Carvedilol and exercise combination therapy improves systolic but not diastolic function and reduces plasma osteopontin in Col4a3-/- Alport mice

Julian C. Dunkley, Camila I. Irion, Keyvan Yousefi, Serene A. Shehadeh, Guerline Lambert, Krista John-Williams, Keith A Webster, Jeffrey J. Goldberger, Lina A. Shehadeh

Research output: Contribution to journalArticlepeer-review

Abstract

There are currently no Food and Drug Administration-approved treatments for heart failure with preserved ejection fraction (HFpEF). Here we compared the effects of exercise with and without a/b-adrenergic blockade with carvedilol in Col4a3-/- Alport mice, a model of the phenogroup 3 subclass of HFpEF with underlying renal dysfunction. Alport mice were assigned to the following groups: no treatment control (n = 29), carvedilol (n = 11), voluntary exercise (n = 9), and combination carvedilol and exercise (n = 8). Cardiac function was assessed by echocardiography after 4-wk treatments. Running activity of Alport mice was similar to wild types at 1 mo of age but markedly reduced at 2 mo (1.3 ± 0.40 vs. 4.5 ± 1.02 km/day, P < 0.05). There was a nonsignificant trend for increased running activity at 2 mo by carvedilol in the combination treatment group. Combination treatments conferred increased body weight of Col4a3-/- mice (22.0 ± 1.18 vs. 17.8 ± 0.29 g in untreated mice, P < 0.01), suggesting improved physiology, and heart rates declined by similar increments in all carvedilol-treatment groups. The combination treatment improved systolic parameters; stroke volume (30.5 ± 1.99 vs. 17.8 ± 0.77 μL, P < 0.0001) as well as ejection fraction and global longitudinal strain compared with controls. Myocardial performance index was normalized by all interventions (P < 0.0001). Elevated osteopontin plasma levels in control Alport mice were significantly lowered only by combination treatment, and renal function of the Alport group assessed by urine albumin creatinine ratio was significantly improved by all treatments. The results support synergistic roles for exercise and carvedilol to augment cardiac systolic function of Alport mice with moderately improved renal functions but no change in diastole.

Original languageEnglish (US)
Pages (from-to)H1862-H1872
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume320
Issue number5
DOIs
StatePublished - May 2021

Keywords

  • Carvedilol
  • Diastolic dysfunction
  • Exercise
  • HFpEF
  • Osteopontin

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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