Edema formation in congestive heart failure and the underlying mechanisms

Abstract

Congestive heart failure (HF) is a complex disease state characterized by impaired ventricular function and insufficient peripheral blood supply. The resultant reduced blood flow characterizing HF promotes activation of neurohormonal systems which leads to fluid retention, often exhibited as pulmonary congestion, peripheral edema, dyspnea, and fatigue. Despite intensive research, the exact mechanisms underlying edema formation in HF are poorly characterized. However, the unique relationship between the heart and the kidneys plays a central role in this phenomenon. Specifically, the interplay between the heart and the kidneys in HF involves multiple interdependent mechanisms, including hemodynamic alterations resulting in insufficient peripheral and renal perfusion which can lead to renal tubule hypoxia. Furthermore, HF is characterized by activation of neurohormonal factors including renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system (SNS), endothelin-1 (ET-1), and anti-diuretic hormone (ADH) due to reduced cardiac output (CO) and renal perfusion. Persistent activation of these systems results in deleterious effects on both the kidneys and the heart, including sodium and water retention, vasoconstriction, increased central venous pressure (CVP), which is associated with renal venous hypertension/congestion along with increased intra-abdominal pressure (IAP). The latter was shown to reduce renal blood flow (RBF), leading to a decline in the glomerular filtration rate (GFR). Besides the activation of the above-mentioned vasoconstrictor/anti-natriuretic neurohormonal systems, HF is associated with exceptionally elevated levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). However, the supremacy of the deleterious neurohormonal systems over the beneficial natriuretic peptides (NP) in HF is evident by persistent sodium and water retention and cardiac remodeling. Many mechanisms have been suggested to explain this phenomenon which seems to be multifactorial and play a major role in the development of renal hyporesponsiveness to NPs and cardiac remodeling. This review focuses on the mechanisms underlying the development of edema in HF with reduced ejection fraction and refers to the therapeutic maneuvers applied today to overcome abnormal salt/water balance characterizing HF.

Keywords: Na+ retention; cardiorenal syndrome; edema; heart failure; intra-abdominal pressure; mechanisms; neurohumoral; renal venous congestion.

FIGURE 1

Mechanisms of edema formation in HFrEF. Myocardial damage of various etiologies may lead to cardiac dysfunction as evident by reduced cardiac output and ejection fraction. The resultant reduced organ blood flow promotes activation of neurohormonal systems (SNS, RAAS, AVP, and ET-1) which leads to salt and fluid retention, often exhibited as pulmonary congestion, peripheral edema, dyspnea, and fatigue. Unique relationship between the heart and the kidney plays a central role in this phenomenon. Specifically, the interaction between the heart and kidney in HF is complex and involves multiple interdependent mechanisms which includes (1) hemodynamic alterations resulting in insufficient peripheral and kidney perfusion, (2) HF is characterized by elevated central venous pressure (CVP), which is associated with renal venous hypertension/congestion along with increased intra-abdominal pressure (IAP). The latter was shown to reduce RBF, leading to a decline in GFR. Moreover, persistent activation of neurohormonal factor along with reduced renal response to NPs aggravates the hypoperfusion and hypofiltration due to their vasoconstrictive and tubular Na+ and H₂O retaining properties which further aggravates CVP and IAP and eventually the development of edema. ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; AVP, arginine vasopressin; ET-1, endothelin 1; LV, left ventricle; NPs, natriuretic peptides; RAAS, renin angiotensin aldosterone system; SNS, sympathetic nervous system.

FIGURE 2

Impact of congestive venous pressure (CVP) and increased intra-abdominal pressure (IAP) on kidney function in heart failure. Elevated CVP is transmitted back to the renal veins leading to renal dysfunction (A). The contribution of renal venous congestion to renal dysfunction in HF is complex and involves multiple mechanisms, including increased pressure along the renal vasculature without decline in ΔP, decreasing the net pressure gradient filtration pressure (NFP) across the glomerulus and thereby reduced GFR (C). In addition, the increase in renal venous pressure can increase intrarenal interstitial pressure leading to compression of the tubules, increased tubular fluid pressure (B), with reduced GFR due to an increase in hydrostatic pressure in the Bowman’s capsule (C). In addition, reduced GFR and sodium excretion may develop secondary to intra-abdominal hypertension (IAH), a hallmark feature of decompensated CHF (A–C). The diverse deleterious renal effects of elevated IAP may overlap with those of venous congestion. There is a direct compression of abdominal contents that result in a prominent reduction in RBF (compression of renal arteries) and elevation in renal parenchymal and renal vein pressures (A–C). RBF, renal blood flow; GFR, glomerular filtration rate; CVP, central venous pressure; IAP, intraabdominal pressure; PTP, proximal tubular pressure. ΔP, hydrostatic pressure gradient.

FIGURE 3

Algorithm for decongestive therapy.