Mineralocorticoid Escape by the Kidney But Not the Heart in Experimental Asymptomatic Left Ventricular Dysfunction

Abstract

Abstract-Unlike healthy subjects, overt congestive heart failure cannot "escape" the sodium-and water-retaining actions of mineralocorticoid excess. It is undefined whether escape occurs in asymptomatic left ventricular dysfunction (ALVD), which is characterized by preserved sodium homeostasis, natriuretic peptide activation, and normal circulating aldosterone. We hypothesized that, in ALVD, mineralocorticoid excess with exogenous deoxycorticosterone acetate (DOCA) would overwhelm renal compensatory mechanisms, resulting in sodium and water retention, and promote renal and cardiac collagen deposition. ALVD was induced in 2 groups (Nϭ5 each) of dogs by tachypacing at 180 bpm. Urine was collected daily and blood drawn at baseline and days 2, 5, 8, and 11. One group served as control (ALVD), and the other received DOCA (ALVDϩDOCA) starting at day 2 of pacing. Urine flow and sodium excretion were unchanged in the ALVD group. In ALVDϩDOCA, urine flow and sodium excretion decreased on the first 2 days DOCA was given but normalized starting day 4. Urine flow and urinary cGMP excretion increased in ALVDϩDOCA after DOCA escape. Plasma atrial natriuretic peptide, B-type natriuretic peptide, and cGMP increased equally in both groups. There were no differences in cardiorenal and hemodynamic parameters in an acute study on day 11. Although renal collagen area fraction was similar, left ventricular collagen area fraction in ALVDϩDOCA was significantly higher than in ALVD (3.3Ϯ0.4% versus 2.0Ϯ0.2%; Pϭ0.012). We conclude that ALVD can escape the sodium-and water-retaining effects of mineralocorticoid excess. Despite renal escape, increased left ventricular collagen deposition suggests that the heart but not the kidney failed to escape the tissue effects of DOCA. Key Words: basic science Ⅲ experimental models Ⅲ extracellular matrix Ⅲ heart failure Ⅲ kidney physiology/pathophysiology Ⅲ mineralocorticoids T he kidney plays a key role in the syndrome of congestive heart failure (CHF), especially with respect to the congestive symptoms associated with overt CHF. 1 It is increasingly appreciated that the syndrome of overt CHF is frequently preceded by a chronic stage in which Ϸ50% of subjects with decreased left ventricular (LV) ejection fraction have no heart failure (HF) symptoms, termed "asymptomatic LV dysfunction" (ALVD). 2,3 Importantly, patients with ALVD are at increased risk for progression to overt CHF and show increased mortality. 4,5 In contrast to overt CHF, ALVD is characterized by the kidney's ability to preserve urinary sodium excretion despite ventricular dysfunction. This occurs in the setting of increased plasma levels of atrial and B-type natriuretic peptide (ANP and BNP, respectively) and, in the absence of diuretic therapy, lack of activation of the renin-angiotensin-aldosterone system. 6,7 The mechanism of progression from ALVD and sodium balance to clinical symptoms of congestion and sodium retention remains unclear, although studies in experimental HF suggest that it may involve the activation of aldosterone,...

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

“…Further studies are needed to investigate possible early activation of aldosterone. The activation of aldosterone at 16 wk without marked sodium and water retention is consistent with the phenomenon of mineralocorticoid escape (3,8). Specifically, the kidney escaped from the sodium-retaining properties of aldosterone excess, as we previously demonstrated in a canine model of mild LV dysfunction (8).…”

“…The activation of aldosterone at 16 wk without marked sodium and water retention is consistent with the phenomenon of mineralocorticoid escape (3,8). Specifically, the kidney escaped from the sodium-retaining properties of aldosterone excess, as we previously demonstrated in a canine model of mild LV dysfunction (8). Relevant to this pathological role of aldosterone in this model of mild CKD is the study by Edwards et al (12) that have recently demonstrated using magnetic resonance imaging that spironolactone, in patients with early mild CKD, resulted in a reduced LVH in association with a reduction in proteinuria.…”

Mineralocorticoid Accelerates Transition to Heart Failure With Preserved Ejection Fraction Via “Nongenomic Effects”

“…We previously demonstrated cardiac fibrosis with exogenous mineralocorticoid excess alone in experimental systolic dysfunction34 and increased fibrosis and diastolic dysfunction in renal wrapping induced hypertension35; although DOCA also increased BP in the renal hypertension model. Here we confirm and extend these findings in pressure overload induced produced by TAC, independent of further BP elevation or increased salt intake/nephrectomy and provide insight into the mechanism whereby pressure overload hypertrophy sensitizes the heart to mineralocorticoids.…”

Dietary sodium modulation of aldosterone activation and renal function during the progression of experimental heart failure

“…Thus, contrary to current practice guideline recommendations, dietary sodium restriction may be detrimental particularly in early stage HF and contribute to the premature acceleration of PRA and excess aldosterone activation, and a more moderate sodium diet may aid in delaying the neurohormonal progression of early HF. It should be noted that in the study by Costello‐Boerrigter et al , in a canine model of early asymptomatic LV dysfunction, exogenous administration of the mineralocorticoid DOCA (deoxycorticosterone acetate) to mimic aldosterone failed to induce sodium retention but did induce early cardiac fibrosis. While findings are variable in the reported literature and our data do not support a recommendation for a specific desirable dietary sodium cut‐off point in humans, the current study supports the conclusion that careful assessment of dietary sodium in the setting of HF merits further prospective investigation, particularly in patients with Stage B and compensated Stage C HF receiving optimal medical therapy.…”