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Simvastatin mitigates increases in risk factors for and the occurrence of cardiac disease following 10 Gy total body irradiation.

Lenarczyk M, Su J, Haworth ST, Komorowski R, Fish BL, Migrino RQ, Harmann L, Hopewell JW, Kronenberg A, Patel S, Moulder JE, Baker JE - Pharmacol Res Perspect (2015)

Bottom Line: TBI resulted in a sustained increase in total- and LDL-cholesterol (low-density lipoprotein-cholesterol), and triglycerides.TBI resulted in cellular peri-arterial fibrosis, whereas control hearts had less collagen and fibrosis.Simvastatin mitigated the severity of this myocardial infarction at 20 and 80 days following TBI.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiothoracic Surgery, Medical College of Wisconsin Milwaukee, Wisconsin.

ABSTRACT
The ability of simvastatin to mitigate the increases in risk factors for and the occurrence of cardiac disease after 10 Gy total body irradiation (TBI) was determined. This radiation dose is relevant to conditioning for stem cell transplantation and threats from radiological terrorism. Male rats received single dose TBI of 10 Gy. Age-matched, sham-irradiated rats served as controls. Lipid profile, heart and liver morphology and cardiac mechanical function were determined for up to 120 days after irradiation. TBI resulted in a sustained increase in total- and LDL-cholesterol (low-density lipoprotein-cholesterol), and triglycerides. Simvastatin (10 mg/kg body weight/day) administered continuously from 9 days after irradiation mitigated TBI-induced increases in total- and LDL-cholesterol and triglycerides, as well as liver injury. TBI resulted in cellular peri-arterial fibrosis, whereas control hearts had less collagen and fibrosis. Simvastatin mitigated these morphological injuries. TBI resulted in cardiac mechanical dysfunction. Simvastatin mitigated cardiac mechanical dysfunction 20-120 days following TBI. To determine whether simvastatin affects the ability of the heart to withstand stress after TBI, injury from myocardial ischemia/reperfusion was determined in vitro. TBI increased the severity of an induced myocardial infarction at 20 and 80 days after irradiation. Simvastatin mitigated the severity of this myocardial infarction at 20 and 80 days following TBI. It is concluded simvastatin mitigated the increases in risk factors for cardiac disease and the extent of cardiac disease following TBI. This statin may be developed as a medical countermeasure for the mitigation of radiation-induced cardiac disease.

No MeSH data available.


Related in: MedlinePlus

Simvastatin mitigates cardiac ventricular dysfunction. Cardiac mechanical function at 20, 80 and 120 days after 10 Gy TBI alone (blue), 10 Gy TBI plus simvastatin (10 mg/kg bw/day) (red), and simvastatin (10 mg/kg bw/day) alone (green) compared with age-matched, sham-irradiated control (black). Data shown as means + SD, n = 3–6/group. *P < 0.05 vs. control. TBI, total body irradiation.
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fig05: Simvastatin mitigates cardiac ventricular dysfunction. Cardiac mechanical function at 20, 80 and 120 days after 10 Gy TBI alone (blue), 10 Gy TBI plus simvastatin (10 mg/kg bw/day) (red), and simvastatin (10 mg/kg bw/day) alone (green) compared with age-matched, sham-irradiated control (black). Data shown as means + SD, n = 3–6/group. *P < 0.05 vs. control. TBI, total body irradiation.

Mentions: To determine whether TBI resulted in mechanical injury to the heart, global radial and circumferential strains were determined using 2D echocardiography in intact rats. At 20 days after TBI, hearts had a significantly increased global radial strain and circumferential strain compared with age-matched controls (Fig.5). Administration of simvastatin after TBI mitigated this effect. Simvastatin alone had no effect on mechanical function. At 80 days after TBI, hearts showed reduced global radial strain and circumferential strain compared with age-matched controls (Fig.5). Simvastatin mitigated this reduction in radial and circumferential strain following TBI. Simvastatin alone decreased global circumferential strain after 80 days. At 120 days after TBI, global radial and circumferential strain was decreased to a greater extent than observed at 80 days. Simvastatin administered after TBI again mitigated this decrease in cardiac function at 120 days. Simvastatin alone increased radial and circumferential strain in nonirradiated rat hearts (Fig.5).


Simvastatin mitigates increases in risk factors for and the occurrence of cardiac disease following 10 Gy total body irradiation.

Lenarczyk M, Su J, Haworth ST, Komorowski R, Fish BL, Migrino RQ, Harmann L, Hopewell JW, Kronenberg A, Patel S, Moulder JE, Baker JE - Pharmacol Res Perspect (2015)

Simvastatin mitigates cardiac ventricular dysfunction. Cardiac mechanical function at 20, 80 and 120 days after 10 Gy TBI alone (blue), 10 Gy TBI plus simvastatin (10 mg/kg bw/day) (red), and simvastatin (10 mg/kg bw/day) alone (green) compared with age-matched, sham-irradiated control (black). Data shown as means + SD, n = 3–6/group. *P < 0.05 vs. control. TBI, total body irradiation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492761&req=5

fig05: Simvastatin mitigates cardiac ventricular dysfunction. Cardiac mechanical function at 20, 80 and 120 days after 10 Gy TBI alone (blue), 10 Gy TBI plus simvastatin (10 mg/kg bw/day) (red), and simvastatin (10 mg/kg bw/day) alone (green) compared with age-matched, sham-irradiated control (black). Data shown as means + SD, n = 3–6/group. *P < 0.05 vs. control. TBI, total body irradiation.
Mentions: To determine whether TBI resulted in mechanical injury to the heart, global radial and circumferential strains were determined using 2D echocardiography in intact rats. At 20 days after TBI, hearts had a significantly increased global radial strain and circumferential strain compared with age-matched controls (Fig.5). Administration of simvastatin after TBI mitigated this effect. Simvastatin alone had no effect on mechanical function. At 80 days after TBI, hearts showed reduced global radial strain and circumferential strain compared with age-matched controls (Fig.5). Simvastatin mitigated this reduction in radial and circumferential strain following TBI. Simvastatin alone decreased global circumferential strain after 80 days. At 120 days after TBI, global radial and circumferential strain was decreased to a greater extent than observed at 80 days. Simvastatin administered after TBI again mitigated this decrease in cardiac function at 120 days. Simvastatin alone increased radial and circumferential strain in nonirradiated rat hearts (Fig.5).

Bottom Line: TBI resulted in a sustained increase in total- and LDL-cholesterol (low-density lipoprotein-cholesterol), and triglycerides.TBI resulted in cellular peri-arterial fibrosis, whereas control hearts had less collagen and fibrosis.Simvastatin mitigated the severity of this myocardial infarction at 20 and 80 days following TBI.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiothoracic Surgery, Medical College of Wisconsin Milwaukee, Wisconsin.

ABSTRACT
The ability of simvastatin to mitigate the increases in risk factors for and the occurrence of cardiac disease after 10 Gy total body irradiation (TBI) was determined. This radiation dose is relevant to conditioning for stem cell transplantation and threats from radiological terrorism. Male rats received single dose TBI of 10 Gy. Age-matched, sham-irradiated rats served as controls. Lipid profile, heart and liver morphology and cardiac mechanical function were determined for up to 120 days after irradiation. TBI resulted in a sustained increase in total- and LDL-cholesterol (low-density lipoprotein-cholesterol), and triglycerides. Simvastatin (10 mg/kg body weight/day) administered continuously from 9 days after irradiation mitigated TBI-induced increases in total- and LDL-cholesterol and triglycerides, as well as liver injury. TBI resulted in cellular peri-arterial fibrosis, whereas control hearts had less collagen and fibrosis. Simvastatin mitigated these morphological injuries. TBI resulted in cardiac mechanical dysfunction. Simvastatin mitigated cardiac mechanical dysfunction 20-120 days following TBI. To determine whether simvastatin affects the ability of the heart to withstand stress after TBI, injury from myocardial ischemia/reperfusion was determined in vitro. TBI increased the severity of an induced myocardial infarction at 20 and 80 days after irradiation. Simvastatin mitigated the severity of this myocardial infarction at 20 and 80 days following TBI. It is concluded simvastatin mitigated the increases in risk factors for cardiac disease and the extent of cardiac disease following TBI. This statin may be developed as a medical countermeasure for the mitigation of radiation-induced cardiac disease.

No MeSH data available.


Related in: MedlinePlus