Abstract
BackgroundThe additive effects of obesity and metabolic syndrome on left ventricular (LV) maladaptive remodeling and function in hypertension are not characterized.MethodsWe compared an obese spontaneously hypertensive rat model (SHR-ob) with lean spontaneously hypertensive rats (SHR-lean) and normotensive controls (Ctr). LV-function was investigated by cardiac magnetic resonance imaging and invasive LV-pressure measurements. LV-interstitial fibrosis was quantified and protein levels of phospholamban (PLB), Serca2a and glucose transporters (GLUT1 and GLUT4) were determined by immunohistochemistry.ResultsSystolic blood pressure was similar in SHR-lean and SHR-ob (252 ± 7 vs. 242 ± 7 mmHg, p = 0.398) but was higher when compared to Ctr (155 ± 2 mmHg, p < 0.01 for both). Compared to SHR-lean and Ctr, SHR-ob showed impaired glucose tolerance and increased body-weight. In SHR-ob, LV-ejection fraction was impaired vs. Ctr (46.2 ± 1.1 vs. 59.6 ± 1.9%, p = 0.007). LV-enddiastolic pressure was more increased in SHR-ob than in SHR-lean (21.5 ± 4.1 vs. 5.9 ± 0.81 mmHg, p = 0.0002) when compared to Ctr (4.3 ± 1.1 mmHg, p < 0.0001 for both), respectively. Increased LV-fibrosis together with increased myocyte diameters and ANF gene expression in SHR-ob were associated with increased GLUT1-protein levels in SHR-ob suggestive for an upregulation of the GLUT1/ANF-axis. Serca2a-protein levels were decreased in SHR-lean but not altered in SHR-ob compared to Ctr. PLB-phosphorylation was not altered.ConclusionIn addition to hypertension alone, metabolic syndrome and obesity adds to the myocardial phenotype by aggravating diastolic dysfunction and a progression towards systolic dysfunction. SHR-ob may be a useful model to develop new interventional and pharmacological treatment strategies for hypertensive heart disease and metabolic disorders.
Highlights
Hypertension, obesity and metabolic syndrome are highly prevalent cardiovascular diseases and risk factors in industrialized countries [1]
At 38 weeks of age, bodyweight index was significantly higher compared to Lean spontaneously hypertensive rats (SHR)-lean and Ctr (Figure 1B)
Cardiac index was reduced in Obese spontaneously hypertensive rats (SHR-ob) compared to Ctr and SHR-lean mainly due to reduced stroke volume as heart rate did not differ significant between
Summary
Hypertension, obesity and metabolic syndrome are highly prevalent cardiovascular diseases and risk factors in industrialized countries [1]. Metabolic syndrome amplifies cardiovascular risk associated with high blood pressure independent of the effect of several traditional cardiovascular risk factors in hypertensive subjects [9]. The aim of the present study was to systematically characterize maladaptive remodeling processes (functional, histological and molecular) in an obese spontaneously hypertensive rat model carrying an additional mutation in the leptin receptor (SHR-ob) [12] compared tolean spontaneously hypertensive rats (SHR-lean) and normotensive controls (Ctr). The SHR-ob rat is an unique animal model expressing multiple abnormal phenotypes including obesity, hypertension, hyperinsulinemia and hyperlipidemia [12]. The additive effects of obesity and metabolic syndrome on left ventricular (LV) maladaptive remodeling and function in hypertension are not characterized
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