Novel pathomechanisms of cardiomyocyte dysfunction in a model of heart failure with preserved ejection fraction

Abstract

AimsHeart failure with preserved ejection fraction (HFpEF) is increasingly common, but the underlying cellular mechanisms are not well understood. We investigated cardiomyocyte function and the role of SEA0400, an Na + /Ca 2+ exchanger (NCX) inhibitor in a rat model of chronic kidney disease (CKD) Methods and resultsMale Wistar rats were subjected to subtotal nephrectomy (NXT) or sham operation (Sham). After 8 and 24 weeks, in vivo (haemodynamics, echocardiography) and in vitro function (LV cardiomyocyte cell shortening (CS), and Ca 2+ transients (CaT)) were determined without and with SEA0400. In a subgroup of rats, SEA0400 or vehicle was given p.o. (1 mg/kg b.w.) between week 8 and 24. NXT resulted in stable compensated CKD and HFpEF [hypertrophied left ventricle, prolonged LV isovolumetric relaxation constant TAU (IVRc TAU), elevated end diastolic pressure (EDP), increased lung weight (pulmonary congestion), and preserved LV systolic function (EF, dP/dt)]. In NXT cardiomyocytes, the amplitude of CS and CaT were unchanged but relaxation and CaT decay were progressively prolonged at 8 and 24 weeks vs. Sham, individually correlating with diastolic dysfunction in vivo. NCX forward mode activity (caffeine response) was progressively reduced, while NCX protein expression was up-regulated, suggesting increased NCX reverse mode activity in NXT. SEA0400 acutely improved relaxation in NXT in vivo and in cardiomyocytes and improved cardiac remodelling and diastolic function when given chronically.

Hjertesvikt med bevart ejeksjonsfraksjon

“…The few studies investigating similar mechanisms in HFpEF indicate that reduced sodium-calcium exchanger function promotes slower, incomplete relaxation in this condition (13). However, we showed in a recently published study that disrupted calcium homeostasis is not a precondition for diastolic dysfunction (14).…”

Mitochondrial function as a therapeutic target in heart failure

“…Although very early in development, inhibitors of the mitochondrial sodium– calcium– (lithium) exchanger 215 , such as CGP-37157, have been shown to improve cardiac function in preclinical models of HF 216,217 . Inhibiting the sarcolemmal sodium– calcium exchanger might also be a promising approach, as demonstrated in a preclinical model of HFpEF 218 .…”

Adenine-Induced Chronic Renal Failure in Rats: A Model of Chronic Renocardiac Syndrome with Left Ventricular Diastolic Dysfunction but Preserved Ejection Fraction

“…Furthermore, patients with early stages of CKD specifically develop signs of LV diastolic dysfunction prior to the onset of clinical heart failure manifestations [18] suggesting that reduced GFR may contribute to the development of HFpEF. Although the LV abnormalities described in the present study show resemblances to those observed in rats or mice with CKD caused by 5/6 nephrectomy [19][20][21] the ACRF model may have several advantages in addition to not requiring surgery. Rats subjected to 5/6 nephrectomy typically develop only a relatively modest decrease GFR and consequently secondary metabolic changes such as alterations in mineral and bone metabolism are not as pronounced as in ACRF rats [19,[22][23][24].…”

“…Although the LV abnormalities described in the present study show resemblances to those observed in rats or mice with CKD caused by 5/6 nephrectomy [19][20][21] the ACRF model may have several advantages in addition to not requiring surgery. Rats subjected to 5/6 nephrectomy typically develop only a relatively modest decrease GFR and consequently secondary metabolic changes such as alterations in mineral and bone metabolism are not as pronounced as in ACRF rats [19,[22][23][24]. In addition, severe hypertension is a characteristic feature of most 5/6 nephrectomy models [23,25], which makes it difficult to distinguish whether cardiovascular abnormalities are primarily caused by high blood pressure or reduced kidney function.…”