American Heart Journal
Volume 155, Issue 1 , Pages 1-5, January 2008

The pathophysiology of acute heart failure—It is a lot about fluid accumulation

  • Marco Metra, MD

      Affiliations

    • Section of Cardiovascular Diseases, Department of Experimental and Applied Medicine, University of Brescia, Brescia, Italy
    • ,
  • Livio Dei Cas, MD

      Affiliations

    • Section of Cardiovascular Diseases, Department of Experimental and Applied Medicine, University of Brescia, Brescia, Italy
    • ,
  • Michael R. Bristow, MR, MD, PhD

      Affiliations

    • UCHSC Division of Cardiology, University of Colorado, Denver, CO

published online 22 November 2007.

Article Outline

 

Acute heart failure (AHF) is the most common single cause of hospitalization for patients >65 years, accounting for about 2% of all hospitalizations as principal diagnosis and for 4% when listed with other conditions.1, 2 The inhospital mortality of AHF varies from 4%3, 4 to 7% to 8%.5, 6, 7, 8 Follow-up after the hospitalization is characterized by a high incidence of death (8%-15% at 2-3 months)6, 7, 9, 10 and rehospitalizations (30%-38% at 3 months).4, 5, 6, 9 Although the rate of deaths and hospitalizations seems to have reached its peak in the last few years, there is still a continuous increase in the number of AHF episodes because of aging of the population and improvement in cardiovascular care.1, 2, 11

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Editorial of Cotter et al: A comprehensive look at AHF 

In their stimulating editorial, Cotter et al12 challenge the concept that AHF may be simply related to fluid accumulation. They show that the mechanisms involved may be many and more complex. In particular, they distinguish 2 main categories of AHF: acutely decompensated heart failure (ADHF) and acute vascular failure (AVF). The second category is characterized by increased vascular resistance and aortic impedance, a high systemic blood pressure, and frequently normal left ventricular (LV) ejection fraction.

Cotter et al12 propose that, different from the widely held belief, fluid accumulation is not the main characteristic but just one of many aspects of AHF presentation. Trying to organize the multiple mechanisms involved in the pathogenesis of either ADHF or AVF, they have grouped them into mechanisms activated in the initial phase and mechanisms activated in the amplification phase. The mechanisms responsible for the initiation of an episode of ADHF are impaired cardiac contractility, possibly further reduced by ischemia, arrhythmias, inflammation, and/or acute progression of myocardial dysfunction, and renal insufficiency, possibly further impaired by hypoperfusion caused by the low cardiac output. It is then recognized that these mechanisms may also lead to fluid accumulation. The mechanisms causing AVF are, in contrast, increased peripheral vascular resistance and aortic impedance causing LV diastolic dysfunction and, importantly, rather than fluid accumulation, blood redistribution from the peripheral circulation to the pulmonary circulation. The latter occurs secondary to increased pulmonary venous pressure, with consequent increased pressure in the pulmonary capillary bed and pulmonary interstitial and alveolar edema. The mechanisms that may intervene in the amplification phase include arrhythmias, myocardial necrosis, right ventricular failure, respiratory failure, leakage of the alveolar-capillary membrane and decreased alveolar fluid removal, and renal failure.12 This phase is therefore characterized by further worsening of cardiac function and by development of multiorgan failure, primarily pulmonary and renal.

Cotter et al12 are to be applauded for their effort to highlight the multiple mechanisms that may initiate an episode of AHF and then worsen it. The distinction between ADHF and vascular AHF may be essential for our understanding and treatment of AHF, and this concept should be endorsed and further tested in prospective trials designed to specifically intervene in one category versus the other. The ADHD/AVF construct was previously proposed by the same authors,13 and it is largely embodied in the classification of the AHF guidelines of the European Society of Cardiology.14 In fact, most episodes of AHF can be classified into these main categories. According to the recent EuroHeart Failure Survey II, ADHF accounts for 65.4% of the cases of AHF, and hypertensive AHF and acute pulmonary edema, which may both be grouped, at least partially, into the category of vascular AHF, account for 16.2% and 11.4% of the episodes, respectively.5

Cotter et al12 have nicely shown the multiple mechanisms that may cause AHF. We agree that they are all extremely important, and the authors have made an important contribution in describing them. We also agree that most of the episodes of AVF occur in the absence of fluid accumulation and as a consequence of increased aortic impedance with increased LV filling pressure, pulmonary venous and capillary pressure, and lung fluid accumulation. This hypothesis is also consistent with the rapid onset of vascular AHF,13, 14 the frequent finding of high blood pressure,4, 15 and the beneficial effects of vasodilator therapy as compared with high doses of diuretics in some patients.16 Cotter et al12 propose that elements of both types of AHF may be operating in most patients, with a minority dominated by one set of mechanisms versus the other. However, in contradistinction to Cotter et al,12 we suggest that the mechanisms involved in ADHF are different from those involved in AVF, with fluid accumulation being the essential and main mechanism of ADHF. We will summarize herein the critical data demonstrating the pathophysiologic importance of fluid accumulation, with pulmonary congestion and peripheral edema, in these patients.

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Fluid accumulation in AHF 

At the time of hospitalization 

Despite the multiple mechanisms that may be involved in the pathogenesis of AHF, fluid accumulation remains the most important factor causing hospitalization of patients with AHF. Dyspnea, pulmonary rales, and/or peripheral edema are by far the most common symptoms and clinical signs reported in AHF surveys of patients hospitalized for AHF (Table I).4, 7, 10, 17, 18, 19 As noted by Cotter et al,12 dyspnea and pulmonary rales may not necessarily imply fluid accumulation, but rather, a redistribution of fluid from the peripheral to the pulmonary circulation. This is the case for most patients admitted with acute pulmonary edema or de novo AHF (ie, AVF). However, patients with ADHF have more gradual clinical worsening, characterized by progressive increase in body weight and peripheral edema. Fluid accumulation is therefore generally the cause of their hospitalization.

Table I. Symptoms and signs causing AHF hospitalization in patients enrolled in registries and surveys
Study (acronym or site)Zurich and Helsinki7ADHERE3IMPACT-HF registry10OPTIMIZE-HF4Worcester, MA18Italian survey on AHF6EFICA19
Year2005200520052006200520062006
No. of patients312652755674861226042807581
Dyspnea (%)948977/47⁎61/44⁎93100
Orthopnea (%)72 41 36
Fatigue (%) 37 28
Chest pain36 30 14
Rales (%) 676464 8782
Peripheral edema (%) 6659657059/39†27

⁎The first value refers to dyspnea on exertion, the second to dyspnea at rest.

†Indicated as peripheral congestion and jugular venous pressure >6 cm.

Before the hospitalization 

Heart failure (HF) management programs have been developed for early detection of clinical deterioration and prevention of HF hospitalizations. Accurate control of body weight is an essential component of most of these programs.20, 21 However, body weight is a relatively insensitive index of fluid accumulation, and research is focusing on tools able to detect fluid accumulation at earlier stages.

New devices monitoring intrathoracic impedance or pulmonary artery pressure are currently being evaluated for early detection of lung fluid accumulation and prevention of HF hospitalizations. Intrathoracic impedance is inversely related to lung fluid content and pulmonary wedge pressure. It may be measured through either implantable devices22 or noninvasive impedance cardiography.23 A study performed using an implantable device has shown that a 12% ± 5% decrease in intrathoracic impedance occurs at a mean of 18 ± 10 days before the onset of worsening HF symptoms in patients with HF.22 Measurement of thoracic electrical impedance every 2 weeks by means of noninvasive impedance cardiography has shown a decrease in stroke index and an increase in thoracic fluid content in the visit before the episode of clinical HF decompensation. The finding of both a low stroke index and an increased thoracic fluid content was associated with a 6.5-fold increase in subsequent hospitalization compared with normal values. An intermediate 3-fold increase in risk was associated with either a low stroke index or increased intrathoracic fluid content.23

Continuous monitoring of right ventricular pressures through an implantable hemodynamic monitor has shown that an increase in right ventricular pressure occurs 4 ± 2 days before most episodes of clinical exacerbations of HF.24 In the largest prospective study completed to date, 274 patients with New York Heart Association class III to IV HF were implanted with a hemodynamic monitor and randomized to treatment based on knowledge of hemodynamic data and compared with controls without hemodynamic monitoring. Knowledge of hemodynamic data was associated with a 22% decrease in HF events, which reached statistical significance (−41%, P = .03) compared with control, in New York Heart Association class III patients.25 Monitoring of plasma biomarkers, namely, brain natriuretic peptide, has been proposed as surrogate of hemodynamic measurements and may also be useful for prevention of HF hospitalizations.26

After the hospitalization: relation with prognosis 

Freedom from congestion at the time of discharge is one of the most powerful predictors of a favorable prognosis in the patients who have been hospitalized for ADHF. Because clinical signs have a relatively low sensitivity (58%) for the detection of elevated pulmonary wedge pressure,27 direct measurement by pulmonary artery catheterization or related parameters, such as serum brain natriuretic peptide or a restrictive pattern of LV filling on Doppler echocardiography, is useful for prognostic stratification of patients admitted for ADHF.28, 29, 30 Similarly, lack of congestion is associated with low mortality in ambulatory patients.31, 32, 33 Patients with 3 to 5 signs of congestion (orthopnea, jugular venous stasis, peripheral edema, weight gain, or need to increase diuretic doses) at a 1-month reassessment after an ADHF hospitalization had a 3-fold increase in mortality and a 2-fold increase in hospitalizations, compared with those who had remained free of congestion, in a recent analysis of patients enrolled in the ESCAPE trial.34

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Pathogenetic mechanisms 

Multiple data therefore consistently demonstrate the central role of fluid accumulation in the pathogenesis of symptoms and clinical signs leading to worsening symptoms of HF and patient hospitalization. Fluid accumulation and increased intraventricular pressure may also have long-term untoward effects. Increased LV filling pressure and myocardial stretch are among the most powerful mechanisms causing neurohormonal activation, activation of adverse gene expression programs, and induction of myocyte apoptosis in patients with HF. Fluid overload and increased ventricular volumes therefore foster LV remodeling and mitral regurgitation both directly, through myocardial stretch, and indirectly, through the activation of renin-angiotensin-aldosterone, adrenergic, and cytokine systems.35 Fluid accumulation and increased intraventricular pressure also cause coronary hypoperfusion and subendocardial ischemia, which may further impair cardiac function. They also contribute to impaired exercise capacity, as demonstrated by studies showing that fluid removal is associated with an improvement in exercise duration in patients with stable chronic HF, seemingly free of clinical signs of congestion.36, 37

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What to do 

The importance of fluid congestion in patients with HF does not imply that this recognition necessarily leads to effective treatment. Since its introduction into clinical practice in the 1960s, furosemide remains the mainstay, if not, generally, the only, treatment for fluid accumulation. This occurs despite the increasing awareness of the potential untoward effects of loop diuretics on the progression of HF and HF prognosis.38, 39, 40 Furosemide administration is, in fact, associated with potentially lethal electrolyte abnormalities, neurohormonal activation, worsening renal function, and lastly, resistance to its administration.41, 42, 43 Measurements to inhibit the untoward effects and/or increase the potency of loop diuretics are therefore urgently needed. One such alternative, ultrafiltration, allows removal of isotonic fluid and, different from diuretic therapy, is not associated with neurohormonal activation.44 New devices have overcome most of the limitations of this procedure. Recently, ultrafiltration has been associated with a greater weight loss and lower incidence of rehospitalizations in a randomized trial comparing it with intravenous furosemide therapy in patients with ADHF. No significant difference in symptoms was observed between the 2 treatments, however.45 In contrast, increased weight loss with the oral vasopressin antagonist tolvaptan has been associated with improvement in dyspnea but no change in short- or long-term clinical course compared with placebo, in the large EVEREST trial, performed in 4133 patients with ADHF.46, 47 It may be speculated that the increased hypo-osmotic water diuresis induced by tolvaptan may affect only short-term symptoms, whereas isotonic fluid removal by ultrafiltration has long-term beneficial effects on the incidence of HF decompensation episodes. However, the results of the EVEREST trial are also consistent with the lack of importance of vasopressin as a mechanism causing HF progression and/or loss of efficacy of tolvaptan in the long-term. The apparently superior results with ultrafiltration may, on the other hand, be related to the unblinded design of the studies performed.

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Concluding remarks 

We agree with Cotter et al12 that what is needed are prospective trials testing therapeutic interventions designed to mitigate fluid overload or vascular dysfunction specifically, in patients exhibiting a dominance of one set of mechanisms versus the other. The active control for each of these could and should be “nonspecific” treatment of AHF according to guidelines, driven by diuretic therapy. Given the poor outcomes and high study withdrawal rates in this very ill patient population, these trials will be quite challenging to perform. However, the high incidence of HF hospitalizations, an excellent end-point for clinical trials, in these patients, means that sample sizes need not be large. Based on the magnitude of the unmet need and the size of the market, this scenario should provide the necessary incentive to attract investment in resources required to address the problem.

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PII: S0002-8703(07)00822-8

doi:10.1016/j.ahj.2007.10.011

American Heart Journal
Volume 155, Issue 1 , Pages 1-5, January 2008

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