), as nitrate can be metabolized to produce NO via the nitrate-nitrite-NO pathway. The purpose of this study was to prospectively investigate the association between habitual dietary nitrate intakes and the incidence of self-reported CVD-related complications within a representative sample of middle-aged Australian women (1946⁻1951 cohort of the Australian Longitudinal Study on Women's Health). Women free from disease at baseline who had completed the food frequency questionnaire data were included. Generalized estimating equations were used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) across quartiles for nitrate intakes. Of the 5324 women included for analysis, there were 1951 new cases of CVD-related complications over 15-years of follow-up. Women reporting higher total dietary nitrate intakes (Q4 > 78.2 mg/day) and vegetable nitrate intakes (Q4 > 64.4 mg/day) were 25% and 27% reduced risk of developing CVD-related complications respectively, compared with women reporting low total (Q1 < 45.5 mg/day) and vegetable nitrate intakes (Q1 < 34.8 mg/day). Our findings were consistent with other observational data indicating that dietary nitrate may explain some of the cardiovascular benefits of vegetable consumption.
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Vegetable-derived bioactive nitrate and cardiovascular health.
Bondonno, CP, Blekkenhorst, LC, Liu, AH, Bondonno, NP, Ward, NC, Croft, KD, Hodgson, JM
Molecular aspects of medicine. 2018;:83-91
Abstract
Vegetable derived nitrate is now recognised as an important bioactive phytochemical with cardioprotective properties. Nitrate, through the recently described enterosalivary nitrate-nitrite-nitric oxide (NO) pathway, increases NO, a molecule pivotal for cardiovascular health. Clinical trials have observed that dietary nitrate has similar effects to NO when supplied exogenously. These effects include reduced blood pressure and improvements in other markers of vascular health such as endothelial function, arterial stiffness, ischemia reperfusion injury, blood flow, and platelet aggregation. Few observational studies, however, have examined dietary nitrate intake and long term cardiovascular health outcomes. This represents a significant gap in the literature. There is also a lingering concern about a possible carcinogenic effect of nitrate intake. Additionally, a number of potential factors that could impact nitrate to nitrite to NO reduction have been identified. This review will provide an overview of the evidence to date that nitrate, through its effects on endogenous NO and vascular health, is an important bioactive cardioprotective component of a diet rich in vegetables.
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Nitrate-rich vegetables do not lower blood pressure in individuals with mildly elevated blood pressure: a 4-wk randomized controlled crossover trial.
Blekkenhorst, LC, Lewis, JR, Prince, RL, Devine, A, Bondonno, NP, Bondonno, CP, Wood, LG, Puddey, IB, Ward, NC, Croft, KD, et al
The American journal of clinical nutrition. 2018;(6):894-908
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Abstract
BACKGROUND Emerging evidence suggests that increasing intakes of nitrate-rich vegetables may be an effective approach to reduce blood pressure. OBJECTIVE Our primary aim was to determine whether daily consumption of nitrate-rich vegetables over 4 wk would result in lower blood pressure. DESIGN Thirty participants with prehypertension or untreated grade 1 hypertension were recruited to a randomized controlled crossover trial with 4-wk treatment periods separated by 4-wk washout periods. Participants completed 3 treatments in random order: 1) increased intake (∼200 g/d) of nitrate-rich vegetables [high-nitrate (HN); ∼150 mg nitrate/d], 2) increased intake (∼200 g/d) of nitrate-poor vegetables [low-nitrate (LN); ∼22 mg nitrate/d], and 3) no increase in vegetables (control; ∼6 mg nitrate/d). Compliance was assessed with the use of food diaries and by measuring plasma nitrate and carotenoids. Nitrate metabolism was assessed with the use of plasma, salivary, and urinary nitrate and nitrite concentrations. The primary outcome was blood pressure assessed by using 24-h ambulatory, home, and clinic measurements. Secondary outcomes included measures of arterial stiffness. RESULTS Plasma nitrate and nitrite concentrations increased with the HN treatment in comparison to the LN and control treatments (P < 0.001). Plasma carotenoids increased with the HN and LN treatments compared with the control (P < 0.01). HN treatment did not reduce systolic blood pressure [24-h ambulatory-HN: 127.4 ± 1.1 mm Hg; LN: 128.6 ± 1.1 mm Hg; control: 126.2 ± 1.1 mm Hg (P = 0.20); home-HN: 127.4 ± 0.7 mm Hg; LN: 128.7 ± 0.7 mm Hg; control: 128.3 ± 0.7 mm Hg (P = 0.36); clinic-HN: 128.4 ± 1.3 mm Hg; LN: 130.3 ± 1.3 mm Hg; control: 129.8 ± 1.3 mm Hg (P = 0.49)] or diastolic blood pressure compared with LN and control treatments (P > 0.05) after adjustment for pretreatment values, treatment period, and treatment order. Similarly, no differences were observed between treatments for arterial stiffness measures (P > 0.05). CONCLUSION Increased intake of nitrate-rich vegetables did not lower blood pressure in prehypertensive or untreated grade 1 hypertensive individuals when compared with increased intake of nitrate-poor vegetables and no increase in vegetables. This trial was registered at www.anzctr.org.au as ACTRN12615000194561.