Diagnosis and Management of Acute Heart Failure

Nomenclature and Definition

A variety of overlapping terms have been used to characterize AHF in the literature, including “acute heart failure syndromes” (AHFS), “acute decompensated heart failure” (ADHF), “acute decompensation of chronic heart failure” (ADCHF), “worsening heart failure” (WHF), and “hospitalization for heart failure” (HHF). Although none of these is universally accepted, we will use the terminology “acute heart failure” in this chapter for simplicity. Broadly speaking, AHF can be defined as the new onset or recurrence of symptoms and signs of HF requiring urgent or emergent therapy and resulting in unscheduled care or hospitalization. An important source of confusion with this proposed definition is the word “acute”—although this suggests a sudden onset of symptoms, many patients may have a more sub-acute course, with gradual worsening of symptoms that ultimately reaches a level of severity sufficient to seek unscheduled medical care.

Scope of the Problem

In the United States, HF is the primary diagnosis for more than 1 million hospitalized patients annually, and a secondary diagnosis for an additional 3 million hospitalizations. Similar numbers of hospitalizations are reported in Europe. The direct and indirect costs associated with HF approach 40 billion US dollars per year in the United States, and the majority of these expenditures are related to the costs of hospitalizations. ^, As noted earlier, the overall prevalence of chronic heart failure continues to grow. However, recent data suggest that the age-adjusted rate of HHF has begun to decrease, at least for primary heart failure events. To what extent these changes are related to more effective treatments of chronic heart failure or alternatively, changes in care to create alternative care pathways for avoiding hospitalization is unknown. Changes in medical care (especially in the United States) have led to increased efforts to manage milder forms of WHF without hospitalization, utilizing outpatient diuretic clinics and observation units, although available data suggest that even these milder forms of decompensation are still associated with adverse prognosis. ^, Despite these potentially encouraging trends, AHF will be a major clinical and economic problem for health care systems for the foreseeable future. An important development in the understanding of the epidemiology, clinical characteristics, and outcomes of patients with AHF has been the development of large, relatively unselected registries of AHF which provide a “real-world” perspective on the epidemiology and outcomes of AHF worldwide ( Table 49.1 ).

Ejection Fraction

On the basis of available registry data, 40% to 50% of patients hospitalized have heart failure with preserved ejection fraction (HFpEF). Important epidemiologic differences exist between heart failure with reduced ejection fraction (HFrEF) and HFpEF (see Chapter 48 ). The in-hospital mortality of patients with HFpEF appears to be lower compared with that of patients with HFrEF, but post-discharge rehospitalization rates and long-term mortality after hospitalization are similarly high for both groups. Patients with AHF and HFpEF are more likely to be rehospitalized for and to die from non-CV causes than patients with AHF and HFrEF, reflecting their more advanced age and greater burden of comorbidity. More recently, the concept of heart failure with “mid-range ejection fraction” or “mildly reduced ejection fraction,” that is, HF-mrEF, has been proposed as an additional refinement of the standard HFrEF vs HFpEF dichotomy, but specific data on AHF outcomes in this group are limited ( Fig. 49.2 ).

Age, Race, and Gender

There are significant differences in the epidemiology of AHF based on age, race, and gender. AHF disproportionally affects older people, with a mean age of 75 years in large registries. AHF affects men and women almost equally, but there are important differences by gender. In the ADHERE registry women admitted for AHF were older than men (74 vs. 70 years), and more frequently had preserved systolic function (51% vs. 28%). Differences in ethnic groups have been studied most extensively in the United States and have focused primarily on differences between African American and white patients. In the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry, African American patients admitted with AHF were younger (64 vs. 75 years), more likely to have left ventricular (LV) systolic dysfunction (57% vs. 51%) with a lower mean EF (35% vs. 40%), hypertensive cause for heart failure (39% vs. 19%), renal dysfunction, and diabetes compared to the non–African American group. Lower crude mortality rates have been reported for African Americans compared to non–African American patients, but when adjustments are made for these differences in comorbidities and age, mortality rates are similar.

Comorbidities

Concomitant diseases are very common in patients admitted with AHF, reflective of the older population. These comorbidities not only represent diseases that are risk factors for the development of heart failure, but also can complicate diagnosis and management. Hypertension is the most prevalent concurrent condition, present in approximately two-thirds of the patients (see also Chapter 26 ), whereas coronary artery disease (CAD) is present in about half and dyslipidemia in over one-third (see Chapters 27 and 40 ). ^, Other conditions that are the result of the vascular injury produced by these diseases, such as stroke, peripheral vascular disease, and chronic kidney disease are also very common in patients with AHF. Diabetes mellitus is present in over 40% of US patients, most likely related to increasing incidence of obesity, and ranges from 27% to 38% in Europe. The interaction between heart failure status and diabetes has been a subject of substantial interest, given the evolving data that some classes of anti-diabetic drugs, specifically the sodium-glucose co-transporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists, have a favorable impact on heart failure outcomes (see Chapter 50 ). Atrial fibrillation can both precipitate AHF and complicate its management.

Global Differences in Acute Heart Failure

Although the majority of data continues to emerge from North America and from Europe, AHF is increasingly recognized as a global issue, and important differences between regions of the world have emerged in terms of epidemiology, therapy, and outcomes. Although there are a variety of country- or region-specific registries (see Table 49.1 ), to date most available data highlighting these differences have come from large global outcome trials. Although these studies can provide important insight into regional differences, they suffer from inherent selection bias of clinical trials and may not be truly representative of the general population. The recently reported REPORT-HF registry provides a more contemporary assessment of AHF globally (see Table 49.1 ).

Congestion

Systemic or pulmonary congestion often due to a high ventricular diastolic pressure dominates the clinical presentation of most patients hospitalized for AHF. Congestion can be seen as a final common pathway producing clinical symptoms leading to hospitalization. An oversimplified view of AHF pathophysiology is that gradual increases in intravascular volume lead to symptoms of congestion and clinical presentation, and normalization of volume status with diuretic therapy results in restoration of homeostasis. Although some data suggest that increases in body weight often precede decompensation and hospitalization for HF, careful studies using implantable hemodynamic monitors suggest that increases in invasively measured LV filling pressures can occur without substantial changes in body weight. These observations have led to increasing interest in the concept of volume redistribution and the dynamic role of the vasculature as a contributing mechanism to decompensation in heart failure (discussed in more detail in “Vascular Mechanisms” section below).

One important concept is the distinction between “clinical congestion” and “hemodynamic congestion.” Although patients present with signs and symptoms of systemic congestion such as dyspnea, rales, elevated jugular venous pressure (JVP), and edema, this state is often preceded by “hemodynamic congestion,” defined as high ventricular diastolic pressures without overt clinical signs. Similarly, clinical congestion may resolve with treatment but hemodynamic congestion may persist, leading to a high risk of rehospitalization. It has been postulated that hemodynamic congestion may contribute to the progression of HF because it may result in increased wall stress as well as in renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) activation. This may trigger a variety of molecular responses in the myocardium, including myocyte loss and increased fibrosis. The natriuretic peptides (see Chapter 47 ), which are the intrinsic counter-regulatory hormone in heart failure, may have abnormal processing that leads to diminished biologic activity in patients with advanced heart failure. In addition, elevated diastolic filling pressures may decrease coronary perfusion pressure, resulting in sub-endocardial ischemia that may further exacerbate cardiac dysfunction. Increased LV filling pressures can also lead to acute changes in ventricular architecture (more spherical shape), contributing to worsening mitral regurgitation. These mechanisms also play an important role in pathologic remodeling of the ventricle, a chronic process that may be accelerated by each episode of decompensation. Consistent with this paradigm is the well-established clinical observation that each hospitalization for AHF heralds a substantial worsening of the long-term prognosis, an effect that appears additive with recurrent hospitalizations. Data from studies with implantable hemodynamic monitors have confirmed that chronically elevated filling pressures (i.e., hemodynamic congestion) are associated with increased risk of future events. With the recognition of congestion as the most common aspect of AHF presentation, there has been a formal attempt to better assess and quantitate congestion in heart failure.

Myocardial Function

Although a variety of extra-cardiac factors play important roles in AHF, impairments of cardiac function (systolic, diastolic, or both) remain central to our understanding of this disorder (see also Chapter 46 ). Changes in systolic function and decreased arterial filling can initiate a cascade of effects that are adaptive in the short term but maladaptive when elevated chronically, including stimulation of the SNS and RAAS. Activation of these neurohormonal axes leads to vasoconstriction, sodium and water retention, volume redistribution from other vascular beds, increases in diastolic filling pressures, and clinical symptoms. In patients with underlying ischemic heart disease, initial defects in systolic function may initiate a vicious cycle of decreasing coronary perfusion, increased myocardial wall stress, and progressively worsening cardiac performance. Increased LV filling pressures and changes in LV geometry can worsen functional mitral regurgitation, further decreasing cardiac output.

Importantly, abnormalities in diastolic function are present in heart failure patients regardless of EF. The impairment of the diastolic phase may be related to passive stiffness, abnormal active relaxation of the left ventricle, or both. Hypertension, tachycardia, and myocardial ischemia (even in the absence of CAD) can further impair diastolic filling. All of these mechanisms contribute to higher LV end-diastolic pressures, which are reflected back to the pulmonary capillary circulation. Diastolic dysfunction alone may be insufficient to lead to AHF, but it serves as the substrate on which other precipitating factors (such as atrial fibrillation, CAD, or hypertension) lead to decompensation. One underappreciated aspect of myocardial function in AHF relates to the interdependence of the left and right ventricles. Because of the constraints of the pericardial space, distention of either ventricle due to increased filling pressures can result in direct impingement of diastolic filling of the other ventricle. This may be particularly operative in clinical scenarios leading to abrupt failure of the right ventricle (such as pulmonary embolism or right ventricular (RV) infarction), resulting in diminished filling of the left ventricle and arterial hypotension.

The availability of increasingly sensitive assays for circulating cardiac troponins has led to evolution of our understanding of the role of myocardial injury in AHF pathophysiology. Data from both registries and clinical trial populations indicate that circulating cardiac troponins are elevated in a large proportion of patients with AHF, even in the absence of clinically overt myocardial ischemia. ^, In a representative analysis of data from the RELAX-AHF study using a highly sensitive assay, 90% of patients enrolled had a troponin T level above the 99th percentile upper reference limit at baseline, and troponin elevation was associated with post-discharge outcomes out to 180 days ( Fig. 49.4 ).

The precise mechanisms mediating myocardial injury in AHF are poorly defined, but increased myocardial wall stress, decreased coronary perfusion pressure, increased myocardial oxygen demand, endothelial dysfunction, activation of the neurohormonal and inflammatory pathways, platelet activation, and altered calcium handling may all contribute to myocyte injury even in the absence of epicardial CAD. Specific therapeutic interventions that may increase myocardial oxygen demand (such as positive inotropic agents) or decrease coronary artery perfusion pressure (such as some vasodilators) may exacerbate myocardial injury and further contribute to the cycle of decompensation. Whether avoidance of myocardial injury is a specific target for therapy in AHF remains a subject of active investigation.

Renal Mechanisms

The kidney plays two fundamental roles relative to the pathophysiology of HF: it modulates loading conditions of the heart by controlling intravascular volume and is responsible for neurohormonal outputs (i.e., the RAAS system). Abnormalities of renal function are extremely common in patients with AHF and may be underestimated by creatinine alone. Baseline chronic kidney disease is an established risk factor for poor outcomes in AHF (see Risk Stratification section later), but our understanding of the implications of changes in renal function during AHF treatment has continued to evolve. The term “cardio-renal syndrome” has been increasingly used to describe pathologic interactions between the cardiac and renal axes in the setting of heart failure. Although specific definitions and nomenclature have varied, in the context of AHF the cardio-renal syndrome describes the clinical situation of worsening measures of renal function in the setting of persistent congestion. This clinical scenario has been associated with poor outcomes in a variety of observational studies. Multiple studies have investigated the pathophysiology and risk factors for this phenomenon, which is related to an intricate interplay of patient characteristics (age), comorbidities (baseline renal function as assessed by glomerular filtration rate [GFR], diabetes mellitus, hypertension), neurohormonal activation (especially of RAAS and SNS), and hemodynamic factors (central venous congestion, and less frequently arterial underfilling with renal hypoperfusion), as well as other factors such as activation of inflammatory cascades and oxidative stress. Although often assumed to be related to low cardiac output and renal blood flow, careful hemodynamic studies have repeatedly confirmed that the strongest predictor of worsening renal function in heart failure patients relates to elevated central venous pressure (CVP), which is reflected back to the renal veins and leads directly to changes in GFR. Importantly, recent data have emphasized the importance of evaluating changes in renal function in the context of the overall clinical picture. Worsening renal function in the setting of ongoing clinical improvement is generally reflective of successful decongestion and does not portend a poor prognosis ( Fig. 49.5 ). Although there has been substantial interest in the utility of newer biomarkers to identify episodes of frank kidney injury prior to changes in markers of renal function, the clinical utility of these markers remains uncertain. A detailed classification system for understanding the interplay between cardiac performance and renal function has been proposed and provides a framework for understanding the complex pathophysiology underlying the cardio-renal syndrome.

Vascular Mechanisms

While abnormalities in cardiac function are central to the pathogenesis of AHF, there is increasing appreciation for the importance of the peripheral vasculature in this disorder. Abnormalities of endothelial function related to nitric oxide dependent regulation of vascular tone are well described in heart failure. Arterial stiffness, which is related to but distinct from blood pressure, increases cardiac loading conditions and is associated with incident heart failure and worse outcomes. Peripheral vasoconstriction in the setting of AHF redistributes blood centrally, increasing pulmonary venous congestion and edema. As noted earlier, elevated CVP reduces renal function, resulting in greater fluid retention, which further elevates venous pressures. Peripheral arterial vasoconstriction increases afterload, LV filling pressures, and post-capillary pulmonary venous pressures, resulting in worsening of pulmonary edema and dyspnea. This increased afterload causes greater ventricular wall stress and increased myocardial ischemia and cardiac arrhythmias. Abnormal vascular compliance also predisposes these patients to marked blood pressure liability with relatively minor changes in intravascular volume, causing precipitous increases in afterload and ultimately in LV filling pressures resulting in pulmonary congestion. The effects of this vascular abnormality are amplified by LV diastolic dysfunction.

The clinical observation that vasodilator treatment can improve dyspnea in many acutely hypertensive patients without significant diuresis has led to the concept that afterload-contractility mismatch can lead to increased diastolic filling pressures in the setting of minimal total body volume changes. Similarly, the recognition of the large capacitance of the venous (in particular the splanchnic circulation) system has led to increased interest in volume shifts from the “venous reservoir” into the effective circulatory volume as a potentially important and under-recognized mechanism in AHF. These shifts can be mediated by SNS activation, and this has been proposed as a potential explanation between the apparent disconnect between changes in filling pressures and changes in body weight during chronic hemodynamic monitoring. Whether fluid shifts involving this venous reservoir can be modulated therapeutically is a subject of active investigation.

Neurohormonal and Inflammatory Mechanisms

Although elevations of circulating neurohormones are well-documented in patients with AHF, the precise role of neurohormonal activation in the pathophysiology of AHF remains to be fully delineated. Increased plasma concentrations of norepinephrine, plasma renin activity, aldosterone, and endothelin-1 (ET-1) have all been reported in patients with AHF—all of these axes are associated with vasoconstriction and volume retention, which could contribute to myocardial ischemia and congestion, thus exacerbating cardiac decompensation. Inflammatory activation and oxidative stress may also play a role. Pro-inflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6 are elevated in patients with AHF and have direct negative inotropic effects on the myocardium as well as increasing capillary permeability and inducing endothelial dysfunction. ^, In addition to direct effects, this activation stimulates the release of other factors, such as the potent pro-coagulant tissue factor and ET-1, which can lead to further myocardial suppression, disruption of the pulmonary alveolar capillary barrier, and increased platelet aggregation and coagulation (potentially worsening ischemia).

Classification

The inherent heterogeneity of AHF makes the development of a comprehensive classification scheme difficult, and no single classification system has garnered universal acceptance. There are several relevant domains to consider in classifying patients with AHF ( Fig. 49.7 ). These include underlying substrate (i.e., whether there is a prior history of structural heart disease or a background of chronic HF), severity (from mild symptoms to cardiogenic shock), acuity (gradual onset vs. sudden/acute onset), and triggers (which may be readily apparent or unknown). Each of these concepts is discussed briefly below.

Symptoms of Acute Heart Failure

The most common reasons for patients to seek medical care for AHF are symptoms related to congestion. A list of the most common presenting symptoms is provided in Table 49.2 . Dyspnea is the most common symptom and is present in over 90% of patients presenting with AHF. The duration and time course of symptom onset can vary markedly as noted above. The sensation of dyspnea is a complex phenomenon that is influenced by multiple physiologic, psychological, and social factors, and can vary dramatically between patients. Patients may also present with symptoms related to systemic venous congestion, including peripheral edema, weight gain, early satiety, and increasing abdominal girth. Importantly, atypical symptoms can predominate, especially in older patients, where fatigue, depression, altered mental status, and sleep disruptions may be the primary complaints. Bendopnea, or the sensation of dyspnea on bending over, is a commonly reported symptom that has recently been validated experimentally.

Physical Examination

Despite advances in diagnostics technology, biomarkers, and imaging, heart failure remains a clinical diagnosis and the physical examination continues to play a fundamental role (see Chapter 13, Chapter 48 ). A useful framework in the bedside evaluation of patients with AHF is that developed by Stevenson and colleagues, which focuses on the adequacy of perfusion (“cold” vs. “warm”) and congestion at rest (“wet” vs. “dry”). While this framework does not completely encompass the heterogeneity of AHF, it does focus the evaluation on two critical aspects that will significantly influence both prognosis and choice of treatments.

Assessing blood pressure is a critical part in the evaluation of patients with AHF; hypotension is one of the strongest predictors of poor outcomes and helps to define appropriate therapeutic interventions. SBP is typically normal or elevated in patients with AHF, with almost 50% presenting with SBP greater than 140 mm Hg. The combination of underlying hypertension and the marked increase in sympathetic stimulation that accompanies AHF can result in elevations of SBP consistent with hypertensive urgencies or emergencies (12% of patients had an SBP over 180 mm Hg on admission). Patients with very low SBP are uncommon, with only 2% of patients in ADHERE presenting with an SBP less than 90 mm Hg. Although blood pressure is generally related to cardiac output and the state of organ perfusion, it is important to recognize that hypotension and hypoperfusion are not synonymous. Patients with systemic hypoperfusion may present with normal blood pressure, and similarly patients with advanced forms of heart failure may have chronically low blood pressure not associated with acute hypoperfusion. Pulse pressure (the difference between systolic and diastolic blood pressure) is a useful measure that is an indirect marker of cardiac output. A low pulse pressure is a marker of a low cardiac output and confers an increased risk in patients admitted with AHF. A high pulse pressure may alert the physician to a high output state including the possibility of unrecognized thyrotoxicosis, aortic regurgitation, or anemia.

The JVP is a barometer of systemic venous hypertension and is the single most useful physical examination finding in the assessment of patients with AHF. The accurate assessment of the JVP is highly dependent on examiner skill. The JVP reflects the right atrial pressure, which typically (although not always) is an indirect measure of LV filling pressures. JVP may not reflect LV filling pressures in isolated RV failure (e.g., from pulmonary hypertension or RV infarct), and significant tricuspid regurgitation can complicate the assessment of the JVP because the large “CV wave” of tricuspid regurgitation can lead to its overestimation.

Rales or inspiratory crackles are the most common physical examination finding and have been noted in 66% to 87% of patients admitted for AHF. However, rales are often not heard in patients with a background of chronic heart failure and pulmonary venous hypertension, due to increased lymphatic drainage, reinforcing the important clinical pearl that the absence of rales does not necessarily imply normal LV filling pressures. Cool extremities with palpable peripheral pulses suggest decreased peripheral perfusion consistent with a marginal cardiac index, marked vasoconstriction, or both. Of note, the temperature should be assessed at the lower leg as opposed to the foot, and this assessment is relative to the temperature of the examiner’s hands.

Peripheral edema is present in up to 65% of patients admitted with AHF and is less common in patients presenting with predominantly low-output heart failure or cardiogenic shock. As with rales, the presence of edema has a reasonable positive predictive value for AHF but a low sensitivity, so its absence does not exclude that diagnosis. Edema due to AHF is usually dependent, symmetric, and pitting. It is estimated that a minimum of 4 liters of extracellular fluid is accumulated to produce clinically detectable edema.

Other Diagnostic Testing

Risk Stratification

Risk stratification can serve as important clinical tools by helping to identify those patients at both ends of the spectrum of risk; patients who are at very high risk may be observed more closely or treated more intensively, whereas patients at low risk may avoid hospitalization altogether or need less rigorous follow-up and monitoring. A variety of predictive models have been developed in AHF, which can generally be divided into two groups: those focused on in-hospital mortality, and those focused on post-discharge events (death or rehospitalization). Commonly used predictive models are summarized in Table 49.3 . Although individual models differ, several variables occur repeatedly in risk models in a variety of settings: older age, lower blood pressure, higher heart rate, higher BUN and creatinine, and hyponatremia. In settings where natriuretic peptides are available, they are also powerful predictors of long-term risk, although they may be stronger predictors at hospital discharge than on admission.