Flavonols reduce aortic atherosclerosis lesion area in apolipoprotein E deficient mice: A systematic review and meta-analysis

<div><p>Diets rich in flavonoids have been reported to have beneficial effects in the primary prevention of cardiovascular events. There are limited data, however, on the cardiovascular benefits of purified flavonoids. The aim of this systematic review and meta-analysis was to examine the reported effects of isolated flavonoids on aortic atherosclerosis in a mouse model. Medline, Pubmed, Science direct and Web of Science were searched to identify studies which examined the effect of isolated flavonoids on aortic atherosclerosis in apolipoprotein E deficient mice. A meta-analysis was performed to determine the overall effect of the flavonoids, and sub-analyses were performed to compare the effects of the flavonols and flavan-3-ols. Eleven studies, which examined a total of 208 mice receiving a flavonoid and 126 control mice, were included. Overall the flavonoids significantly reduced aortic atherosclerosis (SMD 1.10, 95% CI 0.69, 1.51). Of the 18 flavonoid interventions examined 12 were flavonols and 3 were flavan-3-ols. Sub-analyses suggested that the flavonols (SMD 1.31, 95% CI 0.66, 1.91) but not the flavan-3-ols (SMD 0.33, 95% CI -0.19, 0.85) significantly decreased atherosclerosis area. Of the eleven studies, only one examined histological markers of atherosclerosis plaque stability. Most studies did not report blinding of outcome assessors or reproducibility of the primary outcome, and did not justify the sample size used and flavonoid dose administered. Based on the included studies, the flavonols appear to be the most effective flavonoids for reducing aortic atherosclerotic lesion area in apolipoprotein E deficient mice.</p></div

Effects of oxytocin and angiotensin II on mean arterial pressure and heart rate.

<p>Mean arterial blood pressure (mmHg) and heart rate (beats/min) after 1, 7 and 28 days of subcutaneous infusion of saline (control), low dose oxytocin (LDOT), high dose oxytocin (HDOT), angiotensin II (AngII), a combination of angiotensin II and low dose oxytocin (AngII + LDOT) or angiotensin II and high dose oxytocin (AngII + HDOT). Data represent medians with interquartile range (n = 5–8). Asterisks (*) indicate significant difference from the control group on the same day (* P<0.05, ** P<0.01). Clear bars represent saline, low dose oxytocin (LDOT) or high dose oxytocin (HDOT) controls, and filled bars represent angiotensin II, or a combination of angiotensin II and low or high dose oxytocin.</p

Effects of oxytocin on angiotensin II-induced renal damage.

<p>Representative Masson’s trichrome stained histological sections of the renal cortex and medulla showing effects of oxytocin on angiotensin II induced renal damage. Pathological changes in the kidney were assessed by histological evaluation of glomerular necrosis, tubular degeneration, necrosis and epithelial sloughing and interstitial fibrosis (‡), and vascular congestion and extravasation (†). The original magnification was x100. Changes in renal function due to intra-renal damage were also evaluated as plasma urea to creatinine ratio and creatinine clearance. Measurements were made 28 days following the infusion of saline (control), low dose oxytocin (LDOT), high dose oxytocin (HDOT), angiotensin II (AngII), a combination of angiotensin II and low dose oxytocin (AngII + LDOT), or angiotensin II and high dose oxytocin (AngII + HDOT). Data represent the mean ± SEM (n = 6) and asterisks (*) on bar graphs indicate significant difference from the control group (* P<0.05, ** P<0.01).</p

Effect of different flavonoids on atherosclerosis lesion area in ApoE^-/- mice and key aspects of the methods of the included studies.

<p>Effect of different flavonoids on atherosclerosis lesion area in ApoE^-/- mice and key aspects of the methods of the included studies.</p

Preferred Reporting Items of Systematic Review and Meta-analyses (PRISMA) flow diagram.

<p>A total of 1192 articles were identified from Science direct, Web of Science, Pubmed and Medline. Of these, 26 full-text articles were assessed for eligibility and 11 articles were included in the review. Eight studies were excluded as they did not measure atherosclerosis lesion area. One study was excluded as it administered a crude extract. Three studies were excluded because sample sizes could not be retrieved and three studies were excluded because of insufficient data for lesion area comparison. <i>From</i>: Mohar D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). <i>P</i>referred <i>R</i>eporting <i>I</i>tems for <i>S</i>ystematic Reviews and <i>M</i>eta-<i>A</i>nalyses: The PRISMA Statement. PLOS Med 6(7): e1000097. doi:<a href="https://doi.org/10.1371/journal.pmed1000097" target="_blank">10.1371/journal.pmed1000097</a> <b>For more information, visit</b> <a href="http://www.prisma-statement.org" target="_blank">www.prisma-statement.org</a>.</p

Effects of oxytocin on angiotensin II-induced cardiac hypertrophy.

<p>Representative hematoxylin and eosin stained histological sections of the interventricular septal wall of the heart (original magnification x400) showing changes in cardiac myocyte size, left ventricular mass and heart to body weight ratio. Left ventricular mass index and heart weight were quantified at day 21 and 28 respectively following the infusion of saline (control), low dose oxytocin (LDOT), high dose oxytocin (HDOT), angiotensin II (AngII), a combination of angiotensin II and low dose oxytocin (AngII + LDOT) or angiotensin II and high dose oxytocin (AngII + HDOT). Data on bar graphs represent mean ± SEM (n = 6–8). Asterisks (*) indicate significant difference from the control group (* P<0.05, ** P<0.01).</p

Forest plot showing the effects of flavonoids on atherosclerosis lesion area.

<p><b>Sub-analyses were performed to test the effect of flavonols, flavan-3-ols, isoflavones and flavone glycosides on atherosclerosis lesion area.</b> The meta-analysis included 11 studies and a total of 18 flavonoid comparisons. Comparisons were made using standard mean differences and a random effects model. SD, standard deviation; CI, confidence interval; Std, standard; EMIQ, enzymatically modified isoquercitrin; S, Aortic Sinus; T, Thoracic Aorta.</p

Effects of oxytocin and angiotensin II on systolic and diastolic blood pressure.

<p>Systolic and diastolic blood pressure (mmHg) after 1, 7 and 28 days of subcutaneous infusion of saline (control), low dose oxytocin (LDOT), high dose oxytocin (HDOT), angiotensin II (AngII), a combination of angiotensin II and low dose oxytocin (AngII + LDOT) or angiotensin II and high dose oxytocin (AngII + HDOT). Data represent medians with interquartile range (n = 5–8). Asterisks (*) indicate significant difference from the control group on the same day (* P<0.05, ** P<0.01). Clear bars represent saline, low dose oxytocin (LDOT) or high dose oxytocin (HDOT) controls, and filled bars represent angiotensin II, or a combination of angiotensin II and low or high dose oxytocin.</p

Effects of oxytocin and angiotensin II on plasma urea and creatinine concentrations, and plasma electrolytes and osmolality.

<p>Data represent mean ± SEM, n = 5–6 per group, asterisks (*) and bold indicate significant difference from control group (* P<0.05, ** P<0.01). LDOT, low dose oxytocin; HDOT, high dose oxytocin; AngII, angiotensin-II.</p><p>Effects of oxytocin and angiotensin II on plasma urea and creatinine concentrations, and plasma electrolytes and osmolality.</p

Effects of oxytocin and angiotensin II on plasma ANP and renin concentration.

<p>Plasma ANP and, prorenin and renin concentrations were quantified following the administration of saline (control), low dose oxytocin (LDOT), high dose oxytocin (HDOT), angiotensin II (AngII), a combination of angiotensin II and low dose oxytocin (AngII + LDOT) or angiotensin II and high dose oxytocin (AngII + HDOT) for 28 days. Data represent mean ± SEM (n = 5). Asterisks (*) indicate significant difference from the control group (* P<0.05, ** P<0.01).</p