1. ¹Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA
2. ²Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, USA
3. ³Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, USA
4. ⁴Purdue University-University of Alabama at Birmingham Botanicals Center for Age-related Disease, University of Alabama at Birmingham, Birmingham, AL, USA
5. ⁵Burnham Institute for Medical Research, Orlando, FL, USA

Correspondence: Dr PA Wood, DVM, PhD, Metabolic Signaling & Disease Program, Diabetes and Obesity Research Center, Burnham Institute for Medical Research at Lake Nona, 6400 Sanger Road, Orlando, FL 32827, USA. E-mail: pwood@burnham.org

Received 24 March 2009; Revised 26 June 2009; Accepted 29 June 2009; Published online 7 September 2009.

Abstract

Cardiac hypertrophy is a common finding in human patients with inborn errors of long-chain fatty acid oxidation. Mice with either very long-chain acyl-coenzyme A dehydrogenase deficiency (VLCAD–/–) or long-chain acyl-coenzyme A dehydrogenase deficiency (LCAD–/–) develop cardiac hypertrophy. Cardiac hypertrophy, initially measured using heart/body weight ratios, was manifested most severely in LCAD–/– male mice. VLCAD–/– mice, as a group, showed a mild increase in normalized cardiac mass (8.8% hypertrophy compared with all wild-type (WT) mice). In contrast, LCAD–/– mice as a group showed more severe cardiac hypertrophy (32.2% increase compared with all WT mice). On the basis of a clear male predilection, we analyzed the role of dietary plant estrogenic compounds commonly found in mouse diets because of soy or alfalfa components providing natural phytoestrogens or isoflavones in cardioprotection of LCAD–/– mice. Male LCAD–/– mice fed an isoflavone-free test diet had more severe cardiac hypertrophy (58.1% hypertrophy compared with WT mice fed the same diet). There were no significant differences in the female groups fed any of the diets. Echocardiography measurement performed on male LCAD-deficient mice fed a standard diet at the age of 3 months confirmed the substantial cardiac hypertrophy in these mice compared with WT controls. Left ventricular (LV) wall thickness of the interventricular septum and posterior wall was remarkably increased in LCAD–/– mice compared with that of WT controls. Accordingly, the calculated LV mass after normalization to body weight was increased by about 40% in the LCAD–/– mice compared with WT mice. In summary, we found that metabolic cardiomyopathy, expressed as hypertrophy, developed in mice because of either VLCAD deficiency or LCAD deficiency; however, LCAD deficiency was the most profound and seemed to be attenuated either by endogenous estrogen (in females) or by phytoestrogens present in the diet as isoflavones (in males).