Evidence of Renal Dysfunction, and Sclerotic Damage Secondary to Chronic Heart Failure; an Inbred Rat Model of Type 2 Cardiorenal Syndrome

Cardiovascular disease is the leading killer within the western world. Direct pathological interactions have been shown to exist between cardiovascular disease, and the development of renal disease, and vice versa. This has become known as cardiorenal syndrome. Type 2 cardiorenal syndrome, a subtype in which chronic heart disease leads to a progressive loss of renal function, and morphological damage, has not been convincingly reproduced in an animal model. The current study addresses this by using a chronic myocardial infarction model in inbred Lewis rats. Male Lewis rats were subjected to a permanent occlusion of the left anterior descending coronary artery (LAD), or sham surgery (sham), and were maintained for 90 days. This produced infarcts comprising an average of 24.2 % of the wet weight of the entire left ventricle at 90 days, and corresponded to increased plasma cardiac troponin I concentrations, measured 4 hours after the ligation procedure. There was no weight difference between sham, and LAD, animals at 90 days. Ventricular function was measured by Langendorff perfusion. LAD occluded animals had significantly decreased left ventricular developed pressure, unpaced ex vivo heart rate, and systolic, and diastolic rate pressure derivatives. These findings were indicative of diastolic heart failure. This corresponded to an increase in pro-inflammatory interleukin-1 beta, but no other residual evidence of cytokine activiation in myocardial tissue was found at this timepoint. Ventricular hypertrophy, wall thinning, and dilation, was seen through histological staining with Picrosirius Red and Fast Green, and supported by physical measurements of ventricular mass. There was no perturbation to haemotological parameters in these animals. Analysis of renal function revealed decreased true creatinine clearance, and increased fractional excretion of sodium, and increased urinary protein. This corresponded to an increase in tissue growth factor beta, and increased renal caspase 3/7 activity. The presence of renal damage was confirmed through histological evidence of glomerulosclerosis, and tubulointerstitial fibrosis in the cortex, and medulla. This evidence shows renal disease formation in rats secondary to heart failure. This study strongly suggests that this model is able to reliably produce disease closely resembling the clinical manifestation of type 2 cardiorenal syndrome. This provides an experiemental framework to study pathophysiological mechanisms, and therapeutic interventions, of type 2 cardiorenal syndrome