Impairment of cardiac function and energetics in experimental renal failure.

Abstract

Cardiac function and energetics in experimental renal failure in the rat (5/6 nephrectomy) have been investigated by means of an isolated perfused working heart preparation and an isometric Langendorff preparation using 31P nuclear magnetic resonance (31P NMR). 4 wk after nephrectomy cardiac output of isolated hearts perfused with Krebs-Henseleit buffer was significantly lower (P < 0.0001 ) at all levels of preload and afterload in the renal failure groups than in the pair-fed sham operated control group. In control hearts, cardiac output increased with increases in perfusate calcium from 0.73 to 5.61 mmol/ liter whereas uremic hearts failed in high calcium perfusate.Collection of 31p NMR spectra from hearts of renal failure and control animals during 30 min normoxic Langendorff perfusion showed that basal phosphocreatine was reduced by 32% to 4.7 ,mol/g wet wt (P < 0.01) and the phosphocreatine to ATP ratio was reduced by 32% (P < 0.01) in uremic hearts. During low flow ischemia, there was a substantial decrease in phosphocreatine in the uremic hearts and an accompanying marked increase in release of inosine into the coronary effluent (14.9 vs 6.1 jsM, P < 0.01).We conclude that cardiac function is impaired in experimental renal failure, in association with abnormal cardiac energetics and increased susceptibility to ischemic damage. Disordered myocardial calcium utilization may contribute to these derangements. (J. Clin. Invest.

Myocardial bioenergetic abnormalities in experimental uremia

“…More recent work by Patel et al 17 demonstrated that patients with CKD had lower PCr/ATP ratios than hypertensive patients with and without LVH. This observation confirms the much earlier findings of Raine et al 18 who found that the uremic rat (partial nephrectomy [PNx]) had significantly lower PCr/ATP ratios in the uremic group compared to sham (SH)-operated control animals. This reduction in the PCr/ATP ratio was accompanied by reduced contractile indices in the functional assessment of the uremic hearts.…”

“…Total creatine was not measured in these experiments, but it is noteworthy that Raine et al 18 did not find any reduction in total creatine in the uremic heart despite finding significant reductions in PCr/ATP ratios in the isolated perfused heart. Reduced total creatine therefore appears unlikely to be the cause of the abnormalities seen in the uremic heart.…”

Uremic Cardiomyopathy and Insulin Resistance

“…92,93 Previous work on IRI demonstrated that cell death occurs through necrosis and apoptosis and that inhibiting apoptosis during reperfusion significantly improves outcomes. 94 -96 Cardiomyocyte apoptosis also plays a causal role in the development of uremic 97 and nonuremic heart failure, whereas inhibiting apoptosis reduces cardiac dysfunction in heart failure.…”

“…98,99 Maintaining cardiac function requires timely de novo production of ATP; however, the production of ATP is reduced within the uremic heart, as evidenced by a decreased phosphocreatine-ATP ratio. 92 In addition to uremic heart, this restriction has multiple causes, including decreased oxygen and substrate supply as a result of impaired capillarymyocyte exchange, metabolic remodeling, and alterations in creatine kinase. Compromised ATP synthesis also results in a loss of mitochondrial membrane potential and functional deterioration, resulting in a further decline in ATP production and contributing to the inability of the uremic heart to adapt to hemodynamic alterations, 92,100 a situation similar to that in the failing human heart.…”

Renal Damage after Myocardial Infarction Is Prevented by Renin-Angiotensin-Aldosterone-System Intervention

“…Impaired renal function is detrimental for the heart (renocardiac interaction) both in clinical (1)(2)(3)(4)(5)(6)(7)(8) and in experimental (9,10) settings. Impaired cardiac function is detrimental to the kidney (cardiorenal interaction), which is less well characterized and only in experimental settings.…”