The estimated annual cost of heart failure in the United States, including direct and indirect costs, totals $31 billion; however, by 2030 the total cost of heart failure is projected to increase to nearly $70 billion [2]. Ambulatory care, which includes emergency room visits, takes its toll of nearly $14.7 billion a year, and heart transplantation involves expenditures of less than $30 million annually [7]. Ambulatory patients with persistent Class IV symptoms have a one-year mortality rate that approaches 50%. Those who can maintain relief from congestion regain a prognosis similar to that of Class II patients, with a one-year mortality of approximately 20% to 25%. Emergency department visits and subsequent hospitalizations for ADHF continue to constitute a major public health burden, with hospitalizations for heart failure having increased from 577,000 in 1985 to more than 1 million in 2010 in the United States [8,9].

The estimated annual cost of heart failure in the United States, including direct and indirect costs, totals $31 billion; however, by 2030 the total cost of heart failure is projected to increase to nearly $70 billion [2]. Ambulatory care, which includes emergency room visits, takes its toll of nearly $14.7 billion a year, and heart transplantation involves expenditures of less than $30 million annually [7]. Ambulatory patients with persistent Class IV symptoms have a one-year mortality rate that approaches 50%. Those who can maintain relief from congestion regain a prognosis similar to that of Class II patients, with a one-year mortality of approximately 20% to 25%. Emergency department visits and subsequent hospitalizations for ADHF continue to constitute a major public health burden, with hospitalizations for heart failure having increased from 577,000 in 1985 to more than 1 million in 2010 in the United States [8,9].

Although heart failure is a major public health problem, there are no national screening efforts to detect the disease at its earlier stages, as there are for breast and prostate cancer or osteoporosis. The guidelines for the evaluation and management of heart failure, published in 2013 by the American College of Cardiology Foundation and the American Heart Association (ACCF/AHA), and updated in 2017 and 2022 by the American College of Cardiology, the AHA, and the Heart Failure Society of America (ACC/AHA/HFSA), have defined the factors that render a patient at high risk for heart failure [10]. These guidelines are based on a classification of heart failure with emphasis on its evolution and progression, known as the four stages of heart failure. Patients with Stage A heart failure are at high risk for the development of heart failure but have no apparent structural abnormality of the heart. Patients with Stage B heart failure (pre-heart failure) have a structural abnormality of the heart but have never had symptoms of heart failure. Patients with Stage C heart failure have a structural abnormality of the heart and current or previous symptoms of heart failure. Patients with Stage D heart failure have end-stage symptoms of heart failure that are refractory to standard treatment [10,11]. This staged classification underscores the fact that established risk factors and structural abnormalities are necessary for the development of heart failure. This system is a departure from the traditional New York Heart Association (NYHA) classification, which has primarily been used as a shorthand to describe functional limitations of patients with Stage C or Stage D heart failure. Patients with Stage C heart failure can be classified according to the trajectory of their symptoms [10,12]. The NYHA classes are [10]:

Several neurohormonal changes, including a raised catecholamine level, overactivity of the renin-angiotensin-aldosterone system (RAAS), and elevation of natriuretic peptides, occur when heart failure becomes chronic. These changes are related to an increased mortality rate in patients with heart failure. Initially, these systems are thought to have compensatory effects, but eventually they contribute to increased vascular resistance and ventricular remodeling. According to the neurohormonal hypothesis, heart failure progresses due to the deleterious effects of the activated endogenous neurohormonal system on the heart and circulation. Both norepinephrine and epinephrine can cause an increased metabolic rate, with levels being markedly raised in patients with heart failure and cardiac cachexia. Additionally, cortisol and aldosterone plasma levels, as well as plasma renin activity, are particularly elevated in patients with cardiac cachexia, suggesting a specific association between the development of body wasting and the presence of neurohormonal activation in heart failure [19].

Thus, consequences of decreased cardiac output and increased filling pressures lead to changes that are initially compensatory and help to restore cardiovascular homeostasis. However, shortly afterward, they are maladaptive and result in progressive neurohormonal activation and left ventricular remodeling. Systolic and diastolic heart failure result in a decrease in stroke volume. This leads to activation of peripheral and central baro- and chemo-reflexes that are capable of eliciting a marked increase in sympathetic nerve traffic. The ensuing elevation in plasma norepinephrine directly correlates with the degree of cardiac dysfunction and has significant prognostic implications. From a hemodynamic standpoint, increased vasoconstriction mediated by norepinephrine, angiotensin II, endothelin, vasopressin, and increased cardiac inotropy and chronotropy alters renal salt and water handling and enhances venous tone to facilitate end organ perfusion. The marked increase in cardiac and renal adrenergic activity reaffirms the fact that both the RAAS and the sympathetic system are co-activated and co-regulated.

Brain natriuretic peptide, also known as B-type natriuretic peptide or BNP, was initially isolated from porcine brain in 1988 [22]. Despite its name, it is produced predominantly by the ventricular myocyte [23]. More accurately, N-terminal pro B-type natriuretic peptide (NT-proBNP) is the cardiac prohormone that is released from the ventricles in response to left ventricular volume expansion and pressure overload (i.e., to regulate blood pressure and fluid balance), and enzymes quickly convert NT-proBNP into the neurohormone BNP [24,25]. NT-proBNP and BNP levels are known to be elevated in patients with left ventricular dysfunction and to correlate with echocardiographic findings, NYHA classification, and severity of heart failure [26]. The use of NT-proBNP and BNP as biomarkers in human heart failure continues to emerge, particularly as reference values, diagnostic sensitivities, specificities, positive predictive values, and cut-points become better defined for each [10]. For the purposes of this course, both biomarkers used in clinical practice will be referred to as BNP.

The National Institutes of Health-sponsored Studies of Left Ventricular Dysfunction (SOLVD) in patients with chronic left ventricular dysfunction, but without signs of severe heart failure, demonstrated humoral activation that was characterized by increases in circulating ANP without activation of the circulating RAAS in the absence of diuretic treatment. Based upon the known biology of the natriuretic peptide system, it may play a key role in preserving the compensated state of symptomatic left ventricular dysfunction. Severe heart failure, unlike asymptomatic left ventricular dysfunction, is a syndrome characterized by sodium retention, action of RAAS, and elevation of both circulating ANP and BNP. Human and animal models of chronic severe heart failure are characterized by an attenuated natriuretic response to endogenous and exogenous natriuretic peptides. It has been suggested that the diminished renal response to cardiac natriuretic peptides plays an important role in the pathophysiology of sodium retention and systemic and renal vasoconstriction observed in severe heart failure, thus contributing to disease progression [31].

A key role for angiotensin II in mediating renal hyporesponsiveness to the natriuretic peptide system appears to be fundamental to severe heart failure. The natriuretic peptides and angiotensin II have renal actions at the same vascular and tubular sites within the kidneys. Angiotensin II may oppose the renal effects of the natriuretic peptides at both the glomerulus and the renal tubule, preventing the full natriuretic activity of this peptide. This in turn contributes to the sodium retention and edema formation of severe heart failure.

Tumor necrosis factor has been implicated in response to various infectious or inflammatory conditions. Elevations in levels of tumor necrosis factor have been consistently observed in heart failure and seem to correlate with the degree of myocardial dysfunction. Tumor necrosis factor levels correlate positively with the degree of insulin resistance in heart failure and may be an important etiologic factor, as has been shown in the context of obesity-related insulin resistance [34]. Experimental studies also suggest that local production of this cytokine may have toxic effects on the myocardium. Genetic factors, including angiotensin-converting enzyme (ACE) gene and beta-adrenergic receptor polymorphisms, may influence the natural history of disease progression and response to treatment [29].

Based upon their elevation in chronic heart failure, circulating ANP and BNP have emerged as important diagnostic serum markers. With the known elevation of plasma BNP in heart failure, studies have focused upon its diagnostic usefulness. Elevated BNP has been found to be an excellent discriminator of cardiac and noncardiac dyspnea [31]. BNP was first used in the evaluation of dyspnea to measure the natriuretic hormones ANP and BNP in 52 patients presenting with acute dyspnea [39]. It was found that admission plasma BNP concentrations more accurately reflected the final diagnosis than ejection fraction or concentration of plasma ANP.

Finding a simple blood test that would aid in the diagnosis and management of patients with heart failure would clearly have a favorable impact on the staggering costs associated with heart failure. The fact that a point-of-care assay for BNP has been approved by the U.S. Food and Drug Administration gives the clinician an opportunity to explore its potential usefulness. Serial point-of-care testing of BNP is of immense help in patients presenting to urgent care clinics. Patients who present to urgent care with dyspnea and BNP levels greater than 480 pg/mL have nearly 30-fold increased risk for a cardiac event in the next six months. BNP might also serve as a screen for patients referred for echocardiography. A low BNP level makes abnormal echocardiographic indices of left ventricular dysfunction (both systolic and diastolic) highly unlikely. In patients with clinical heart failure and normal ventricular function, a high BNP correlates to diastolic filling patterns across the mitral valve and should probably be considered as part of the "criterion standard" for diagnosing diastolic dysfunction. BNP might also serve as a screening and early prevention tool for asymptomatic patients at high risk for heart disease, such as those with diabetes mellitus [10]. BNP might also be an effective way to improve the in-hospital management of patients admitted with decompensated heart failure [10,29,41,42,43].

BNP levels are also elevated early in the course of an acute myocardial infarction. A second peak of BNP measured two to four days after a myocardial infarction is associated with remodeling of the heart and is a strong predictor of subsequent left ventricular dysfunction and mortality.

There has been marked interest in the use of statin therapy in established heart failure in the last decade. In one study, statin therapy was associated with a reduction in mortality in patients with heart failure who were prescribed the drug [57]. These effects remained after accounting for the propensity to be treated with a statin upon hospital discharge. In addition to a reduction in overall mortality with statins, there was a 15% reduction in combined mortality and cardiovascular morbidity. The researchers concluded that statin therapy was associated with significantly improved five-year mortality and morbidity in patients with heart failure who were discharged from the hospital [57]. A meta-analysis of primary- and secondary-prevention trials found that statins modestly reduced the risk of nonfatal heart failure hospitalization and a composite of nonfatal heart failure hospitalization and death, with no difference in risk reduction between patients who did or did not suffer myocardial infarction [58]. Statins are recommended to prevent symptomatic heart failure and adverse cardiovascular events in patients with a recent or remote history of myocardial infarction or acute coronary syndrome [10].

In 2015, the novel cardiovascular agent ivabradine (a sinoatrial node modulator) was approved in the United States for the management of stable heart failure [70]. Ivabradine acts by inhibiting the hyperpolarization-activated cyclic nucleotide-gated channels within the SA node. The drug is indicated for patients who have symptoms of heart failure that are stable, who have a normal heartbeat with a resting heart rate of at least 70 beats per minute, and who are also taking beta-blockers at the highest dose they can tolerate [10,70]. Possible side effects include atrial fibrillation, bradycardia, phosphenes, and hypertension [59,70].

Also in 2015, the combination angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan was approved for the treatment of heart failure after having been found to reduce the rate of cardiovascular death and hospitalization related to heart failure in these patients [10,71]. However, results of a study published in 2019 indicate that the agent did not result in a significantly lower rate of total hospitalizations or deaths from heart failure [72]. This study included 4,822 patients with NYHA Class II to IV heart failure and ejection fraction ≥45% randomly assigned to receive sacubitril (97 mg)/valsartan (103 mg) twice daily, or valsartan (160 mg) twice daily. The incidence of death from cardiovascular causes was 8.5% in the sacubitril/valsartan group and 8.9% in the valsartan group. There were 690 hospitalizations for heart failure in the sacubitril/valsartan group and 797 hospitalizations in the valsartan group [72].

Abnormal myocardial conduction can also lead to delays in ventricular conduction and bundle-branch block. Left bundle-branch block is a significant predictor of sudden death and a common finding in patients with myocardial failure. Its presence also affects the mechanical events of the cardiac cycle by causing abnormal ventricular activation and contraction, ventricular dyssynchrony, delayed opening and closure of the mitral and aortic valves, and abnormal diastolic function. Hemodynamics reveal a reduced ejection fraction, decreased cardiac output and arterial pressure, paradoxical septal motion, increased left ventricular volume, and mitral regurgitation. Ventricular arrhythmias are thought to be secondary to dispersion of normal conduction through nonhomogenous myocardial tissue, which promotes repetitive ventricular arrhythmias.

To identify patients in whom ventricular dyssynchrony may be a problem, the presence of a bundle-branch block or intraventricular conduction delay on a standard electrocardiogram has been used, as these findings are the manifestation of ventricular dyssynchrony. In fact, the presence of a wide QRS complex has been shown to be an independent or contributing risk factor in patients with heart failure, with the degree of conduction delay possibly serving as a marker of disease severity.

ICDs are pacemaker-like devices that continuously monitor the heart rhythm and deliver life-saving shocks if a dangerous heart rhythm is detected. They can significantly improve survival in certain groups of patients with heart failure who are at high risk of ventricular fibrillation. ICDs also have the ability to act as pacemakers for too-slow heart rates and can be modified to provide resynchronization therapy.

Outcomes and results of the MIRACLE trial have shown CRT in patients with NYHA Class III/IV heart failure provides a variety of beneficial effects, including improved quality of life, increased six-minute walk distance, improved NYHA functional class ranking, increased peak ventilatory oxygen, improved treadmill exercise time, reduced QRS duration, improved cardiac structure and function, and fewer hospitalizations over six months [10,50].

According to clinical trial results with selected patients, CRT:

The management of heart failure has become increasingly difficult. One of the greatest challenges in managing chronic heart failure is obtaining objective data that signals disease progression or therapeutic effectiveness. It is believed that hemodynamic parameters, such as indices of cardiac output, contractility, fluid content of the chest, and ventricular workload, provide the needed information to augment medical decision making. However, in the past, it was neither feasible nor cost-effective to obtain serial hemodynamic measurements in outpatient settings. Heart failure professionals had to rely on clinical signs and symptoms of worsening heart failure as their primary source of data for clinical decision making in these settings. The development and evolution of impedance cardiography, also referred to as thoracic electrical bioimpedance, specially adapted for measuring cardiac stroke volume is a valid, accurate, and reproducible alternative for obtaining the needed hemodynamic data. Impedance cardiography utilizes changes in thoracic electrical impedance to estimate changes in blood volume in the aorta and changes in fluid volume in the thorax [107]. The device is a hemodynamic monitor that uses thoracic electrical bioimpedance (TEB). TEB is a method of measuring the impedance or resistance to the flow of electricity through the chest cavity. Because this resistance changes with respiration and pulsatile flow of blood through the chest, this technique can be used to measure respiratory and hemodynamic parameters.

Despite significant advances in scientific knowledge and technology in the latter half of the 20th century, one of the greatest challenges in managing patient care is the need for readily accessible, objective data that signals disease progression and/or treatment effectiveness. Obtaining, recording, and trending this data is dependent upon technology that produces valid, reproducible, and cost-effective measurements of cardiac function in a timely manner. While both invasive and noninvasive technologies have been developed and used effectively in the assessment, diagnosis, and evaluation of treatment outcomes, most require specialized environments, costly equipment, and specially trained medical personnel to obtain and/or interpret the data. Because of the cost and/or risk associated with these technologies, repeated hemodynamic measures that would enhance medical management and fine tuning of care are not obtained in ambulatory care settings, which is the focus of care for a major portion of the population of patients with heart failure for a significant period of illness.

The primary care physician (PCP) is the anchor of the team, the person with whom patients have the strongest relationship, and the person who orchestrates care decisions that the other team members carry out. The PCP traditionally controls access to specialists. In a heart failure disease-management program, the PCP also plays this role, with the help of algorithms and protocols to improve outcomes. PCPs provide most of the care for patients with heart failure. Even in the hospital, cardiologists care for fewer than one-third of all patients admitted for heart failure. In fact, the cardiologist may refer patients to the PCP after guideline recommendations are implemented. In this way, patient referrals move both to and from specialty and primary care physicians.

To illustrate this, a study done in Portland, Oregon, at the Oregon Health Sciences University, evaluated the clinical and cost outcomes of care provided by their university-based heart failure outpatient management program [124]. Evaluation of the study showed success of the program intervention in reducing hospitalization and emergency room visits and in improving patients' quality of life and functional status. The improved clinical outcomes should be attributed to the comprehensive management strategies provided by specialized physicians and nurses that allowed for close symptom surveillance; timely interventions, such as augmentation of drug therapy; and promotion of patients' adherence to medical regimens and self-care recommendations. The positive effect of the program intervention might be caused in part by an optimized medical regimen, such as the use of a more aggressive ACEI dosage, initiation of beta-blockers, and the approach of pre-emptive hospitalization in two-thirds of hospital events after referral. The study also showed that a comprehensive heart failure management program should be designed to care for patients in the outpatient setting before an episode of decompensated heart failure that required emergent hospitalization. This implies that hospitalization, the most costly intervention, should be managed and integrated prospectively into the care paradigm, rather than being a reactive, uncontrolled patient safety net resulting from a failure of the care process.

Patients with poorly controlled heart failure require careful assessment at each visit [10]. The initial visit should focus on evaluating the type and cause of cardiomyopathy and excluding noncardiac diagnoses. Chest x-ray is a useful initial diagnostic test [10]. Symptoms of heart failure vary depending on the cause. Patients with systolic heart failure usually present with classic early symptoms of orthopnea and paroxysmal nocturnal dyspnea. Symptoms can become more subtle as left ventricular dysfunction worsens. Patients with diastolic heart failure (normal left ventricular ejection fraction, but impaired filling of the ventricle) are likely to present with exercise intolerance, dyspnea, and fatigue. Patients with cardiac amyloidosis may present with dyspnea, fatigue, fluid buildup in the abdomen and legs, and difficulty lying flat at night [126]. All patients with suspected heart failure should undergo a thorough physical examination and electrocardiography. Patients with suspected cardiac amyloidosis should be screened for serum and urine monoclonal light chains. Bone scintigraphy should be performed to confirm the diagnosis [10]. The presence of an S3 gallop and Q waves suggests systolic heart failure due to coronary artery disease, but clinical criteria alone are often insufficient for diagnosis. An S3 gallop increases with volume overload. Thus, objective assessment of the left ventricular ejection fraction using echocardiography or radionuclide ventriculography is usually necessary to determine appropriate treatment. Echocardiography is preferred because it can help evaluate diastolic as well as systolic dysfunction. It is also more effective in evaluating valvular dysfunction, which is often associated with cardiomyopathy. Patients who present with symptoms that are compatible with heart failure should be evaluated for disorders that may cause similar symptoms [10]. Complaints of fatigue and dyspnea on exertion should prompt an ongoing differential diagnosis, including chronic obstructive pulmonary disease, asthma, hypothyroidism, anemia, and chronic infections or inflammatory diseases. Heart failure can be particularly difficult to diagnose in patients with lung disease, who may present with abnormal lung sounds and nocturnal worsening of symptoms that seem to be caused by heart failure [127]. The importance of monitoring serum potassium levels should be stressed due to the risk for hypokalemia or hyperkalemia.

Patients with poorly controlled heart failure require careful assessment at each visit [10]. The initial visit should focus on evaluating the type and cause of cardiomyopathy and excluding noncardiac diagnoses. Chest x-ray is a useful initial diagnostic test [10]. Symptoms of heart failure vary depending on the cause. Patients with systolic heart failure usually present with classic early symptoms of orthopnea and paroxysmal nocturnal dyspnea. Symptoms can become more subtle as left ventricular dysfunction worsens. Patients with diastolic heart failure (normal left ventricular ejection fraction, but impaired filling of the ventricle) are likely to present with exercise intolerance, dyspnea, and fatigue. Patients with cardiac amyloidosis may present with dyspnea, fatigue, fluid buildup in the abdomen and legs, and difficulty lying flat at night [126]. All patients with suspected heart failure should undergo a thorough physical examination and electrocardiography. Patients with suspected cardiac amyloidosis should be screened for serum and urine monoclonal light chains. Bone scintigraphy should be performed to confirm the diagnosis [10]. The presence of an S3 gallop and Q waves suggests systolic heart failure due to coronary artery disease, but clinical criteria alone are often insufficient for diagnosis. An S3 gallop increases with volume overload. Thus, objective assessment of the left ventricular ejection fraction using echocardiography or radionuclide ventriculography is usually necessary to determine appropriate treatment. Echocardiography is preferred because it can help evaluate diastolic as well as systolic dysfunction. It is also more effective in evaluating valvular dysfunction, which is often associated with cardiomyopathy. Patients who present with symptoms that are compatible with heart failure should be evaluated for disorders that may cause similar symptoms [10]. Complaints of fatigue and dyspnea on exertion should prompt an ongoing differential diagnosis, including chronic obstructive pulmonary disease, asthma, hypothyroidism, anemia, and chronic infections or inflammatory diseases. Heart failure can be particularly difficult to diagnose in patients with lung disease, who may present with abnormal lung sounds and nocturnal worsening of symptoms that seem to be caused by heart failure [127]. The importance of monitoring serum potassium levels should be stressed due to the risk for hypokalemia or hyperkalemia.

Included in the treatment plan for heart failure in eligible patients is some time for exercise or regular physical activity [10]. Most patients in the clinic are able to exercise by walking. If patients have not been exercising at all, they begin by walking one to two blocks three times per week. Gradually, they increase their distance and time. They use symptoms of shortness of breath and fatigue as their guide to increase or decrease exercise. The benefit to the patient is not only physical but psychologic as well. On initiation of exercise, self-confidence, self-esteem, and stamina can improve [130]. After many years of restricting patients with heart failure from aerobic exercise, researchers have demonstrated that aerobic exercise training in patients with heart failure results in improved exercise duration, less fatigue, faster pace of activities, and improved general well-being. Given the threat of complications related to increased myocardial oxygen demand in the face of isometric exercise, patients are usually counseled to avoid lifting significant weight (>20 lbs) or performing exercises that cause strain (e.g., performing a Valsalva maneuver). Because inactivity leads to decline in function, exercise tolerance should be assessed at each visit for patients who are not responding well to treatment.

Noncompliance with heart failure treatment plans was found to be common and appeared to increase as heart failure progressed. There are many reasons that patients may not comply with a therapeutic regimen. Lack of knowledge, poor motivation, decreased understanding, lower perceived self-efficacy, forgetfulness, and decreased support from family and other caregivers have been identified as factors that contribute to noncompliance. Patients may not comply with a prescribed regimen because they are unconvinced of the benefits of doing so or because they perceive that the side effects or inconveniences of following the regimen outweigh any benefits. If cost is a factor in noncompliance, suggestions for lower-cost medications or financial assistance programs should be provided. Another important factor that contributes to patient noncompliance and rehospitalization for worsening heart failure is inadequate discharge planning and follow-up after discharge.

Coronary artery disease has emerged as the major etiologic factor in the development of heart failure in the United States and other developed nations. As techniques used for percutaneous and surgical revascularization continue to improve, the ability to protect myocardium from ischemia and/or infarction can only be expected to increase. An exciting possibility is the potential for delivery of growth factors, such as vascular endothelium growth factor or basic fibroblast growth factor, to areas of myocardium jeopardized by insufficient blood flow as a result of atherosclerotic coronary artery disease. Coronary artery growth factor therapy is an intriguing possibility as a means of protecting myocardium and preventing heart failure.

Four major approaches to augmentation of diseased myocardium have been instituted—three clinically and one still in animal models. These include cardiomyoplasty, left ventriculectomy, transmyocardial laser revascularization, and myocyte/myoblast cell transplantation. The newest and potentially most exciting technique to rehabilitate diseased and dysfunctional myocardium is muscle cell transplantation using either skeletal myoblasts or fetal cardiomyocytes. Finally, cardiac replacement strategies have continued to evolve and are anticipated to bring continued new approaches to the treatment of end-stage heart failure. A number of new immunosuppressive agents that are more efficacious and less toxic have been released for clinical use or are in clinical trials. More than 5,000 heart transplants are performed annually worldwide, while the estimated need for organ replacement is, at minimum, 10 times that number [140].

There are two stages of DSC certification programs. The first stage is comprised of collection and analysis of four or more performance measures defined by the facility, two of which are required to be related to or identified in clinical practice guidelines for that program [144]. The second stage involves adoption of standardized performance measures as defined by the Joint Commission. Six core measures have been established by the Joint Commission for heart failure center certification [145]: