An episode of acute heart failure syndromes (AHFS) can be defined as a rapid or gradual onset of signs and symptoms of heart failure that result in hospital admission. Over 70% of AHFS events are the result of worsening chronic heart failure.1 Other causes of AHFS include new-onset heart failure due to an acute coronary event, such as a myocardial infarction (MI), and end-stage or refractory heart failure that is not responsive to therapy. It is a growing problem, and the prognosis for patients with AHFS remains poor. Current understanding of the pathophysiology of AHFS can aid in the identification of potential therapeutic targets.
The pathophysiology of AHFS is complex, and can arise from a variety of pathophysiological mechanisms. Approximately 60% of hospitalised patients have a history of coronary artery disease (CAD), 53% to 70% have hypertension, fewer than 30% have atrial fibrilation (AF) or a history of AF, and more than 40% have type 2 diabetes (see Table 1).2-5
Potential pathophysiological targets for therapy include treating congestion, controlling blood pressure, preventing myocardial injury, improving renal function, and treating the associated conditions that contribute to the pathophysiology of AHFS.
Controlling Blood PressureÔÇöVascular and Cardiac Heart Failure
'VascularÔÇÖ failure accounts for up to half of all AHFS admissions, and is characterized by elevated systolic blood pressure.2,5 The elevated blood pressure usually develops rapidly and is possibly related to increased filling pressures and increased sympathetic tone, and results in redistribution of fluids (from systemic to pulmonary circulation) and further activation of neurohormones. These patients are often older and are more likely to be women with a relatively preserved ejection fraction. Symptoms in these patients usually develop abruptly and the patients have pulmonary rather than systemic congestion (e.g. peripheral edema).
'CardiacÔÇÖ failure is the other common type of acute heart failure and represents 40% to 50% of admissions for AHFS. It is characterized by a normal systolic blood pressure, usually with a history of progressive or chronic heart failure. These patients are often younger, with symptoms and signs developing gradually over days or weeks, and typically have significant systemic congestion and a reduced ejection fraction. They may also have minimal pulmonary congestion (clinical and/or radiographic) despite high ventricular filling pressures. This type of heart failure will be referred to as 'cardiacÔÇÖ failure. This classification of 'vascularÔÇÖ and 'cardiacÔÇÖ failure provides a conceptual framework that needs further validation.
Preventing Myocardial Injury
Myocardial injury is being recognized as a common and important element of the pathophysiology of AHFS, and preventing myocardial injury should be a major treatment goal for patients with AHFS.
Several studies, including the Pilot Randomized Study of Nesiritide Versus Dobutamine in Heart Failure (PRESERVD-HF), have shown that a significant number of patients with AHFS have increased serum troponin levels that correlate with poor long-term prognosis. Although the significance of troponin release in patients with ischemic or primary cardiomyopathy is not well understood, it probably represents myocardial injury.
Patients with chronic heart failure not only have myocyte hypertrophy and/or myocyte apoptosis or necrosis, but a significant number of patients with either ischemic or non-ischemic cardiomyopathy and reduced systolic function also have viable but non-contractile myocardium. This condition can occur for a variety of reasons, including excessive neurohumoral stimulation, hemodynamic overload, and ischemia. It has been hypothesized that the decrease in cardiac contractility that occurs in heart failure is an important compensatory mechanism that decreases energy use by the failing myocardium and thereby improves the long-term survival of cardiac myocytes.6
In contrast to chronic heart failure, during AHFS there is further worsening of hemodynamic function (particularly with very high end-diastolic pressures) and further activation of neurohormones. In addition, the medications used in treating AHFS often result in increased contractility and/or decreased blood pressure. Those changes (high left ventricular (LV) diastolic pressure, decreased blood pressure, increased contractility) may result in myocardial injury (necrosis), particularly in patients with CAD, who often have hibernating myocardium and endothelial dysfunction, or patients with primary cardiomyopathy with viable but non-contractile myocardium (myocardium at risk). This may lead to further progression of heart failure. Accordingly, the pathophysiological conditions seen in AHFS may be the 'perfect stormÔÇÖ for myocardial injury (see Figure 1).
Congestion and myocardial injury may progressively exacerbate one another. For example, myocardial injury may occur as a result of increased LV wall stress caused by high filling pressures, whereas congestion may be secondary to a myocardial injury.
The key factor that contributes to the pathophysiology of AHFS is congestion. Data from large trials and recent registries have shown that the majority of hospitalisations for AHFS are due to congestion, rather than a low cardiac output.2,5 Congestion may arise out of poor compliance with medications or as a result of dietary indiscretion.
Although it is thought that congestion starts as a compensatory mechanism in response to reduced cardiac performance, clinical and experimental data suggest that congestion actually contributes to the progression of AHFS. Increased LV filling pressures augment LV wall stress, change the shape of the ventricle (making it more spherical) resulting in reposition of papillary muscles with secondary mitral insufficiency,7,8 and may cause subendocardial ischemia leading to myocyte death by apoptosis or necrosis. The congestion (high filling pressures) may be particularly deleterious in patients with AHFS with hypotension and/or CAD and hibernating myocardium. The increased LV filling pressures may also lead to impaired venous drainage into the coronary veins and right atrium, contributing to the impairment of diastolic function.9,10 The therapeutic goal in AHFS is to achieve the lowest LV filling pressure without decreasing cardiac output or increasing heart rate.
Improving Renal Function
The cardiorenal syndrome also plays an important role in AHFS; it carries a grim prognosis and is at least as powerful an adverse prognostic factor as most clinical variables, including ejection fraction and New York Heart Association (NYHA) functional class. Renal function that worsens during hospitalization is a more important predictor of adverse outcomes than baseline renal function.11-14
Recent data from the Acute Decompensated Heart Failure National Registry (ADHERE)15 have demonstrated the important role of renal dysfunction in the pathophysiology and adverse outcomes associated with hospitalization for worsening chronic heart failure. Classification and regression analyses from ADHERE showed that blood urea nitrogen (BUN) (at a cut-off of 43mmHg), serum creatinine (at a cut-off of 2.75mg/dL), and systolic blood pressure (at a cut-off of 115mmHg) discriminate between low- and high-risk patients. This analysis identified four subgroups of patients at low, intermediate, high, and very high risk, with an in-hospital mortality of 2%, 6%, 13%, and 20%, respectively.15 Retrospective analyses from other studies have shown that high BUN and BUN/creatinine ratio on admission are associated with a two-fold increase in one-year post-discharge mortality.16,17
In heart failure, decreased cardiac output results in hypovolemia, which triggers the production of neurohormones by the kidney, such angiotensin II and aldosterone from the renin-angiotensin-aldosterone system. Angiotensin II induces secretion of vasopressin by the anterior pituitary gland and endothelin-1 by endothelial cells. This neurohormonal activation results in fluid retention, sodium retention, and vasoconstriction, which increases myocardial wall stress and decreases cardiac performance. Vasoconstriction also decreases glomerular filtration, thereby impairing renal function and increasing sodium and water retention. This establishes a deleterious positive-feedback loop resulting in the chronic elevation of neurohormones and the worsening of heart failure.
Treating Co-morbities that Contribute to the Pathophysiology of AHFS
A high incidence of co-morbidities, such as CAD, hypertension, type 2 diabetes, and AF is associated with AHFS.18 These co-morbidities may each play a role in worsening cardiac function, and their treatment is important in the management of AHFS.
CAD is one of the major underlying disease states in AHFS. Endothelial dysfunction often accompanies CAD and can lead to reduced responsiveness of blood vessels to changes in blood flow and pressure, thereby increasing vascular resistance. The chronic coronary flow reduction associated with CAD results not only in myocardial necrosis and apoptosis, but in myocardial hibernation. Hibernation may develop as an adaptive response to a sustained reduction of myocardial blood flow. Thus, the level of tissue perfusion is sufficient to maintain cellular viability but insufficient for normal contractile function. In addition, medications commonly employed in AHFS, like dobutamine and milrinone, may further decrease coronary perfusion by decreasing blood pressure and increasing heart rate and contractility in myocardial tissue that is not ready to contract.
Hypertension may develop rapidly due to high filling pressures and activation of neurohormones or can precede, and be a precipitant of, AHFS. An acute increase in systolic blood pressure, particularly in patients with aortic arteriosclerosis and diastolic dysfunction, may be the main cause for AHFS with relatively preserved systolic function.19,20 Almost 50% of AHFS patients present with hypertension and a relatively preserved systolic function.
The first-line therapy in this group with vascular failure is probably a vasodilator (i.e. nitroglycerin) rather than a diuretic because many of these patients do not have chronic systemic congestion, but rather an acute redistribution of fluid into the lungs due to an acute and severe increase in afterload (blood pressure).
More than 20% to 30% of patients with AHFS have AF. AF with a rapid ventricular response may precipitate or cause AHFS, particularly in patients with hypertension (increase in afterload) and diastolic dysfunction (in which the atrium contributes up to 40% of the cardiac output). AF may be particularly deleterious in patients with diastolic dysfunction because diastolic time that decreases during rapid ventricular response, with further reduction in diastolic function, may precipitate AHFS. Over 40% of patients who present with AHFS have type 2 diabetes. In addition to the diabetic state contributing independently to LV dysfunction, these patients are more likely to have hypertension, arteriosclerotic heart disease, and renal dysfunction. The overall contribution of diabetes to AHFS remains to be determined.
Traditionally, the key short-term treatment goals for AHFS have been to improve hemodynamics while preserving organ function (see Table 2). However, in light of recent findings that myocardial injury may play an important role in AHFS, the preservation of myocardium should also be a major goal of therapy. The challenge facing physicians is that some of the current agents for AHFS, such as dobutamine and milrinone, may have deleterious effects on renal function and the myocardium. There is, therefore, a large un-met need for agents that can improve hemodynamics without injuring the myocardium. One new agent that may be well-suited for this application is levosimendan, which enhances hemodynamics and has anti-ischemic and antistunning effects. Phase 3 trials with levosimendan are being conducted to help determine its role in the treatment of patients with AHFS.
Other therapeutic targets for AHFS therapy include neurohormonal and inflammatory activation.
Admission levels of B-type natriuretic peptide (BNP) are known to be prognostic in patients with AHFS.21-23 Moreover, decreases in BNP levels during hospitalization for AHFS are associated with a lower rate of death and 30-day readmissions.24 Therefore, therapies that lower BNP during hospitalization for AHFS may have beneficial effects. Nesiritide is a recombinant form of human BNP and has been shown to improve dyspnea and patient global assessments at three hours after initiation of treatment in patients with AHFS.25 However, recent meta-analyses indicate that nesiritide may have a deleterious effect on renal function and short-term mortality.26,27 Inflammatory markers, such as interleukin-6 (IL-6) and tumor necrosis factor ╬▒ (TNF-╬▒), are also being investigated as potential prognostic markers and therapeutic targets in AHFS. Currently, BNP and inflammatory markers are not specific therapeutic targets.
Vasopressin levels are often elevated in AHFS patients28 and seem to be associated with adverse clinical outcomes. The development of vasopressin receptor antagonists has been hampered for several years by the lack of non-peptide, orally available compounds. In the last few years, several selective receptor antagonists have been developed as oral and/or intravenous formulations. Tolvaptan, a selective vasopressin V2 receptor antagonist, and Conivaptan, a combined V1a/V2 receptor antagonist, have been shown to reduce body weight by inducing aquaresis and improve hemodynamics in patients with congestive heart failure.29,30 Thus, inhibition of vasopressin may play a role in future therapies for reducing systemic congestion in patients with AHFS. In addition, mild hyponatremia, which is present in more than 20% of patients admitted with AHFS appears to be a major predictor of prognosis.31 Because tolvaptan is associated with a rapid and sustained normalization of serum sodium, this may be another method by which vasopressin antagonists may improve clinical outcomes.
Apart from the activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system,32 increased endothelin (ET)-1 production contributes to neurohormonal activation in heart failure. Indeed, plasma levels of ET-1 are elevated and strong independent predictors of death.33,34 The non-selective ET receptor antagonist tezosentan was studied in the Randomized Intravenous TeZosentan (RITZ) trials, which consisted of four phase 3 studies enrolling patients with acute heart failure requiring hospitalization, and in the recently presented Value of Endothelin Receptor Inhibition with Tezosentan in Acute heart failure Studies (VERITAS). Although previous studies demonstrated an improvement in pulmonary and systemic hemodynamics,35 results of these trials have been discouraging in terms of clinical benefits. These results confirm the complex pathophysiology of AHFS.36
AHFS can arise from a variety of pathophysiological mechanisms and current knowledge and understanding of the disease is constantly being developed, exploring the impact of current and novel therapies on short-term and long-term outcomes.Ôûá