Chronic Alternate-Day Fasting Results in Reduced Diastolic Compliance and Diminished Systolic Reserve in Rats

doi:10.1016/j.cardfail.2010.05.007

Journal of Cardiac Failure

Volume 16, Issue 10, October 2010, Pages 843-853

https://doi.org/10.1016/j.cardfail.2010.05.007 Get rights and content

Abstract

Background

Based on animal experiments and limited data from the few human trials, alternate-day fasting (ADF) resulted in weight loss, prolonged life, reduced metabolic risk factors for diabetes and cardiovascular diseases, and reduced prevalence of age-related diseases. The present study is the first comprehensive examination of the long-term effects of ADF on general cardiovascular fitness in rats.

Methods and Results

Four-month-old male Sprague-Dawley rats were started on ADF or continued on ad libitum diets and followed for 6 months with serial echocardiography. A comprehensive hemodynamic evaluation including a combined dobutamine–volume stress test was performed at the end of the study, and hearts were harvested for histological assessment. The 6-month-long ADF diet resulted in a 9% reduction (P < .01) of cardiomyocyte diameter and 3-fold increase in interstitial myocardial fibrosis. Left ventricular chamber size was not affected by ADF and ejection fraction was not reduced, but left atrial diameter was increased 16%, and the ratio of early (E) and late atrial (A) waves, in Doppler-measured mitral flow was reduced (P < .01). Pressure-volume loop analyses revealed a “stiff” heart during diastole in ADF rats, whereas combined dobutamine and volume loading showed a significant reduction in left ventricular diastolic compliance and a lack of increase in systolic pump function, indicating a diminished cardiac reserve.

Conclusion

Chronic ADF in rats results in development of diastolic dysfunction with diminished cardiac reserve. ADF is a novel and unique experimental model of diet-induced diastolic dysfunction. The deleterious effect of ADF in rats suggests that additional studies of ADF effects on cardiovascular functions in humans are warranted.

Section snippets

Methods

All animal procedures were approved by the National Institute on Aging Animal Care and Use Committee. Four-month-old male Sprague-Dawley rats (n = 40) were randomly assigned to be fed either every day (AL group, n = 20) or to alternate-day fasting (ADF group, n = 20) with a standard rat diet (NIH-07, Harlan Teklad, Indianapolis, IN). These feeding regimens lasted 6 months. Echocardiographic assessment of cardiac morphometry and function was conducted before assigning rats to a specific diet and

Body Weight

During the 6 months of observation, the body mass in AL increased by 28% (P < .001). Consistent with the reduced average weekly food consumption, the rate of weight gain in ADF rats was significantly attenuated, and at the end of the 6-month diet period (when rats were 10 months old), the weight of rats in the ADF group increased by only 6% (Fig. 1).

Echocardiography

During the 6-month experimental period, end-systolic volume (ESV) increased by 49% (P < .001) similarly in both the AL and ADF diet groups (Fig. 2

Discussion

The present results have uncovered a striking deleterious effect of cardiac structure and function in rats maintained on an ADF diet compared with rats on the usual AL diet. Chronic ADF resulted in reduction of cardiomyocyte size and increased myocardial fibrosis. The fibrotic ADF hearts manifested diastolic dysfunction at rest and a diminished diastolic and systolic reserve capacity: during a volume/dobutamine stress, the ADF heart was unable to increase its filling volume, despite a greater

Acknowledgments

Authors are grateful to Dr. Paul Chantler for assisting with allometric scaling for body weight, to Ms. Veena Shetty for statistical help, and to Ms. Tina Turner and Mrs. Shannon Marshall for technical assistance.

Disclosures

None.

References (33)

B. Martin et al.
Caloric restriction and intermittent fasting: two potential diets for successful brain aging
Ageing Res Rev
(2006)
K.A. Varady et al.
Alternate-day fasting and chronic disease prevention: a review of human and animal trials
Am J Clin Nutr
(2007)
R.G. Katare et al.
Chronic intermittent fasting improves the survival following large myocardial ischemia by activation of BDNF/VEGF/PI3K signaling pathway
J Mol Cell Cardiol
(2009)
M.P. Mattson et al.
Beneficial effects of intermittent fasting and caloric restriction on the cardiovascular and cerebrovascular systems
J Nutr Biochem
(2005)
R.L. Walford et al.
Dietary restriction and aging: historical phases, mechanisms and current directions
J Nutr
(1987)
J.L. Barger et al.
The retardation of aging by caloric restriction: its significance in the transgenic era
Exp Gerontol
(2003)
C.P. Appleton et al.
Estimation of left ventricular filling pressures using two-dimensional and Doppler echocardiography in adult patients with cardiac disease. Additional value of analyzing left atrial size, left atrial ejection fraction and the difference in duration of pulmonary venous and mitral flow velocity at atrial contraction
J Am Coll Cardiol
(1993)
P.S. Douglas
The left atrium: a biomarker of chronic diastolic dysfunction and cardiovascular disease risk
J Am Coll Cardiol
(2003)
A.M. Pritchett et al.
Diastolic dysfunction and left atrial volume: a population-based study
J Am Coll Cardiol
(2005)
T.S. Tsang et al.
Left atrial volume as a morphophysiologic expression of left ventricular diastolic dysfunction and relation to cardiovascular risk burden
Am J Cardiol
(2002)

D.W. Kitzman et al.

Exercise intolerance

Heart Fail Clin

(2008)

P. Razeghi et al.

Mechanical unloading of the heart activates the calpain system

J Mol Cell Cardiol

(2007)

D. Roman-Campos et al.

Cardiac structural changes and electrical remodeling in a thiamine-deficiency model in rats

Life Sci

(2009)

L. Castello et al.

Alternate-day fasting protects the rat heart against age-induced inflammation and fibrosis by inhibiting oxidative damage and NF-kB activation

Free Radic Biol Med

(2010)

L.K. Heilbronn et al.

Alternate-day fasting in nonobese subjects: effects on body weight, body composition, and energy metabolism

Am J Clin Nutr

(2005)

J.B. Johnson et al.

Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma

Free Radic Biol Med

(2007)

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: Fully funded by Intramural Research Program, National Institute on Aging.

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Basic Science and Experimental StudyChronic Alternate-Day Fasting Results in Reduced Diastolic Compliance and Diminished Systolic Reserve in Rats

Abstract

Background

Methods and Results

Conclusion

Section snippets

Methods

Body Weight

Echocardiography

Discussion

Acknowledgments

Disclosures

Ageing Res Rev

Am J Clin Nutr

J Mol Cell Cardiol

J Nutr Biochem

J Nutr

Exp Gerontol

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

Am J Cardiol

Heart Fail Clin

J Mol Cell Cardiol

Life Sci

Free Radic Biol Med

Am J Clin Nutr

Free Radic Biol Med

Basic Science and Experimental Study
Chronic Alternate-Day Fasting Results in Reduced Diastolic Compliance and Diminished Systolic Reserve in Rats