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

Am J Physiol Heart Circ Physiol. 2021 May 1;320(5):H1862-H1872. doi: 10.1152/ajpheart.00535.2020. Epub 2021 Mar 26.

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 α/β-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.NEW & NOTEWORTHY In an Alport mouse model of heart failure with preserved ejection fraction (HFpEF), exercise and carvedilol synergistically improved systolic function without affecting diastole. Carvedilol alone or in combination with exercise also improved kidney function. Molecular analyses indicate that the observed improvements in cardiorenal functions were mediated at least in part by effects on serum osteopontin and related inflammatory cytokine cascades. The work presents new potential therapeutic targets and approaches for HFpEF.

Keywords: HFpEF; carvedilol; diastolic dysfunction; exercise; osteopontin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Antagonists / pharmacology*
  • Animals
  • Autoantigens / genetics
  • Biomarkers / blood
  • Carvedilol / pharmacology*
  • Collagen Type IV / deficiency*
  • Collagen Type IV / genetics
  • Combined Modality Therapy
  • Diastole
  • Disease Models, Animal
  • Down-Regulation
  • Exercise Therapy*
  • Heart Failure / blood
  • Heart Failure / genetics
  • Heart Failure / physiopathology
  • Heart Failure / therapy*
  • Mice
  • Mice, 129 Strain
  • Mice, Knockout
  • Nephritis, Hereditary / blood
  • Nephritis, Hereditary / genetics
  • Nephritis, Hereditary / physiopathology
  • Nephritis, Hereditary / therapy*
  • Osteopontin / blood*
  • Recovery of Function
  • Systole
  • Ventricular Dysfunction, Left / blood
  • Ventricular Dysfunction, Left / genetics
  • Ventricular Dysfunction, Left / physiopathology
  • Ventricular Dysfunction, Left / therapy*
  • Ventricular Function, Left / drug effects*

Substances

  • Adrenergic beta-Antagonists
  • Autoantigens
  • Biomarkers
  • Collagen Type IV
  • Spp1 protein, mouse
  • type IV collagen alpha3 chain
  • Carvedilol
  • Osteopontin