Cyclosporine attenuates pressure-overload hypertrophy in mice while enhancing susceptibility to decompensation and heart failure

Tomomi Meguro, Chull Hong, Kuniya Asai, Gen Takagi, Timothy A. McKinsey, Eric N. Olson, Stephen F. Vatner

Research output: Contribution to journalArticle

143 Citations (Scopus)

Abstract

Left ventricular hypertrophy (LVH) is a compensatory mechanism to cope with pressure overload. Recently, a calcineurin pathway mediating LVH and its prevention by cyclosporine was reported. We examined whether calcineurin mediates LVH due to pressure overload in mice. Pressure overload was induced by aortic banding in 53 mice (32 treated with cyclosporine [25 mg · kg-1 · d-1], 21 treated with vehicle). There were 17 sham-operated mice (9 treated with vehicle, 8 treated with cyclosporine). At 3 weeks after surgery, LV weight to body weight was greater in the nontreatment banded group (4.39 ± 0.16 mg/g) than in the cyclosporine-treated banded group (3.95±0.14 mg/g, P<0.05), with both groups being greater compared with the entire group of sham-operated mice (3.02±0.04 mg/g). The pressure gradient between the ascending and abdominal aorta was not different between the cyclosporine- treated (49.6±6.1 mm Hg) and nontreatment groups (48.7±4.6 mm Hg). Although LV systolic pressure was lower in the cyclosporine-treated banded animals, LV systolic wall stress was similar in the nontreatment banded group and in the cyclosporine-treated group. However, LV dP/dt was lower (P=0.05) in the cyclosporine-treated banded group (4774±656 mm Hg/s) than in the nontreatment banded group (6604±516 mm Hg/s). During the protocol, 23 of 32 mice in the cyclosporine-treated group and 9 of 21 mice in the nontreatment group died. All deaths occurred within 10 days after surgery. Deaths caused by heart failure were 7.2-fold higher (P<0.05) in the cyclosporine-treated group, whereas deaths due to other causes were not different between the 2 groups. In addition, LV function of mice was assessed at 48 hours after banding; LV ejection fraction measured with echocardiography was lower (P<0.05) in the cyclosporine-treated banded group (66±3.0%) than in the nontreatment banded group (79±1.5%), whereas LV systolic wall stresses were similar. Calcineurin phosphatase activity was depressed similarly in both cyclosporine-treated groups compared with both nontreatment groups. Thus, cyclosporine could attenuate, but not prevent, LVH at the expense of inhibiting an important compensatory mechanism in response to pressure overload, resulting in reduced LV wall stress and function and increased susceptibility to decompensation and heart failure.

Original languageEnglish (US)
Pages (from-to)735-740
Number of pages6
JournalCirculation Research
Volume84
Issue number6
StatePublished - Apr 2 1999

Fingerprint

Hypertrophy
Cyclosporine
Heart Failure
Pressure
Left Ventricular Hypertrophy
Calcineurin
Abdominal Aorta
Ambulatory Surgical Procedures
Echocardiography
Aorta
Body Weight
Blood Pressure
Weights and Measures

Keywords

  • Aortic banding
  • Ca
  • Calcineurin
  • Left ventricular hypertrophy

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Cyclosporine attenuates pressure-overload hypertrophy in mice while enhancing susceptibility to decompensation and heart failure. / Meguro, Tomomi; Hong, Chull; Asai, Kuniya; Takagi, Gen; McKinsey, Timothy A.; Olson, Eric N.; Vatner, Stephen F.

In: Circulation Research, Vol. 84, No. 6, 02.04.1999, p. 735-740.

Research output: Contribution to journalArticle

Meguro, T, Hong, C, Asai, K, Takagi, G, McKinsey, TA, Olson, EN & Vatner, SF 1999, 'Cyclosporine attenuates pressure-overload hypertrophy in mice while enhancing susceptibility to decompensation and heart failure', Circulation Research, vol. 84, no. 6, pp. 735-740.
Meguro, Tomomi ; Hong, Chull ; Asai, Kuniya ; Takagi, Gen ; McKinsey, Timothy A. ; Olson, Eric N. ; Vatner, Stephen F. / Cyclosporine attenuates pressure-overload hypertrophy in mice while enhancing susceptibility to decompensation and heart failure. In: Circulation Research. 1999 ; Vol. 84, No. 6. pp. 735-740.
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abstract = "Left ventricular hypertrophy (LVH) is a compensatory mechanism to cope with pressure overload. Recently, a calcineurin pathway mediating LVH and its prevention by cyclosporine was reported. We examined whether calcineurin mediates LVH due to pressure overload in mice. Pressure overload was induced by aortic banding in 53 mice (32 treated with cyclosporine [25 mg · kg-1 · d-1], 21 treated with vehicle). There were 17 sham-operated mice (9 treated with vehicle, 8 treated with cyclosporine). At 3 weeks after surgery, LV weight to body weight was greater in the nontreatment banded group (4.39 ± 0.16 mg/g) than in the cyclosporine-treated banded group (3.95±0.14 mg/g, P<0.05), with both groups being greater compared with the entire group of sham-operated mice (3.02±0.04 mg/g). The pressure gradient between the ascending and abdominal aorta was not different between the cyclosporine- treated (49.6±6.1 mm Hg) and nontreatment groups (48.7±4.6 mm Hg). Although LV systolic pressure was lower in the cyclosporine-treated banded animals, LV systolic wall stress was similar in the nontreatment banded group and in the cyclosporine-treated group. However, LV dP/dt was lower (P=0.05) in the cyclosporine-treated banded group (4774±656 mm Hg/s) than in the nontreatment banded group (6604±516 mm Hg/s). During the protocol, 23 of 32 mice in the cyclosporine-treated group and 9 of 21 mice in the nontreatment group died. All deaths occurred within 10 days after surgery. Deaths caused by heart failure were 7.2-fold higher (P<0.05) in the cyclosporine-treated group, whereas deaths due to other causes were not different between the 2 groups. In addition, LV function of mice was assessed at 48 hours after banding; LV ejection fraction measured with echocardiography was lower (P<0.05) in the cyclosporine-treated banded group (66±3.0{\%}) than in the nontreatment banded group (79±1.5{\%}), whereas LV systolic wall stresses were similar. Calcineurin phosphatase activity was depressed similarly in both cyclosporine-treated groups compared with both nontreatment groups. Thus, cyclosporine could attenuate, but not prevent, LVH at the expense of inhibiting an important compensatory mechanism in response to pressure overload, resulting in reduced LV wall stress and function and increased susceptibility to decompensation and heart failure.",
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AU - Hong, Chull

AU - Asai, Kuniya

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AU - Olson, Eric N.

AU - Vatner, Stephen F.

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N2 - Left ventricular hypertrophy (LVH) is a compensatory mechanism to cope with pressure overload. Recently, a calcineurin pathway mediating LVH and its prevention by cyclosporine was reported. We examined whether calcineurin mediates LVH due to pressure overload in mice. Pressure overload was induced by aortic banding in 53 mice (32 treated with cyclosporine [25 mg · kg-1 · d-1], 21 treated with vehicle). There were 17 sham-operated mice (9 treated with vehicle, 8 treated with cyclosporine). At 3 weeks after surgery, LV weight to body weight was greater in the nontreatment banded group (4.39 ± 0.16 mg/g) than in the cyclosporine-treated banded group (3.95±0.14 mg/g, P<0.05), with both groups being greater compared with the entire group of sham-operated mice (3.02±0.04 mg/g). The pressure gradient between the ascending and abdominal aorta was not different between the cyclosporine- treated (49.6±6.1 mm Hg) and nontreatment groups (48.7±4.6 mm Hg). Although LV systolic pressure was lower in the cyclosporine-treated banded animals, LV systolic wall stress was similar in the nontreatment banded group and in the cyclosporine-treated group. However, LV dP/dt was lower (P=0.05) in the cyclosporine-treated banded group (4774±656 mm Hg/s) than in the nontreatment banded group (6604±516 mm Hg/s). During the protocol, 23 of 32 mice in the cyclosporine-treated group and 9 of 21 mice in the nontreatment group died. All deaths occurred within 10 days after surgery. Deaths caused by heart failure were 7.2-fold higher (P<0.05) in the cyclosporine-treated group, whereas deaths due to other causes were not different between the 2 groups. In addition, LV function of mice was assessed at 48 hours after banding; LV ejection fraction measured with echocardiography was lower (P<0.05) in the cyclosporine-treated banded group (66±3.0%) than in the nontreatment banded group (79±1.5%), whereas LV systolic wall stresses were similar. Calcineurin phosphatase activity was depressed similarly in both cyclosporine-treated groups compared with both nontreatment groups. Thus, cyclosporine could attenuate, but not prevent, LVH at the expense of inhibiting an important compensatory mechanism in response to pressure overload, resulting in reduced LV wall stress and function and increased susceptibility to decompensation and heart failure.

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