Abstract
BackgroundDiabetic cardiomyopathy is characterized by systolic and early diastolic ventricular dysfunction. In the metabolic syndrome (MS), ventricular stiffness is additionally increased in a later stage. It is unknown whether this is related to intrinsic cardiomyocyte dysfunction, extrinsic factors influencing cardiomyocyte contractility and/or cardiac function, or a combination of both. A first aim was to study cardiomyocyte contractility and Ca2+ handling in vitro in a mouse model of MS. A second aim was to investigate whether in vivo hypocaloric diet or ACE-inhibition (ACE-I) improved cardiomyocyte contractility in vitro, contractile reserve and Ca2+ handling.MethodsThis study was performed in LDL-receptor (LDLR−/−) and leptin-deficient (ob/ob), double knock-out mice (DKO), featuring obesity, type II diabetes, atherogenic dyslipidemia and hypertension. Single knock-out LDLR−/−, ob/ob and wild type mice were used as controls. Cellular contractility, Ca2+ handling and their response to in vivo treatment with diet or ACE-I were studied in isolated cardiomyocytes at baseline, during β-adrenergic stimulation or increased extracellular Ca2+, using field stimulation and patch-clamp.ResultsIn untreated conditions, prolongation of contraction-relaxation cycle and altered Ca2+ handling are observed in MS. Response to increased extracellular Ca2+ and β-adrenergic stimulation is impaired and could not be rescued by weight loss. ACE-I restored impaired response to β-adrenergic stimulation in MS, but not the decreased response to increased extracellular Ca2+.ConclusionsCardiomyocyte contractility and β-adrenergic response are impaired in MS, due to alterations in cellular Ca2+ handling. ACE-I, but not weight loss, is able to restore cardiomyocyte response to β-adrenergic stimulation in MS.
Highlights
Diabetic cardiomyopathy is characterized by systolic and early diastolic ventricular dysfunction
Animals Experiments were conducted in homozygous LDL-receptor (LDLR−/−) and leptin-deficient, double knock-out mice (DKO) of either gender at 12, 18 and 24 weeks with C57BL/6J (WT), LDLR−/− and ob/ob as reference data
Contractile reserve was studied at 1 Hz by using isoproterenol (50 nM) or by increasing extracellular Ca2+
Summary
Diabetic cardiomyopathy is characterized by systolic and early diastolic ventricular dysfunction. In the metabolic syndrome (MS), ventricular stiffness is increased in a later stage. It is unknown whether this is related to intrinsic cardiomyocyte dysfunction, extrinsic factors influencing cardiomyocyte contractility and/or cardiac function, or a combination of both. Cardiac function is determined by intrinsic cardiomyocyte function, and influenced by myoarchitecture, composition and structure of the extracellular matrix, by preload and afterload. It is unclear whether the in vivo features of heart failure in MS are caused by intrinsic cardiomyocyte dysfunction and/or extrinsic factors influencing cardiomyocyte or cardiac contractility. No studies are available on isolated cardiomyocyte contractility in MS-mice
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