Experimental mild renal insufficiency mediates early cardiac apoptosis, fibrosis, and diastolic dysfunction: a kidney-heart connection

Abstract

Impaired renal function with loss of nephron number in chronic renal disease (CKD) is associated with increased cardiovascular morbidity and mortality. However, the structural and functional cardiac response to early and mild reduction in renal mass is poorly defined. We hypothesized that mild renal impairment produced by unilateral nephrectomy (UNX) would result in early cardiac fibrosis and impaired diastolic function, which would progress to a more global left ventricular (LV) dysfunction. Cardiorenal function and structure were assessed in rats at 4 and 16 wk following UNX or sham operation (Sham); (n = 10 per group). At 4 wk, blood pressure (BP), aldosterone, glomerular filtration rate (GFR), proteinuria, and plasma B-type natriuretic peptide (BNP) were not altered by UNX, representing a model of mild early CKD. However, UNX was associated with significantly greater LV myocardial fibrosis compared with Sham. Importantly, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining revealed increased apoptosis in the LV myocardium. Further, diastolic dysfunction, assessed by strain echocardiography, but with preserved LVEF, was observed. Changes in genes related to the TGF-β and apoptosis pathways in the LV myocardium were also observed. At 16 wk post-UNX, we observed persistent LV fibrosis and impairment in LV diastolic function. In addition, LV mass significantly increased, as did LVEDd, while there was a reduction in LVEF. Aldosterone, BNP, and proteinuria were increased, while GFR was decreased. The myocardial, structural, and functional alterations were associated with persistent changes in the TGF-β pathway and even more widespread changes in the LV apoptotic pathway. These studies demonstrate that mild renal insufficiency in the rat results in early cardiac fibrosis and impaired diastolic function, which progresses to more global LV remodeling and dysfunction. Thus, these studies importantly advance the concept of a kidney-heart connection in the control of myocardial structure and function.

Speckle Tracking Echocardiography Detects Uremic Cardiomyopathy Early and Predicts Cardiovascular Mortality in ESRD

“…TGF-b is a known key player in solid organ fibrosis 42 and has been implicated in the development of UC. 31,43 We observed a significant upregulation of TGF-b in both rat models of UC. Additionally, UC was accompanied by re-expression of the fetally expressed b-myosin heavy chain and increased cardiac expression of brain natriuretic peptide, both of which have been linked to cardiac fibrosis, hypertrophy, and UC.…”

Cardiac Resynchronization Therapy in CKD

“…CKD carries a higher cardiovascular comorbid burden including congestive heart failure (CHF), the prevalence of which is as high as 13%-20% in stage 4-5 CKD patients compared with 1%-2% in those without CKD (2)(3)(4). Reduction in nephron mass induces early cardiac fibrosis, myocardial hypertrophy, and diastolic impairment that portend an increased risk for heart failure (HF) in the CKD population (5)(6)(7). Adequate renin-angiotensin-aldosterone (RAAS) blockade with angiotensin-converting enzyme inhibitors (ACEIs), angiotensin-receptor blockers (ARBs), mineralocorticoid receptor antagonists, and b-adrenergic antagonists remains the mainstay of treatment for CHF (8).…”

Determination and distribution of left ventricular size as measured by noncontrast CT in the Multi-Ethnic Study of Atherosclerosis

“…It is possible that loss of functioning myocardium in mild -moderate CKD and replacement fibrosis may lead to reduction in LV mass and size. 26 In a rodent model of mild renal insufficiency, dUTP nick-end labeling (TUNEL) staining revealed increased apoptosis and loss of myocardium. 26 There is an early increase in intravascular volume of mild-to-moderate CKD in the presence of activated renin-angiotensin-aldosterone system.…”

“…26 In a rodent model of mild renal insufficiency, dUTP nick-end labeling (TUNEL) staining revealed increased apoptosis and loss of myocardium. 26 There is an early increase in intravascular volume of mild-to-moderate CKD in the presence of activated renin-angiotensin-aldosterone system. 27 This may lead to remodeling in the early phase of CKD.…”