Improving prioritization processes for clinical practice guidelines: new methods and an evaluation from the National Heart Foundation of Australia.

BACKGROUND: Releasing timely and relevant clinical guidelines is challenging for organizations globally. Priority-setting is crucial, as guideline development is resource-intensive. Our aim, as a national organization responsible for developing cardiovascular clinical guidelines, was to develop a method for generating and prioritizing topics for future clinical guideline development in areas where guidance was most needed. METHODS: Several novel processes were developed, adopted and evaluated, including (1) initial public consultation for health professionals and the general public to generate topics; (2) thematic and qualitative analysis, according to the International Classification of Diseases (ICD-11), to aggregate topics; (3) adapting a criteria-based matrix tool to prioritize topics; (4) achieving consensus through a modified-nominal group technique and voting on priorities; and (5) process evaluation via survey of end-users. The latter comprised the organization's Expert Committee of 12 members with expertise across cardiology and public health, including two citizen representatives. RESULTS: Topics (n = 405; reduced to n = 278 when duplicates removed) were identified from public consultation responses (n = 107 respondents). Thematic analysis synthesized 127 topics that were then categorized into 37 themes using ICD-11 codes. Exclusion criteria were applied (n = 32 themes omitted), resulting in five short-listed topics: (1) congenital heart disease, (2) valvular heart disease, (3) hypercholesterolaemia, (4) hypertension and (5) ischaemic heart diseases and diseases of the coronary artery. The Expert Committee applied the prioritization matrix to all five short-listed topics during a consensus meeting and voted to prioritize topics. Unanimous consensus was reached for the topic voted the highest priority: ischaemic heart disease and diseases of the coronary arteries, resulting in the decision to update the organization's 2016 clinical guidelines for acute coronary syndromes. Evaluation indicated that initial public consultation was highly valued by the Expert Committee, and the matrix tool was easy to use and improved transparency in priority-setting. CONCLUSION: Developing a multistage, systematic process, incorporating public consultation and an international classification system led to improved transparency in our clinical guideline priority-setting processes and that topics chosen would have the greatest impact on health outcomes. These methods are potentially applicable to other national and international organizations responsible for developing clinical guidelines.

High intraluminal pressure promotes vascular inflammation via caveolin-1.

The aetiology and progression of hypertension involves various endogenous systems, such as the renin angiotensin system, the sympathetic nervous system, and endothelial dysfunction. Recent data suggest that vascular inflammation may also play a key role in the pathogenesis of hypertension. This study sought to determine whether high intraluminal pressure results in vascular inflammation. Leukocyte adhesion was assessed in rat carotid arteries exposed to 1 h of high intraluminal pressure. The effect of intraluminal pressure on signaling mechanisms including reactive oxygen species production (ROS), arginase expression, and NFĸB translocation was monitored. 1 h exposure to high intraluminal pressure (120 mmHg) resulted in increased leukocyte adhesion and inflammatory gene expression in rat carotid arteries. High intraluminal pressure also resulted in a downstream signaling cascade of ROS production, arginase expression, and NFĸB translocation. This process was found to be angiotensin II-independent and mediated by the mechanosensor caveolae, as caveolin-1 (Cav1)-deficient endothelial cells and mice were protected from pressure-induced vascular inflammatory signaling and leukocyte adhesion. Cav1 deficiency also resulted in a reduction in pressure-induced glomerular macrophage infiltration in vivo. These findings demonstrate Cav1 is an important mechanosensor in pressure-induced vascular and renal inflammation.

Change in Blood Pressure Variability Among Treated Elderly Hypertensive Patients and Its Association With Mortality.

Background Information is scarce regarding effects of antihypertensive medication on blood pressure variability (BPV) and associated clinical outcomes. We examined whether antihypertensive treatment changes BPV over time and whether such change (decline or increase) has any association with long-term mortality in an elderly hypertensive population. Methods and Results We used data from a subset of participants in the Second Australian National Blood Pressure study (n=496) aged ≥65 years who had 24-hour ambulatory blood pressure recordings at study entry (baseline) and then after a median of 2 years while on treatment (follow-up). Weighted day-night systolic BPV was calculated for both baseline and follow-up as a weighted mean of daytime and nighttime blood pressure standard deviations. The annual rate of change in BPV over time was calculated from these BPV estimates. Furthermore, we classified both BPV estimates as high and low based on the baseline median BPV value and then classified BPV changes into stable: low BPV, stable: high BPV, decline: high to low, and increase: low to high. We observed an annual decline (mean±SD: -0.37±1.95; 95% CI, -0.54 to -0.19; P<0.001) in weighted day-night systolic BPV between baseline and follow-up. Having constant stable: high BPV was associated with an increase in all-cause mortality (hazard ratio: 3.03; 95% CI, 1.67-5.52) and cardiovascular mortality (hazard ratio: 3.70; 95% CI, 1.62-8.47) in relation to the stable: low BPV group over a median 8.6 years after the follow-up ambulatory blood pressure monitoring. Similarly, higher risk was observed in the decline: high to low group. Conclusions Our results demonstrate that in elderly hypertensive patients, average BPV declined over 2 years of follow-up after initiation of antihypertensive therapy, and having higher BPV (regardless of any change) was associated with increased long-term mortality.

Y Chromosome, Hypertension and Cardiovascular Disease: Is Inflammation the Answer?

It is now becomingly increasingly evident that the functions of the mammalian Y chromosome are not circumscribed to the induction of male sex. While animal studies have shown variations in the Y are strongly accountable for blood pressure (BP), this is yet to be confirmed in humans. We have recently shown modulation of adaptive immunity to be a significant mechanism underpinning Y-chromosome-dependent differences in BP in consomic strains. This is paralleled by studies in man showing Y chromosome haplogroup is a significant predictor for coronary artery disease through influencing pathways of immunity. Furthermore, recent studies in mice and humans have shown that Y chromosome lineage determines susceptibility to autoimmune disease. Here we review the evidence in animals and humans that Y chromosome lineage influences hypertension and cardiovascular disease risk, with a novel focus on pathways of immunity as a significant pathway involved.

HDL Phospholipids, but Not Cholesterol Distinguish Acute Coronary Syndrome From Stable Coronary Artery Disease.

Background Although acute coronary syndromes (ACS) are a major cause of morbidity and mortality, relationships with biologically active lipid species potentially associated with plaque disruption/erosion in the context of their lipoprotein carriers are indeterminate. The aim was to characterize lipid species within lipoprotein particles which differentiate ACS from stable coronary artery disease. Methods and Results Venous blood was obtained from 130 individuals with de novo presentation of an ACS (n=47) or stable coronary artery disease (n=83) before coronary catheterization. Lipidomic measurements (533 lipid species; liquid chromatography electrospray ionization/tandem mass spectrometry) were performed on whole plasma as well as 2 lipoprotein subfractions: apolipoprotein A1 (apolipoprotein A, high-density lipoprotein) and apolipoprotein B. Compared with stable coronary artery disease, ACS plasma was lower in phospholipids including lyso species and plasmalogens, with the majority of lipid species differing in abundance located within high-density lipoprotein (high-density lipoprotein, 113 lipids; plasma, 73 lipids). Models including plasma lipid species alone improved discrimination between the stable and ACS groups by 0.16 (C-statistic) compared with conventional risk factors. Models utilizing lipid species either in plasma or within lipoprotein fractions had a similar ability to discriminate groups, though the C-statistic was highest for plasma lipid species (0.80; 95% CI, 0.75-0.86). Conclusions Multiple lysophospholipids, but not cholesterol, featured among the lipids which were present at low concentration within high-density lipoprotein of those presenting with ACS. Lipidomics, when applied to either whole plasma or lipoprotein fractions, was superior to conventional risk factors in discriminating ACS from stable coronary artery disease. These associative mechanistic insights elucidate potential new preventive, prognostic, and therapeutic avenues for ACS which require investigation in prospective analyses.

Sex-Specific Lifestyle and Biomedical Risk Factors for Chronic Disease among Early-Middle, Middle and Older Aged Australian Adults.

Evidence suggests age and sex differences in risk factors for chronic disease. This study examined lifestyle and biomedical risk factors among men (m) and women (w) in early-middle (25⁻51 years), middle (52⁻64) and older (65+) adulthood. Cross-sectional data from the 2011⁻2012 Australian Health Survey (n = 3024) were analysed. Self-reported dietary, activity, sleep behaviours and collected biomedical data were analysed. Early-middle adults failed to meet fruit, vegetable (95.3%) and sugar-sweetened beverage (SSB, 34.9%) recommendations. Older adults had higher prevalence of overweight/obesity (70%), high blood pressure (38.0%) and fewer met physical activity guidelines (36.3%). Prior to older adulthood, more men consumed SSBs (early-middle m 45.6%, w 24.4%; middle m 26.0%, w 19.3%), and fewer met sedentary behaviour recommendations (early-middle m 43.2%, w 62.1%; middle m 46.4%, w 63.9%). Differences in overweight/obese women in early-middle (44.8%) to middle adulthood (64.7%) were significant. Biomedical risk was greatest in middle age; abnormal cholesterol/lipids increased specifically for women (total cholesterol early-middle 24.9% middle 56.4%; abnormal LDL-cholesterol early-middle 23.1% middle 53.9%). Adherence to lifestyle guidelines was low; particularly among men. While men exhibited greater clinical risk overall, this significantly increased among women in middle-adulthood. Public health strategies to improve lifestyle, monitor and intervene among middle-aged women are warranted.

Between-meal sucrose-sweetened beverage consumption impairs glycaemia and lipid metabolism during prolonged sitting: A randomized controlled trial.

BACKGROUND & AIMS: Chronic overconsumption of sugar-sweetened beverages (SSBs) is associated with unfavourable health effects, including promotion of obesity. However, the acute effects of consuming SSBs on glucose and lipid metabolism remain to be characterized in a real-world, post-prandial context of prolonged sitting. We quantified the acute effects of between-meal SSB consumption compared with water, on glucose and lipid metabolism in habitual soft drink consumers during prolonged sitting. METHODS: Twenty-eight overweight or obese young adults [15 males; 23 ± 3 (mean ± SD) years, body mass index (BMI) 31.0 ± 3.6 kg/m2) participated. During uninterrupted sitting and following standardized breakfast and lunch meals, each participant completed two 7-h conditions on separate days in a randomized, crossover design study. For each condition, participants consumed either a sucrose SSB or water mid-morning and mid-afternoon. Peak responses and total area under the curve (tAUC) over 7 h for blood glucose, insulin, C-peptide, triglyceride and non-esterified fatty acid (NEFA) concentrations were quantified and compared. RESULTS: Compared to water, SSB consumption significantly increased the peak responses for blood glucose (20 ± 4% (mean ± SEM)), insulin (43 ± 15%) and C-peptide (21 ± 6%) concentrations. The tAUC for all these parameters was also increased by SSB consumption. The tAUC for triglycerides was 15 ± 5% lower after SSBs and this was driven by males (P < 0.05), as females showed no difference between conditions. The tAUC for NEFAs was 13 ± 5% lower after the SSB condition (P < 0.05). CONCLUSIONS: Between-meal SSB consumption significantly elevated plasma glucose responses, associated with a sustained elevation in plasma insulin throughout a day of prolonged sitting. The SSB-induced reduction in circulating triglycerides and NEFAs indicates significant modulation of lipid metabolism, particularly in males. These metabolic effects may contribute to the development of metabolic disease when SSB consumption is habitual and co-occurring with prolonged sitting. Clinical Trial Registry number: ACTRN12616000840482, https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12616000840482.

Effects of high- and low-dose aspirin on adaptive immunity and hypertension in the stroke-prone spontaneously hypertensive rat.

Despite its well-known antithrombotic properties, the effect of aspirin on blood pressure (BP) and hypertension pathology is unclear. The hugely varying doses used clinically have contributed to this confusion, with high-dose aspirin still commonly used due to concerns about the efficacy of low-dose aspirin. Because prostaglandins have been shown to both promote and inhibit T-cell activation, we also explored the immunomodulatory properties of aspirin in hypertension. Although the common preclinical high dose of 100 mg/kg/d improved vascular dysfunction and cardiac hypertrophy, this effect was accompanied by indices of elevated adaptive immunity, renal T-cell infiltration, renal fibrosis, and BP elevation in stroke-prone spontaneously hypertensive rats and in angiotensin II-induced hypertensive mice. The cardioprotective effects of aspirin were conserved with a lower dose (10 mg/kg/d) while circumventing heightened adaptive immunity and elevated BP. We also show that low-dose aspirin improves renal fibrosis. Differential inhibition of the COX-2 isoform may underlie the disparate effects of the 2 doses. Our results demonstrate the efficacy of low-dose aspirin in treating a vast array of cardiovascular parameters and suggest modulation of adaptive immunity as a novel mechanism underlying adverse cardiovascular profiles associated with COX-2 inhibitors. Clinical studies should identify the dose of aspirin that achieves maximal cardioprotection with a new awareness that higher doses of aspirin could trigger undesired autoimmunity in hypertensive individuals. This work also warrants an evaluation of high-dose aspirin and COX-2 inhibitor therapy in sufferers of inflammatory conditions who are already at increased risk for cardiovascular disease.-Khan, S. I., Shihata, W. A., Andrews, K. L., Lee, M. K. S., Moore, X.-L., Jefferis, A.-M., Vinh, A., Gaspari, T., Dragoljevic, D., Jennings, G. L., Murphy, A. J., Chin-Dusting, J. P. F. Effects of high- and low-dose aspirin on adaptive immunity and hypertension in the stroke-prone spontaneously hypertensive rat.

Relation of Alcohol Consumption to Risk of Heart Failure in Patients Aged 65 to 84 Years With Hypertension.

Although a high level of alcohol consumption is associated with cardiomyopathy, the benefit or risk of moderate alcohol consumption on incident heart failure (HF) is unknown. This study examined the association between alcohol consumption and risk for HF in older adults with hypertension. The study analyzed data from a cohort of 6,083 participants aged 65 to 84 years at baseline (1995 to 2001) followed for a median of 10.8 years during and after the Second Australian National Blood Pressure Study. Frequency and amount of alcohol consumption were self-reported at baseline and during the clinical trial. The percentages of current drinkers, former drinkers, and never-drinkers at baseline were 4,400 (72%), 394 (6%), and 1,289 (21%), respectively. Incident HF was diagnosed in 183 men and 136 women. After adjustment for multiple confounders, alcohol consumption was not significantly associated with HF. Compared with never-drinkers, the adjusted hazard ratios (95% confidence interval) for those who consume 1 to 7, 8 to 14, and >14 drinks/week at baseline were 0.87 (0.59 to 1.30), 0.96 (0.57 to 1.60), and 0.71 (0.25 to 2.02), respectively in women, and 0.81 (0.47 to 1.38), 0.77 (0.43 to 1.38), and 1.04 (0.59 to 1.84), respectively in men. The findings of lack of an association between alcohol consumption and risk of HF persisted in the analyses comparing the risk of HF across each level of drinking at baseline or at follow-up with never-drinkers. In the present study, there was no evidence for benefit or risk of alcohol consumption, reported at baseline or at follow-up, in relation to incident HF in both men and women.