Mechanisms of Congestion in Acute Decompensated Heart Failure

Abstract

Background

Acute decompensated heart failure (ADHF) poses a challenging paradox of renal and cardiac pathophysiology, with volume excess or “congestion” being a key player. Understanding the mechanisms of congestion is crucial for effectively managing fluid overload and improving patient prognosis.

Summary

In this review, we evaluate the physiology of congestion and explore its implications for management in clinical practice. Mechanisms of congestion can largely be broken down under the subtext of fluid accumulation and fluid redistribution. Fluid accumulation develops as a consequence of neurohormonal dysregulation, physiologic maladaptive mechanisms, and detrimental crosstalk between the heart and the kidney. On the other hand, fluid redistribution evolves due to progressive overriding of compensatory vascular mechanisms, renal injury, and hormonal feedback.

Key Messages

Understanding the complex pathophysiology of congestion in ADHF is crucial for effective volume management and protection against long-term mortality and morbidity risks. By targeting both fluid accumulation and redistribution mechanisms, clinicians can optimize treatment strategies to alleviate congestion and restore hemodynamic stability in patients with ADHF.

Introduction

The kidney and heart maintain intricate communication and interdependence, impacting each other’s function significantly. Conditions affecting one organ can exacerbate the other, leading to adverse patient outcomes [1]. Increased body fluid volume portends poorer outcomes in both acute and chronic heart failures (HFs) linked to increased hospitalizations and cardiovascular mortality [2–4]. Effective decongestion is crucial for long-term mortality and morbidity reduction [4–8]. Volume overload contributes to impaired oxygenation, end-organ damage, prolonged hospital stays, and increased morbidity and mortality [9]. Clinically undistinguished hypervolemia is common in HF patients and associated with increased cardiac filling pressures and poor patient outcomes [10]. Abnormal fluid handling affects multiple organ systems, increasing myocardial water content and impairing contractility [11–13]. Deranged hemodynamics, neurohormonal activation, excessive tubular sodium reabsorption, inflammation, oxidative stress, and nephrotoxins are important for harmful cardiorenal interactions in HF patients [11–14]. Elevation of central venous pressure (CVP) transmitted to the renal veins causes increased interstitial and tubular hydrostatic pressure, lowering net glomerular filtration [15–21]. An increased CVP is independently associated with renal dysfunction and unfavorable outcomes in both acute and chronic HF [19–21], while venous congestion itself triggers endothelial activation, inflammation, and organ dysfunction [22]. [9]. The knowledge gaps in understanding mechanism of congestion lead to poor HF outcomes [23, 24]. The objective of this review was to discuss two principal concepts involved in development of congestion, namely, fluid accumulation and fluid redistribution. We explore various management strategies addressing each of these mechanisms in clinical practice.

Fluid Accumulation

Traditionally, fluid accumulation, especially in acute decompensated heart failure (ADHF) with reduced ejection fraction, is considered the primary component of congestion. This is linked to heightened neurohormonal activity causing inappropriate renal sodium and fluid retention, leading to cardiac function decline and cardiorenal syndrome (CRS). CRS encompasses various pathological interactions between the heart and kidneys, categorized by chronicity and primary organ dysfunction [16]. Although the pathophysiology of each subtype of CRS varies, hypervolemia and the need for its treatment are common denominators.

Renal retention of sodium and water results in expansion of intravascular and interstitial fluid volumes. In response to decreased cardiac output (CO), the kidney attempts to conserve fluid and maintain blood volume. However, the diminished CO leads to insufficient perfusion of the arterial system, resulting in arterial underfilling [25, 26]. This triggers neurohormonal activation, initially maintaining organ perfusion through sympathetic-driven vasoconstriction. However, ongoing fluid accumulation in the interstitial space expands plasma volume compensatory, sustaining intravascular volume expansion over time. Arterial underfilling, exacerbated by systolic dysfunction where only 30–40% of total blood volume resides in the arterial circulation, necessitates significant volume expansion to maintain tissue perfusion [25–27]. This compensatory mechanism initially sustains perfusion but becomes maladaptive, leading to volume overload and organ congestion. Increased blood volume elevates cardiac filling pressures, culminating in clinical signs of congestion. Before symptoms appear, several liters of fluid may accumulate in the interstitial space [28]. Despite diuretic treatment, which only partially reduces fluid excess, a cycle of incomplete response, fluid re-accumulation, and redistribution ensues, contributing to recurrent HF decompensation [28–30]. Hospitalized HF patients face heightened risk of readmission due to these recurring episodes [25–31]. Nonetheless, this once-prevailing concept of “arterial underfilling” as the single perpetrator of CRS cannot be fully explained by clinical observations, as many acute HF patients exhibit preserved CO alongside these phenomena [32–34]. One such study by Hanberg et al. [35] saw a weak inverse correlation between cardiac index (CI) and renal function in HF patients, with no evidence supporting CI as a primary driver of renal dysfunction, regardless of patient subgroup or CI changes over time.

Fluid volume expansion before decompensation has been confirmed by various methods beyond pulmonary artery pressure monitoring [1], including intra-thoracic impedance, B-type natriuretic peptide levels, and clinical assessment [36]. Signs of fluid excess, such as jugular venous distention and edema, are indicative but not universally present in ADHF, occurring in about 60% of cases and 20% of chronic HF cases [37–40]. Intravenous loop diuretics have been used in more than 90% of patients hospitalized for ADHF and remain pivotal in treatment [39, 41].

A progressive accumulation of fluid during an episode of cardiorenal dysfunction raises the total body fluid volume and causes venous congestion. The principal neurohumoral systems activated by HFrEF and HFpEF include the SNS, the renin-angiotensin-aldosterone system (RAAS), and the antidiuretic hormone/arginine vasopressin (AVP) system [42–44]. SNS activation entails increased release of norepinephrine (NE) [45]. Catecholamine-induced augmentation of ventricular contractility and heart rate may preserve CO initially. Nevertheless, with progressive worsening of ventricular function, an overactive SNS and enhanced cardiac NE content can become counterproductive by increasing myocardial oxygen demand and blunting the normal mechanisms that enhance ventricular contractility [46]. Moreover, NE released by an activated renal SNS increases renin release with a consequent increase in angiotensin II (Ang II) and aldosterone that stimulate renal tubular sodium reabsorption at many nephron sites, thereby contributing to the sodium and fluid retention that is characteristic of HF [46]. This is augmented by increased release of AVP that enhances the tubular reabsorption of free water. As such, beta-blockers and alpha-beta blockade with carvedilol, bisoprolol, and metoprolol [47] have well-established roles in the management of HF as do angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers, angiotensin receptor and neprilysin inhibitors, and mineralocorticosteroid receptor antagonists (MRAs) [48].

Each of the factors that normally can stimulate renal renin release is likely activated in HF. These include a decrease in the stretch of the glomerular afferent arteriole from reduced CO, a reduced delivery of chloride to the macula densa from reduced glomerular filtration rate (GFR) and enhanced proximal tubular fluid reabsorption, and an increased beta-1 adrenergic activity from an activated SNS drive [42, 44, 49, 50]. Moreover, studies in experimental models of HF demonstrate the added importance of the local RAAS that can also be activated in chronic HF [51]. Thus, a local cardiac Ang II and ACE system is increased in proportion to the severity of HF [52–56]. HF also induces a local production of aldosterone in proportion to disease severity [57] by induction of aldosterone synthase by AT1 receptor activation [57]. The increased activity of the systemic RAAS contributes to vasoconstriction and fluid accumulation [58], while an activated intrarenal RAAS contributes to NaCl and fluid retention [59, 60] and an activated local cardiac aldosterone system contributes to cardiac remodeling, fibrosis, and diastolic dysfunction [61]. Beta-blockers, ACEIs, angiotensin receptor blockers, sodium-glucose linked transporter 2 inhibitors [62], and MRAs [61, 63–65] reduce cardiovascular endpoints in many trials of patients with HF.

A dysfunctional natriuretic peptide system contributes to fluid accumulation in ADHF. However, a subset of patients with HF do not respond to the rising levels of natriuretic peptides with an increase in the estimated glomerular filtration rate (eGFR) and renal sodium excretion [66, 67]. This may relate in part to downregulation of renal natriuretic peptide receptors [68] and from an enhanced proximal tubular sodium reabsorption in HF that diminishes the delivery of tubular fluid to the major nephron site of action of natriuretic peptides in the distal nephron. Neprilysin inhibits natriuretic peptide metabolism, thereby enhancing its effects while valsartan blocks the AT1 receptor, thereby countering the adverse effects of excessive Ang II signaling. Sacubitril-valsartan was shown in the PARAGON-HF trial to be beneficial in patients with HF with reduced ejection fraction [69].

An increase in AVP activates vasopressin V2 receptors to enhance fluid retention in patients with ADHF and can lead to hyponatremia. The ongoing release of AVP represents dysfunctional baroreflex mechanisms that continue to enhance AVP release with a consequent increase in the reabsorption of free water in the distal nephron of the kidney despite a fall in plasma osmolality that should normally inhibit AVP release. Moreover, AVP also activates vasopressin (V1) receptors in vascular smooth muscle cells that can constrict coronary vessels and stimulate cardiac myocyte proliferation [70, 71]. A meta-analysis of randomized controlled trials of the effect of the V2 receptor antagonist, tolvaptan, in the treatment of HF reported a decrease in body weight and improved congestion without a significant increase in adverse events [72]. Despite these metrics, tolvaptan failed to improve mortality [73] and is expensive. Its precise role in therapy for CHF remains unclear.

There is growing evidence implicating renal afferent and efferent nerve activity in the pathophysiology of fluid retention and cardiac dysfunction in HF [74]. Renal baroreceptor afferent nerves are stimulated in HF by an increase in intrarenal pressure from renal venous congestion [75]. The increase in renal afferent nerve discharge increases renal efferent nerve activity that stimulates renin release. The ensuing combined increases in SNS and RAAS function can drive renal NaCl and fluid retention in CHF, worsening renal function in CKD [60, 76] and increasing peripheral vascular resistance [77]. These adverse effects may be perpetuated by diuretic therapy. Thus, we reported that the administration of loop diuretics to rats also increases intrarenal and intra-tubular pressure greatly, thereby reducing the RBF and the GFR via a mechanism that is dependent on renal afferent nerve activity [78]. Thus, renal congestion evoked by loop diuretic therapy for HF could contribute to both the CRS and diuretic resistance, though some components of this mechanism are yet to be demonstrated in human studies. Despite this drawback, benefits of diuretic usage in acute ADHF remain paramount for optimizing CO and reducing renal venous congestion. Nonetheless, catheter-based renal denervation shows promise for the management of patients with diuretic-resistant HF [79].

An increase in intrarenal interstitial pressure during renal venous congestion can stimulate renin release and Ang II generation [80] and an increase in renal vascular resistance [81]. The increased renal renin release could be a consequence of a decrease in the transmural pressure (or stretch) of the afferent arteriole, a reduction in the GFR and the delivery of NaCl to the macula densa, and an activation of the renal efferent nerves via a renorenal reflex mechanism. Together, these constitute potent stimuli to renin secretion and a rationale for RAAS blockade. Renal negative pressure therapy has the potential to counteract the detrimental effects of renal venous congestion in HF by reducing intrarenal tubular pressure and improving renal function. Renal negative pressure therapy has shown enhanced GFR, diuresis, and natriuresis even in the presence of congestive HF, offering a promising strategy for mitigating the pathophysiological consequences of renal congestion and potentially complementing RAAS blockade therapies [82].

Fluid Redistribution

An intercompartmental redistribution of fluid, rather than an absolute increase in blood volume, can be a major underlying mechanism for congestion in a subset of critically ill patients with fluid overload caused by ADHF. The hypothesis that fluid can shift from the interstitium to the circulating blood volume is supported by the observation that a significant subset of patients with ADHF develop congestion without significant changes in body weight [83]. Moreover, weight gain in HF may follow the increases in cardiac filling pressures rather than preceding them [84].

Fluid redistribution can result from a reduction in the compliance of the splanchnic arterial and venous systems leading to a rapid redistribution of splanchnic fluid into the cardiopulmonary circulation [85]. A reduced splanchnic arterial compliance can increase the systemic resistance and therefore the afterload, while a reduced splanchnic venous compliance can increase venous return and CVP and therefore the preload. Since the failing heart cannot tolerate an increased load, these effects can cause cardiac decompensation [86, 87].

Fallick et al. [85] argued that because congestion does not inevitably result from fluid overload, removal of sodium and water with diuretics may not always be rational and, by depleting the intravascular volume that triggers activation of the SNS and the RAAS, may even worsen renal function and ultimately precipitate a CRS. Indeed, vasodilator therapy for patients with ADHF can reduce vasoconstriction and vascular stiffness and thereby improve cardiac function [88, 89]. Vasodilators may also directly increase renal fluid excretion as they reduce the filtration fraction and oncotic uptake of reabsorbed fluid by the proximal tubule, thereby enhancing the response to loop diuretics [90]. However, the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) study failed to demonstrate significant clinical benefit of vasodilator therapy in ADHF [91]. Moreover, the randomized, double-blinded Diuretic Strategies in Patients with Acute Decompensated Heart Failure (DOSE) study reported that high-dose diuretics for patients with ADHF provided only modest relief of symptoms of congestion [23]. This DOSE trial was originally considered to have a neutral outcome because the symptomatic benefit was counterbalanced by a rise in serum creatinine (sCr). At the time, eGFR was recognized to be negative predictor of mortality, cardiovascular death, and rehospitalization in patients with CHF [92]. However, a study of community-based patients with CHF revealed a U-shaped relationship between eGFR and mortality [93]. While acute kidney injury, congestion, and CKD in patients hospitalized for ADHF clearly do have adverse effects, much of the fall in eGFR that can occur with decongestion therapy in hospital can be related to the anticipated hemodynamic effects of drugs that correct renal glomerular hyperfiltration, such as RAAS inhibitors and sodium-glucose linked transporter 2 inhibitors and MRAs rather than damage to the kidneys. Indeed, a fallen eGFR indicates effective drug dosing. Reviewing the data, Testani et al. concluded that worsening renal function during hospitalization for ADHF is generally benign [94], especially in the context of treatment with ACEis [95], as in the DOSE trial. Therefore, aggressive diuresis with increased doses of intravenous loop diuretics is beneficial for many patients with ADHF to achieve an effective diuresis despite some rise in sCr concentration that is not usually counterproductive in this setting [96].

Fluid accumulation and redistribution represent two complimentary mechanisms for congestion. Future mechanistic studies are needed to clarify the pathophysiologic pathways leading to clinical congestion in ADHF.

Conclusion and Future Directions

Fluid overload in HF correlates with increased morbidity and mortality. Understanding the complex pathophysiology of ADHF and the dynamic interaction between the kidneys and heart is crucial for guiding clinical management and developing evidence-based interventions. Therapeutic options should be selected based on the underlying mechanism of fluid imbalance – whether it is global fluid accumulation or predominant fluid redistribution. For patients with minimal fluid accumulation but significant fluid redistribution, vasodilators may offer greater benefit by improving tissue perfusion and reducing venous congestion. In contrast, patients with significant fluid accumulation, particularly in the setting of HF or renal impairment, will likely require diuretics to facilitate fluid removal and alleviate symptoms of overload. Tailoring therapy to the specific pathophysiological processes is essential for optimizing patient outcomes.

Further research into clinical biomarkers and diagnostic tests that accurately assess volume status and predict decompensation is essential to help inform treatment decisions. Current challenges include the inability to precisely estimate fluid excess and determine optimal fluid status posttreatment, leading to frequent HF rehospitalizations. Biomarkers like natriuretic peptides offer diagnostic and prognostic insights but cannot quantitatively measure fluid excess or guide HF therapy due to multiple influencing factors.

Similarly, sCr elevation, often interpreted as worsening renal function, can prematurely halt decongestive therapies, contributing to poor outcomes in fluid-overloaded HF patients. Methods such as hemoconcentration, lung, and inferior vena cava ultrasound provide simple volume status assessments but require further validation. Blood volume analysis is the most accurate method for extracellular fluid and renal cortical volume measurement but is underutilized due to perceived complexity.

Advancements in technology, like hand-held echocardiography and implantable hemodynamic monitors, show promise for serial hemodynamic monitoring in HF management [97]. Therapy guided by implantable monitors has demonstrated reduced rehospitalizations, regardless of ejection fraction, and suggests potential mortality benefits with pulmonary artery pressure-guided approaches [98].

While ultrasound and bioelectrical impedance analysis offer alternative methods for fluid volume assessment, their comparative effectiveness against blood volume analysis and invasive hemodynamic measures remains uncertain. Rigorous research is necessary to establish their accuracy, sensitivity, and specificity in quantifying fluid excess and monitoring response to fluid removal therapies. Overall, advancing our understanding of ADHF mechanisms alongside validating reliable fluid assessment methods is critical for improving risk stratification, optimizing clinical care, and enhancing outcomes for HF patients.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This review was not supported by any sponsor or funder.

Author Contributions

A.K. and N.P. conceived the presented idea and conducted the literature review for the initial draft. K.M. performed a critical analysis and interpretation of the results to inform and develop the manuscript. All authors contributed to writing and revising the manuscript and approved the final version.

Funding Statement

This review was not supported by any sponsor or funder.