Elsevier

Journal of Cardiac Failure

Volume 23, Issue 2, February 2017, Pages 161-168
Journal of Cardiac Failure

Basic Science and Experimental Studies
Sex-Specific Effects of Adrenergic-Induced Left Ventricular Remodeling in Spontaneously Hypertensive Rats

https://doi.org/10.1016/j.cardfail.2016.09.017Get rights and content

Highlights

  • •

    The role of sex on β-adrenergic–induced dilation in hypertension was assessed.

  • •

    β-Adrenergic stimulation leads to dilation only in male hypertensive rats.

  • •

    An increased fibrosis is involved in the β-adrenergic–induced dilation in males.

  • •

    Dilation precedes systolic chamber dysfunction in male hypertensive rats.

Abstract

Objective

The aim of this work was to determine whether adrenergic-induced left ventricular (LV) dilation and eccentric remodeling in pressure-overload hypertrophy is sex specific.

Methods and Results

Chronic β-adrenoreceptor activation was produced in male and female spontaneously hypertensive rats (SHRs) by means of daily administration of isoproterenol (ISO; 0.04 mg/kg daily) from 9 to 15 months of age. LV chamber dimensions were determined in vivo by means of echocardiography and ex vivo in isolated perfused heart preparations. The acute hemodynamic response to ISO, the degree of myocardial necrosis and apoptosis, and collagen distribution were also assessed. Female SHRs demonstrated inotropic and chronotropic responses to ISO similarly to male SHRs. Compared with control subjects (saline solution vehicle), following chronic ISO administration, LV end-diastolic diameter (mm) was increased in male (ISO 7.8 ± 0.3 vs control 6.6 ± 0.2; P < .001) but not in female (ISO 6.3 ± 0.2 vs control 6.2 ± 0.2; P = .23) SHRs. Similarly, compared with control, ISO administration increased the volume intercept of the LV end-diastolic pressure-volume relation (mL) in male (ISO 0.31 ± 0.02 vs control 0.22 ± 0.01; P < .0001) but not in female (ISO 0.17 ± 0.01 vs control 0.17 ± 0.01; P = 1.00) SHRs. Relative wall thickness was also decreased in male SHRs receiving ISO but not in female SHRs receiving ISO. Chronic ISO administration increased the percentage of area covered by interstitial collagen in male but not in female SHRs. Finally, chronic adrenergic stimulation failed to influence LV chamber or myocardial systolic function in either male or female SHRs.

Conclusions

Male SHRs are more susceptible to adrenergic-induced LV dilation and eccentric LV remodeling than female SHRs. These effects are associated with increased collagen deposition. In pressure-overload hypertrophy, LV dilation and eccentric LV remodeling occur before LV dysfunction in male rats.

Section snippets

Animal Model

The present study was approved by the Animal Ethics Screening Committee of the University of the Witwatersrand (approval no. 2010/21/04) and was conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Male and female 9-month-old SHRs were studied. Animals were maintained on standard rat chow and water ad libitum. They were housed under conditions of controlled ambient temperature with a light-dark cycle of 12 hours. Three different sets

Acute Hemodynamic Responses to ISO

At baseline, FSend, FSmid, and heart rate were similar between male and female SHRs (Table 1). ISO EC50 and Emax for FSend, FSmid, and heart rate were similar between male and female SHRs (Table 1).

Body and Heart Weights

Male SHRs were heavier (P < .0001) and had greater heart and LV weights (P < .0001 and P < .0001, respectively) as well as a greater ratio of LV weight to tibial length (P < .0001) than female SHRs (Table 2). The ratio of LV weight to body weight was lower in male than in female SHRs (Table 2, P

Discussion

The main finding of the present study is that chronic β-adrenergic receptor stimulation produces LV dilation as indexed by an increased LVEDD, an increased intercept (LV V0) of the LVED pressure-volume relation, and therefore a right shift in the LVED pressure-volume relation in male but not in female SHRs. The ISO-induced adverse remodeling was associated with increased collagen deposition in male but not in female SHRs. Importantly, these effects in male SHRs preceded LV systolic chamber or

Disclosures

None.

Acknowledgments

The authors thank Ms Monica Gomes and Dr Aurelie Deroubaix for their excellent technical assistance.

References (21)

  • F.A. Masoudi et al.

    Gender, age and heart failure with preserved left ventricular systolic function

    J Am Coll Cardiol

    (2003)
  • M. Piro et al.

    Sex-related differences in myocardial remodeling

    J Am Coll Cardiol

    (2010)
  • G.R. Norton et al.

    Heart failure in pressure overload hypertrophy: the relative roles of ventricular remodeling and myocardial dysfunction

    J Am Coll Cardiol

    (2002)
  • D.C. Scantlebury et al.

    Why are women more likely than men to develop heart failure with preserved ejection fraction

    Curr Opin Cardiol

    (2011)
  • B.A. Borlaug et al.

    Diastolic and systolic heart failure are distinct phenotypes within the heart failure spectrum

    Circulation

    (2011)
  • D.S. Lee et al.

    Relation of disease pathogenesis and risk factors to heart failure with preserved or reduced ejection fraction: insight from the Framingham Heart Study of the National Heart, Lung and Blood Institute

    Circulation

    (2009)
  • A.K. Chung et al.

    Women have higher left ventricular ejection fractions than men independent of differences in left ventricular volume: the Dallas Heart Study

    Circulation

    (2006)
  • ChengS. et al.

    Age-related left ventricular remodeling and associated risk for cardiovascular outcomes: the Multi-ethnic Study of Atherosclerosis

    Circ Cardiovasc Imaging

    (2009)
  • D. Badenhorst et al.

    β-Adrenergic activation initiates chamber dilatation in concentric hypertrophy

    Hypertension

    (2003)
  • D.G. Veliotes et al.

    Aldosterone receptor blockade prevents the transition to cardiac pump dysfunction induced by β-adrenoreceptor activation

    Hypertension

    (2005)
There are more references available in the full text version of this article.

Cited by (19)

View all citing articles on Scopus

Sources of funding: This work was supported by the University Research Council of the University of the Witwatersrand,and the National Research Foundation of South Africa (NRF grants no. 81345 and 47060).

Author contributions: FSM, MM, GRN, and AJW conceived and designed the experiments. FSM, MM, LM, GRN, and AJW performed the experiments. FSM and AJW analyzed the data. FSM, GRN, and AJW contributed reagents/materials/analysis tools. FM, MM, GRN, and AJW contributed toward manuscript preparation.

View full text
© 2016 Elsevier Inc. All rights reserved.