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

Abstract

There are currently no FDA-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), combination carvedilol and exercise (n=8). Cardiac function was assessed by echocardiography after 4-week treatments. Running activity of Alport mice was similar to wild types at 1-month of age, but markedly reduced at 2 months (1.3±0.40 vs. 4.5±1.02 km/day, p<0.05). There was a non-significant trend for increased running activity at 2 months 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.

Col4a3-/- Mice on Balb/C Background Have Less Severe Cardiorespiratory Phenotype and SGLT2 Over-Expression Compared to 129x1/SvJ and C57Bl/6 Backgrounds

“…The present results support our previous work that implicated cardiorenal factors in the etiology of HFpEF including trends of slightly lower EF in all AS groups [ 28 , 29 ]. Similarly, Neuburg et al [ 49 ] described systolic dysfunction in 10-week-old 129Sv Col4a3 -/- mice and elevated systolic, diastolic and mean BP in both 129Sv and B6 mice.…”

“…Specific contributions of immune system modulation and transcription factors involved in cell proliferation and survival, such as signal transducer and activator of transcription 3 (STAT3), have also been described [ 13 , 60 ]. Recently, our group reported a Col4a3 -/- mouse model of HFpEF secondary to CKD that implicated osteopontin as an etiological effector and carvediol, an α/β adrenergic antagonist, as therapeutic [ 10 , 28 ]. Despite decades of investigation, an established cure for AS remains elusive, and standard treatment for patients is limited to ACE inhibitors that slow disease progression when applied at an appropriate early stage before onset of ESRF [ 16 , 17 , 19 ].…”

“…Recent studies attempting to define the far-reaching properties of SGLT2 inhibitors on cardiorenal disease suggest bidirectional interactions between SGLT2 and the sympathetic nervous system (reviewed in [ 40 ]). Adrenergic pathways are also implicated in the beneficial effects of SGLT2 inhibitors for patients with chronic heart failure [ 73 ], and may be part of the mechanism of action of cardioprotection by carvedilolin Col4a3 -/- -129x1/SvJ mice [ 28 ].…”

“…Our group recently reported that Col4a3 -/- -129J mice reproduce multiple features of heart failure with preserved ejection fraction (HFpEF), including symptoms of systemic hypertension and pulmonary congestion. Disease progression in this model, including cardiac performance and renal functions, was partially ameliorated by treatment with carvedilol, an α/β-adrenergic blocker, effects that were enhanced by exercise training [ 28 , 29 ]. A major goal of the present work is to create a comprehensive reference base for cardiorespiratory phenotypes associated with CKD within the context of murine AS.…”

Pharmacy and Exercise as Complimentary Partners for Successful Cardiovascular Ageing

“…Lastly, studies investigating combined β-blocker and exercise training suggest improvements in exercise capacity in humans with HF or post myocardial infarction [243,244]. In mice with HF, combined beta-blocker and exercise training therapy (4 weeks) provided additive improvements to cardiovascular function compared with individual therapy through reduced HR (17 vs 16 vs 7%), increased stroke volume (71 vs 25 vs 34%) and increased EF (41 vs 34 vs 13%) in combined vs beta-blocker only vs exercise training only, respectively [245]. In support, another study in mice (5-7 months) with HF found combined therapy improved exercise tolerance, reduced mortality, and improved ventricular contractility [246].…”