Andréanne CHABOT, Bao Hua JIANG, Yanfen SHI, Jean-Claude TARDIF and Jocelyn DUPUIS

1. The Role of Aldosterone on Lung Structural Remodeling and Right Ventricular Function in Ischemic Heart Failure Andréanne CHABOT, Bao Hua JIANG, Yanfen SHI, Jean-Claude TARDIF and Jocelyn DUPUIS Research Center of the Montreal Heart Institute Département de Médecine, Université de Montréal, Canada

2. Background Chronic Heart Failure (HF) can induce pulmonary remodeling and RV dysfunction that importantly contribute to morbidity and mortality. RALES and EPHESUS studies have shown that mineralocorticoid receptors (MR) antagonists reduce mortality in HF. Despite proven efficacy, MR’s antagonism is under-used in HF and its mechanisms of action are poorly understood.

3. Aldosterone • Renal effects : •  blood pressure • Water and sodium retention • Potassium excretion • Putative extra renal effects: • vascular, pulmonary and myocardial fibrosis • oxidative stress • endothelial dysfunction. • Aldosterone binds to MR of renal fibroblasts and myofibroblasts to induce renal fibrosis.

4. Hypothesis Aldosterone contributes to lung remodeling and RV dysfunctions in HF by promoting proliferation of lung myofibroblasts (MYFs). Objectives Evaluate Aldosterone's effect on proliferation of lung myofibroblasts. Evaluate Aldactone’s effect on lung remodeling and right ventricular function.

5. Method : Isolated Lung MYFs • Cell culture : first-pass isolated rat lung MYFs. • Treatment with Aldosterone 10-7 for 48h. • Measurement of proliferation rates with CyQUANT essay.

6. Results

7. Method : MI Model Ligation of the AIV branch of the left coronary artery Pulmonary Arteries LA RA X RV LV

8. Method • Presence and infarct size assessed by: • 24h post MI : plasma Troponin-T concentration. if ≥ 5.1 μg/L, then MI ≥ 30% (sens. of 91% and spec. of 84%). * • 5 weeks post MI : Cardiac ultrasound. *Jiang, B.H., et al., Single measurement of troponin T for early prediction of infarct size, congestive heart failure, and pulmonary hypertension in an animal model of myocardial infarction. Cardiovasc Pathol, 2010.

9. Method Surgery Day 0 Sham Group N=8 MI Group N=23 MI+Aldactone Group N=21 Week 2 For 3 W: Aldactone 100mg/kg/day Week 5 Experimental measurements

10. Experimental Measurements Hemodynamic parameters Heart and lung morphometric Cardiac ultrasound Respiratory function testing with the FlexiVent Pressure-volume Relationship V = A-Be-KP Here : A is the estimate of inspiratory capacity B is the estimate of total lung capacity (P = 0) K is the curvature parameter of P V loop P is the pressure V is the volume

11. Troponin T plasma concentration at 24h and infarct size at 5 weeks were comparables.

12. HF induces PH and RVH : not improved by Aldactone.

13. HF induces lung structural remodeling : not improved by Aldactone.

14. HF decreases lung compliance and induces pulmonary restrictive syndrome : not improved by Aldactone.

15. Aldactone does not improve LV function.

16. Aldactone does not improve RV function.

17. Conclusion • Treatment with Aldosterone 10-7M for 48h does not stimulate lung MYFs proliferation. • Aldosterone does not contribute to lung remodeling and RV dysfunction associated with HF. • Other mechanisms of action are responsible for the beneficial effects of MR antagonists.

18. Disclosure Statement Within the past two years: I have not had an affiliation (financial or otherwise) with a commercial organization that may have a direct or indirect connection to the content of my presentation. X I have had an affiliation (financial or otherwise) with a commercial organization that may have a direct or indirect connection to the content of my presentation. Details below. Does your presentation describe the off-label use of a device, product, or drug that is approved for another purpose? If you answered YES, you must disclose this to the audience within your presentation X No Yes