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Oxidized LDL and Fructosamine Associated with Severity of Coronary Artery Atherosclerosis in Insulin Resistant Pigs Fed a High Fat/High NaCl Diet.

Nichols TC, Merricks EP, Bellinger DA, Raymer RA, Yu J, Lam D, Koch GG, Busby WH, Clemmons DR - PLoS ONE (2015)

Bottom Line: Insulin resistance was not associated with atherosclerosis severity.Five additional pigs fed regular pig chow also developed increased insulin resistance but essentially no change in the other variables and little to no detectible coronary atherosclerosis.In pigs fed a high fat/high NaCl diet, glycated proteins are induced in the absence of overt diabetes and this degree of increase is associated with the development of severe and diffuse distal coronary artery atherosclerosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

ABSTRACT

Background: Insulin-resistant subjects develop more severe and diffuse coronary artery atherosclerosis than insulin-sensitive controls but the mechanisms that mediate this atherosclerosis phenotype are unknown.

Research objective: To determine the metabolic parameters that associate with the severity of coronary atherosclerosis in insulin resistant pigs fed a high fat/high NaCl diet.

Key methods: The primary endpoint was severity of coronary atherosclerosis in adult pigs (Sus scrofa, n = 37) fed a high fat diet that also contained high NaCl (56% above recommended levels) for 1 year.

Principal findings: Twenty pigs developed severe and diffuse distal coronary artery atherosclerosis (i.e., severe = intimal area as a percent medial area > 200% in at least 2 coronary artery cross sections and diffuse distal = intimal area as a percent medial area ≥ 150% over 3 sections separated by 2 cm in the distal half of the coronary artery). The other 17 pigs had substantially less coronary artery atherosclerosis. All 37 pigs had blood pressure in a range that would be considered hypertensive in humans and developed elevations in total and LDL and HDL cholesterol, weight gain, increased backfat, and increased insulin resistance (Bergman Si) without overt diabetes. Insulin resistance was not associated with atherosclerosis severity. Five additional pigs fed regular pig chow also developed increased insulin resistance but essentially no change in the other variables and little to no detectible coronary atherosclerosis. Most importantly, the 20 high fat/high NaCl diet-fed pigs with severe and diffuse distal coronary artery atherosclerosis had substantially greater increases (p< 0.05) in oxidized LDL (oxLDL) and fructosamine consistent with increased protein glycation.

Conclusion: In pigs fed a high fat/high NaCl diet, glycated proteins are induced in the absence of overt diabetes and this degree of increase is associated with the development of severe and diffuse distal coronary artery atherosclerosis.

No MeSH data available.


Related in: MedlinePlus

Coronary Artery Atherosclerosis in Insulin Resistant Pigs.Panels A1 to A5: Representative serial sections from the proximal to distal left anterior descending coronary artery are shown from an IR pig with severe and diffuse distal coronary atherosclerosis. The mean intimal area as a percent of medial area for all three coronary arteries for this pig was 203.6% proximally and 338.5% distally. Panels B1 to B5: In contrast, a pig with moderate coronary atherosclerosis had a mean intimal area as a percent of medial area for all three coronary arteries of 11.3% proximally and 5.8% distally. Features of coronary atherosclerosis in rows A and B are shown at higher magnification in rows C and D, respectively: intimal thickening (IT) and calcification in a pig with moderate atherosclerosis (Ca2+ (moderate), Panels B1 and D1), calcification in a pig with severe atherosclerosis (Ca2+ (severe), Panels A4 and C2), fibrous cap (FC, Panel A2 and C1), hemorrhage into the plaque (H, Panels A4 and C3), medial thinning (MT, Panels A4 and D2), necrosis (N, Panels A4 and D3). (Hematoxylin and Eosin, mag bar = 500 μm is shown in B5 for rows A and B; mag bar = 10 μm in all panels in rows C and D).
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pone.0132302.g004: Coronary Artery Atherosclerosis in Insulin Resistant Pigs.Panels A1 to A5: Representative serial sections from the proximal to distal left anterior descending coronary artery are shown from an IR pig with severe and diffuse distal coronary atherosclerosis. The mean intimal area as a percent of medial area for all three coronary arteries for this pig was 203.6% proximally and 338.5% distally. Panels B1 to B5: In contrast, a pig with moderate coronary atherosclerosis had a mean intimal area as a percent of medial area for all three coronary arteries of 11.3% proximally and 5.8% distally. Features of coronary atherosclerosis in rows A and B are shown at higher magnification in rows C and D, respectively: intimal thickening (IT) and calcification in a pig with moderate atherosclerosis (Ca2+ (moderate), Panels B1 and D1), calcification in a pig with severe atherosclerosis (Ca2+ (severe), Panels A4 and C2), fibrous cap (FC, Panel A2 and C1), hemorrhage into the plaque (H, Panels A4 and C3), medial thinning (MT, Panels A4 and D2), necrosis (N, Panels A4 and D3). (Hematoxylin and Eosin, mag bar = 500 μm is shown in B5 for rows A and B; mag bar = 10 μm in all panels in rows C and D).

Mentions: At the end of the study, 20 pigs (6 males and 14 females) fed the high fat/high NaCl diet were found to have met the criteria for both severe and diffuse distal coronary atherosclerosis (Figs 2–4). The other 17 pigs (14 males and 3 females) also fed the same high fat/high NaCl diet had substantially less or moderate coronary atherosclerosis. When the extent of coronary atherosclerosis was compared between the severe and moderate atherosclerosis groups for the proximal and distal halves of the coronary arteries, the severe group had much larger intimal area, percent stenosis, and intimal area as a percent medial area (Figs 3 and 4 and Table 1, p < 0.001). In a logistic regression model that controlled for gender, severe and diffuse coronary atherosclerosis was associated with female pigs (p = 0.003). Such a model that controlled for genotype instead of gender indicated no association of normal versus heterozygous FH genotype with severity of atherosclerosis (p = 0.963). The 5 pigs fed regular, low fat pig chow had little to no detectible coronary atherosclerosis (Table 1).


Oxidized LDL and Fructosamine Associated with Severity of Coronary Artery Atherosclerosis in Insulin Resistant Pigs Fed a High Fat/High NaCl Diet.

Nichols TC, Merricks EP, Bellinger DA, Raymer RA, Yu J, Lam D, Koch GG, Busby WH, Clemmons DR - PLoS ONE (2015)

Coronary Artery Atherosclerosis in Insulin Resistant Pigs.Panels A1 to A5: Representative serial sections from the proximal to distal left anterior descending coronary artery are shown from an IR pig with severe and diffuse distal coronary atherosclerosis. The mean intimal area as a percent of medial area for all three coronary arteries for this pig was 203.6% proximally and 338.5% distally. Panels B1 to B5: In contrast, a pig with moderate coronary atherosclerosis had a mean intimal area as a percent of medial area for all three coronary arteries of 11.3% proximally and 5.8% distally. Features of coronary atherosclerosis in rows A and B are shown at higher magnification in rows C and D, respectively: intimal thickening (IT) and calcification in a pig with moderate atherosclerosis (Ca2+ (moderate), Panels B1 and D1), calcification in a pig with severe atherosclerosis (Ca2+ (severe), Panels A4 and C2), fibrous cap (FC, Panel A2 and C1), hemorrhage into the plaque (H, Panels A4 and C3), medial thinning (MT, Panels A4 and D2), necrosis (N, Panels A4 and D3). (Hematoxylin and Eosin, mag bar = 500 μm is shown in B5 for rows A and B; mag bar = 10 μm in all panels in rows C and D).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4492503&req=5

pone.0132302.g004: Coronary Artery Atherosclerosis in Insulin Resistant Pigs.Panels A1 to A5: Representative serial sections from the proximal to distal left anterior descending coronary artery are shown from an IR pig with severe and diffuse distal coronary atherosclerosis. The mean intimal area as a percent of medial area for all three coronary arteries for this pig was 203.6% proximally and 338.5% distally. Panels B1 to B5: In contrast, a pig with moderate coronary atherosclerosis had a mean intimal area as a percent of medial area for all three coronary arteries of 11.3% proximally and 5.8% distally. Features of coronary atherosclerosis in rows A and B are shown at higher magnification in rows C and D, respectively: intimal thickening (IT) and calcification in a pig with moderate atherosclerosis (Ca2+ (moderate), Panels B1 and D1), calcification in a pig with severe atherosclerosis (Ca2+ (severe), Panels A4 and C2), fibrous cap (FC, Panel A2 and C1), hemorrhage into the plaque (H, Panels A4 and C3), medial thinning (MT, Panels A4 and D2), necrosis (N, Panels A4 and D3). (Hematoxylin and Eosin, mag bar = 500 μm is shown in B5 for rows A and B; mag bar = 10 μm in all panels in rows C and D).
Mentions: At the end of the study, 20 pigs (6 males and 14 females) fed the high fat/high NaCl diet were found to have met the criteria for both severe and diffuse distal coronary atherosclerosis (Figs 2–4). The other 17 pigs (14 males and 3 females) also fed the same high fat/high NaCl diet had substantially less or moderate coronary atherosclerosis. When the extent of coronary atherosclerosis was compared between the severe and moderate atherosclerosis groups for the proximal and distal halves of the coronary arteries, the severe group had much larger intimal area, percent stenosis, and intimal area as a percent medial area (Figs 3 and 4 and Table 1, p < 0.001). In a logistic regression model that controlled for gender, severe and diffuse coronary atherosclerosis was associated with female pigs (p = 0.003). Such a model that controlled for genotype instead of gender indicated no association of normal versus heterozygous FH genotype with severity of atherosclerosis (p = 0.963). The 5 pigs fed regular, low fat pig chow had little to no detectible coronary atherosclerosis (Table 1).

Bottom Line: Insulin resistance was not associated with atherosclerosis severity.Five additional pigs fed regular pig chow also developed increased insulin resistance but essentially no change in the other variables and little to no detectible coronary atherosclerosis.In pigs fed a high fat/high NaCl diet, glycated proteins are induced in the absence of overt diabetes and this degree of increase is associated with the development of severe and diffuse distal coronary artery atherosclerosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

ABSTRACT

Background: Insulin-resistant subjects develop more severe and diffuse coronary artery atherosclerosis than insulin-sensitive controls but the mechanisms that mediate this atherosclerosis phenotype are unknown.

Research objective: To determine the metabolic parameters that associate with the severity of coronary atherosclerosis in insulin resistant pigs fed a high fat/high NaCl diet.

Key methods: The primary endpoint was severity of coronary atherosclerosis in adult pigs (Sus scrofa, n = 37) fed a high fat diet that also contained high NaCl (56% above recommended levels) for 1 year.

Principal findings: Twenty pigs developed severe and diffuse distal coronary artery atherosclerosis (i.e., severe = intimal area as a percent medial area > 200% in at least 2 coronary artery cross sections and diffuse distal = intimal area as a percent medial area ≥ 150% over 3 sections separated by 2 cm in the distal half of the coronary artery). The other 17 pigs had substantially less coronary artery atherosclerosis. All 37 pigs had blood pressure in a range that would be considered hypertensive in humans and developed elevations in total and LDL and HDL cholesterol, weight gain, increased backfat, and increased insulin resistance (Bergman Si) without overt diabetes. Insulin resistance was not associated with atherosclerosis severity. Five additional pigs fed regular pig chow also developed increased insulin resistance but essentially no change in the other variables and little to no detectible coronary atherosclerosis. Most importantly, the 20 high fat/high NaCl diet-fed pigs with severe and diffuse distal coronary artery atherosclerosis had substantially greater increases (p< 0.05) in oxidized LDL (oxLDL) and fructosamine consistent with increased protein glycation.

Conclusion: In pigs fed a high fat/high NaCl diet, glycated proteins are induced in the absence of overt diabetes and this degree of increase is associated with the development of severe and diffuse distal coronary artery atherosclerosis.

No MeSH data available.


Related in: MedlinePlus