Cardiovascular Research Advance Access first published online on August 14, 2007
This version [Corrected Proof] published online on September 16, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm001
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Dyslipidaemia in type II diabetic mice does not aggravate contractile impairment but increases ventricular stiffness
1 Laboratory of Experimental Cardiac Surgery, Department of Cardiovascular Disease, Katholieke Universiteit Leuven, Provisorium I, Minderbroedersstraat 19, K.U.Leuven postbus 01033 – FEHA, 3000 Leuven, Belgium
2 Laboratory of Physiology, Katholieke Universiteit Leuven, Leuven, Belgium
3 Department of Medicine, Unit of Pharmacology and Therapeutics, Université Catholique de Louvain, Belgium
4 Department of Cardiovascular Diseases, Atherosclerosis and Metabolism Unit, Katholieke Universiteit Leuven, Leuven, Belgium
* Corresponding author. Tel: +32 16 337298; fax: +32 16 337855. E-mail address: paul.herijgers{at}med.kuleuven.be
Aims: Type II diabetes, often associated with abdominal obesity, frequently leads to heart failure. Clinical and epidemiological evidence suggests that supplemental dyslipidaemia and hypertension, as clustered in the metabolic syndrome, aggravate the cardiovascular outcome. The differential impact of type II diabetes and the metabolic syndrome on left ventricular function, however, remains incompletely defined.
Methods and results: We studied left ventricular function in vivo using pressure–volume analysis in obese diabetic mice with leptin deficiency (ob/ob) and obese diabetic dyslipidemic mice with combined leptin and low-density lipoprotein-receptor deficiency (DKO). ob/ob and DKO mice developed a diabetic cardiomyopathy, characterized by impaired contractility and relaxation, from the age of 24 weeks onwards. This was—at least partially—explained by increased apoptosis and disturbed Ca2+ reuptake in the sarcoplasmic reticulum (SR) in both mouse models. DKO, but not ob/ob, developed increased end-diastolic ventricular stiffness, paralleled by increased left ventricular myocardial fibrosis. Cardiac output was preserved in ob/ob mice by favourable loading conditions, whereas it decreased in DKO mice.
Conclusions: Type II diabetes in mice leads to impaired contractility and relaxation due to disturbed Ca2+ reuptake in the SR, but only when dyslipidaemia and hypertension are superimposed does vascular–ventricular stiffening increase and left ventricular myocardial fibrosis develop.
KEYWORDS Apoptosis; Athcrosclcrosis; Contractile function; Diabetes; SR (function)
Time for primary review: 22 days
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