#30934: Treatment of Heart Failure: An Update

Sympathetic activity is increased in patients with heart failure and bears a direct relationship to both disease severity and prognosis [21]. The sympathetic nervous system is responsible for maintaining circulatory stability in the face of decreased cardiac output. High levels of circulating norepinephrine can cause peripheral vasoconstriction. This may induce a reflex increase in vagal tone, which is a parasympathetic response. This in turn can reduce the heart's ability to respond to sympathetic stimulation. These effects may contribute to the decreased exercise tolerance experienced by patients with heart failure. Urinary excretion of catecholamines and circulating plasma levels of norepinephrine are elevated. Although sympathetic activity may support cardiovascular function in the short-term, long-term activation may exert adverse effects on the myocardium due to both the increased load caused by vasoconstriction and direct biologic action of norepinephrine on the myocardium [21].

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.

Atrial natriuretic peptide (ANP) and BNP are activated in response to atrial and ventricular volume/pressure expansion. They are released from the atria and ventricles to promote vasodilatation and natriuresis. Their hemodynamic effects are mediated by decreases in ventricular filling pressures, owing to reductions in cardiac preload and afterload. BNP, in particular, produces selective afferent arteriolar vasodilatation and inhibits sodium reabsorption in the proximal convoluted tubule [27].

According to the American College of Cardiology/American Heart Association/Heart Failure Society of America (ACC/AHA/HFSA), measurement of BNP or NT-proBNP is useful for risk stratification in chronic heart failure.

(https://www.ahajournals.org/doi/10.1161/CIR.0000000000001063 Last Accessed: November 21, 2022)

Strength of Recommendation/Level of Evidence: 1A (Strong recommendation based on high-quality evidence from multiple randomized trials or meta-analyses)

BNP is a potent natriuretic, diuretic, and vasorelaxant peptide. It coordinates fluid and electrolyte homeostasis through its activity in the central nervous system and peripheral tissue. BNP promotes vascular relaxation and lowers angiotensin II, aldosterone, and endothelin-1. Its renal effects include increasing glomerular filtration rate and enhancing sodium excretion. Unlike ANP, whose major storage sites include the atria and ventricles, the major source of plasma BNP is cardiac ventricles. This suggests that BNP may be a more sensitive and specific indicator of ventricular disorders than other natriuretic peptides. The stimulus for BNP release is a change in left-ventricular wall stretch and volume overload, suggesting that BNP may be a "distress hormone," more specific for ventricular disorders than are other members of the natriuretic peptide family [28]. BNP is an independent predictor of high left ventricular end-diastolic pressure and is more useful than ANP or norepinephrine for assessing the mortality in patients with chronic heart failure [29]. Plasma levels can be used in diagnosis and prognosis of patients with heart failure, hypertension, myocardial infarction, right ventricular dysfunction, and cor pulmonale [30].

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.

BNP biomarkers have demonstrated clinical utility for heart failure management [10]. However, there is limited information available to support the screening of broad populations to detect undiagnosed heart failure and/or symptomatic left ventricular dysfunction. A 2004 study suggests that elevated levels of BNP can be used as a cost-effective strategy for screening asymptomatic men and women older than 60 years of age with an ejection fraction <40% [32]. Although screening general populations with BNP is not recommended at this time, the results of a large randomized single-center study found that, among patients at risk of heart failure, BNP-based screening combined with collaborative care reduced the combined rates of left ventricular systolic dysfunction, diastolic dysfunction, and heart failure [33]. Further studies are needed to determine the cost-effectiveness and risk of such screening, as well as its impact on quality of life and mortality rate. Patients who are at very high risk of developing cardiomyopathy (e.g., those with a strong family history of cardiomyopathy) are appropriate targets for more aggressive screening, such as 2-D echocardiography, to assess left ventricular function.

The main stimulus for the immune activation in heart failure is not known, but there are three main theories as to why this occurs. One hypothesis states that the heart is the main source of proinflammatory cytokines, as it has been shown that the failing myocardium is capable of producing tumor necrosis factor.

The second hypothesis is that bowel wall edema and ischemia that occur in heart failure due to venous congestion are responsible for bacterial translocation, leading to endotoxin release and subsequent immune activation. This hypothesis is further supported by the finding that patients have elevated concentrations of endotoxin and cytokines during an acute edematous exacerbation, which can be normalized by diuretic therapy. If the second hypothesis is true, it opens up the possibility for therapeutic strategies directed against the bacteria in the bowel wall, the endotoxin itself, or the binding of endotoxin to cells of the immune system.

The third proposed hypothesis is that the extramyocardial cytokine production due to tissue hypoxia may be the primary stimulus for increased tumor necrosis factor production in patients with heart failure. It may be the case that more than one mechanism is involved in causing the immune activation that occurs in heart failure [34].

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].

The correlation between the drop in BNP level and the patient's improvement in symptoms suggests that BNP guided treatment might make "tailored therapy" more effective and may reduce the need for invasive hemodynamic monitoring in selected patients [5,10].

Unfortunately, the signs and symptoms of heart failure are nonspecific, and a helpful history is often not obtainable in acutely ill patients. Dyspnea, a key symptom of heart failure, may also be a nonspecific finding in elderly or obese patients or those with a comorbidity of respiratory disease. Routine laboratory tests, echocardiography, and radiography are also not accurate enough to always make the appropriate diagnosis. It is difficult for clinicians to differentiate patients with heart failure from other diseases, such as pulmonary disease, on the basis of routinely available laboratory tests [29]. BNP measurements can be useful in establishing the cause of acute shortness of breath, but many patients have both pneumonia and heart failure, with high BNP levels and consolidation on the chest x-ray. Patients who present with chronic obstructive pulmonary disease exacerbation that has triggered worsening cor pulmonale may present with dyspnea and major signs of right ventricular volume overload, including massive edema and ascites. The same may be true in the setting of acute right ventricular failure caused by acute pulmonary embolism. In these patients, BNP levels are likely to be high (300–600 pg/mL), although not quite as high as in those with cardiac dyspnea from increased left ventricular end-diastolic pressure.

BNP levels correlate with outcomes in patients with heart failure. During treatment of decompensated heart failure, BNP levels generally decline, and lower BNP levels correlate with better outcomes [44]. A study conducted in 2009 demonstrated that patients with greater percent reduction in BNP or lower BNP levels after treatment of decompensated heart failure had better overall event-free survival, persisting beyond six months after the index episode [45]. Higher baseline levels did not normalize as often as lower levels, indicating that a uniform "target BNP" may not be feasible.

Finally, some patients may present with dyspnea as their clinical manifestation of acute myocardial infarction. BNP is also a marker of necrosis, and its level may be elevated in these patients. Some patients have presented to the emergency department with chest pain and shortness of breath as a manifestation of unstable angina, but no infarction. It is possible that increased BNP levels in these patients represent acute ischemia-induced left ventricular dysfunction and may, in fact, represent patients with large territories of myocardium at risk.

Echocardiography is the preferred method for the documentation of cardiac dysfunction at rest. It is the most important measurement of ventricular function of the left ventricular ejection fraction for distinguishing patients with cardiac systolic dysfunction from patients with preserved systolic function. It is generally considered the single most effective tool in widespread clinical use [46].

Correctly diagnosing heart failure, whether it is of new onset or decompensated, is only the first step, as appropriate triaging of the patient along with maximal treatment is extremely important in ensuring the well-being of the patients. The use of BNP levels might ultimately be helpful not only in assessing whether or not a dyspneic patient has heart failure, but also in making both triage and management decisions. In some emergency departments, the diagnosis of heart failure leads to immediate admission to the hospital. Admission levels of BNP are useful in establishing a prognosis in acutely decompensated heart failure, and predischarge levels can be useful to establish a postdischarge prognosis [10]. Yet, there are many patients who come in with only mild heart failure, often precipitated by dietary indiscretions or noncompliance with medications.

Because BNP is a volume-sensitive hormone with a short half-life (18 to 22 minutes), there may be a future for BNP levels in guiding diuretic and vasodilator therapy in patients presenting to the emergency department with decompensated heart failure. Research has shown that patients who were not readmitted in the 30 days after discharge could be characterized by decreasing BNP levels during hospitalization [28].

The UPSTEP (Use of PeptideS in Tailoring hEart failure Project) study evaluated the tailored treatment of heart failure according to BNP level. A sub-study of UPSTEP assessed the change in percentage between BNP levels at the start of the study versus a specific week (i.e., 2, 6, 10, 16, 24, 36, or 48) [47]. Optimum cut-off percentage levels were obtained using a proportional regression analysis of death, hospitalization, and worsening heart failure. Patients with a decrease in BNP of more than 40% compared with that at study start and/or a BNP level less than 300 ng/L at week 16 had a significantly reduced risk of heart failure mortality and hospitalization [47]. Another study compared 18-month outcomes of BNP-guided versus symptom-guided heart failure therapy [48]. Both therapies resulted in similar rates of survival free of all-cause hospitalizations. BNP-guided therapy improved outcomes in patients 60 to 75 years of age but not in patients older than 75 years of age [48]. Knowing how fast BNP levels drop with treatment and what levels of BNP are needed to ensure patient stability might make it possible to use BNP-guided treatment algorithms for heart failure in the emergency department.

It seems that BNP levels may be helpful in guiding therapy in the outpatient setting. To make this a worthwhile endeavor, the following criteria should be met [29]:

There are many factors other than heart failure that can alter BNP values and circumstances in which BNP levels may be normal or lower than expected despite the presence of heart failure. Factors other than heart failure that can account for high BNP levels include [28]:

Factors that may account for lower-than-expected BNP levels in the presence of heart failure include [28]:

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.

Some physicians prefer to use NT-proBNP levels to diagnose or monitor patients with heart failure. The Cleveland Clinic uses the following reference ranges for NT-proBNP [49]:

The 2022 ACCF/AHA guideline recommends measurement of BNP or NT-proBNP for diagnosis (or exclusion), determining severity, and prognosis of heart failure or ADHF [10]. These biomarkers are useful for guiding medication dosing in certain patients with heart failure, but their usefulness for guiding therapy in ADHF is not established.

Heart failure therapy and research can be viewed from a historical perspective using the "Eras of Heart Therapy," described by William T. Abraham, MD, former Chief, Division of Cardiovascular Medicine at the University of Kentucky [50].

Prior to 1980, during the nonpharmacologic era, treatments focused on lifestyle changes or limitations, such as bed rest, inactivity, and fluid restrictions. Hemodynamic agents, digitalis, and diuretics comprised the mainstay of treatment.

The 1980s marked the beginning of the pharmacologic era, which was heralded by the first Vasodilator Heart Failure Trial (V-Heft). During this time, digitalis and diuretics continued to be mainstays, but vasodilators—particularly the combination of nitrates and hydralazine—played a prominent role. The use of positive inotropes became prevalent.

The pharmacologic era continued into the 1990s, but the decade brought neurohormonal interventions to the forefront. ACEIs, beta-blockers, and spironolactone (for the treatment of advanced heart failure) were shown to alter the natural history of disease progression.

In the wake of disappointing results from drug trials, there has been an increased interest in devices for patients with heart failure. There have been important successes in randomized, controlled trials of cardiac resynchronization devices, implantable cardiac defibrillators, and ventricular assist devices (VADs). The successes of these devices and others to come are likely to have a major impact on clinical practice outcomes for patients with heart failure.

If pharmacologically halting the progression of myocardial pathology or countering the electrophysiologic mechanisms responsible for arrhythmias were possible, one would have no use for implantable defibrillators. In a significant percentage of patients who do not respond adequately to medical therapy, however, prevention or reversal of ventricular remodeling may be achievable with devices that synchronize ventricular contraction, reduce ventricular load, or directly impede ventricular dilatation [51].

According to the ACC/AHA/HFSA, in patients with LVEF ≤40%, ACE inhibitors should be used to prevent symptomatic heart failure and reduce mortality.

(https://www.ahajournals.org/doi/10.1161/CIR.0000000000001063 Last Accessed: November 21, 2022)

Strength of Recommendation/Level of Evidence: 1A (Strong recommendation based on high-quality evidence from multiple randomized trials or meta-analyses)

There is overwhelming evidence that ACEIs should be used in symptomatic and asymptomatic patients with a reduced ejection fraction <40% (HFrEF). ACEIs stabilize cardiac remodeling, improve patient symptoms, prevent hospitalization, and prolong life [10]. Data from the SOLVD Prevention Study, Survival and Ventricular Enlargement (SAVE) study, and the Trandolapril Cardiac Evaluation (TRACE) have shown that asymptomatic patients with left ventricular dysfunction who receive an ACEI will have less development of symptomatic heart failure and hospitalization. Asymptomatic patients with documented left ventricular systolic dysfunction benefit from long-term ACEI therapy. ACEIs markedly enhance survival in patients with signs and symptoms of heart failure after myocardial infarction [10].

ACEIs should be given as the initial therapy in the absence of fluid retention. In patients with fluid retention, ACEIs should be given together with diuretics. The dose of ACEIs should always be initiated at the lower dose level and titrated to the target dose. Changes in systolic and diastolic blood pressure and increases in serum creatinine are usually small in normotensive patients [10]. Regular monitoring of renal function is recommended before administration, one to two weeks after each dose increase, and at three- to six-month intervals [46,53].

Beta-blocker therapy represents a major advance in the treatment of patients with heart failure with depressed ejection fraction [10]. When given in concert with ACEIs, beta-blockers reverse the process of left ventricular remodeling, improve patient symptoms, prevent hospitalization, and prolong life. There are three beta-blockers that have been shown to be effective in reducing the risk of death in patients with chronic heart failure: bisoprolol and sustained-release metoprolol succinate, which competitively block the ß1 receptor, and carvedilol, which competitively blocks the ß1, ß2, and ßa receptors. Use of one of these three beta-blockers is recommended to reduce mortality and hospitalizations in patients with HFrEF, with current or previous symptoms [10]. The favorable findings with these three agents should not be considered a beta-blocker class effect; other beta-blockers are not included in the recommendation for treatment of patients with heart failure [10].

Of the three beta-blockers that are approved for the treatment of heart failure, carvedilol has been studied most extensively. The Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study extended these benefits to patients with more advanced heart failure. When compared with placebo, carvedilol reduced the mortality risk at 12 months by 38% and the relative risk of death or heart failure hospitalization by 31% [10]. In the Carvedilol or Metoprolol European Trial (COMET), carvedilol (25 mg twice daily) was compared with immediate-release metoprolol tartrate (5 mg twice daily) with respect to the primary end point of all-cause mortality. In this study, carvedilol was associated with a 33% reduction in all-cause mortality when compared with metoprolol tartrate. Based on the results of the COMET trial, short-acting metoprolol tartrate is not recommended for use in the treatment of heart failure.

The Compliance and Quality of Life Study Comparing Once-Daily Controlled-Release Carvedilol IR in Patients with Heart Failure (CASPER) was designed to test the hypothesis that the use of controlled-release carvedilol, a once-daily bioequivalent formulation of immediate-release carvedilol, could lead to improved drug-taking compliance. Simplifying a patient's regimen by reducing the frequency of medicine administration has the potential to improve compliance and may have a potentially favorable effect on physiologic measures (e.g., BNP), quality of life, and hospital utilization, as a significant proportion of hospital admissions for decompensated heart failure appear to be related to medication noncompliance. The results of this trial strongly support the safety of a simple and immediate switch from the twice-daily regimen of carvedilol to the once-daily controlled-release formulation. There was no excess of adverse events or safety issues identified [54].

Patients with heart failure have an increased risk for arterial or venous thromboembolic events. In clinical heart failure trials, the rate of stroke ranges from 1.2% to 2.4% per year. Depressed left ventricular function is believed to promote relative stasis of blood in the dilated cardiac chambers with increased risk of thrombus formation. Treatment with warfarin is recommended for all patients with heart failure, chronic or paroxysmal atrial fibrillation, and a history of systemic pulmonary emboli, including stroke or transient ischemic attack. Patients with symptomatic or asymptomatic ischemic cardiomyopathy and documented recent large anterior myocardial infarction or recent myocardial infarction with documented left ventricular thrombus should be treated with warfarin for the initial three months after a myocardial infarction, unless there are contraindications. There is no compelling evidence that warfarin anticoagulation is beneficial in patients with heart failure, although it may be considered in selected patients with heart failure after a careful assessment of the potential risks and benefits [10]. Aspirin therapy is recommended in patients with heart failure and ischemic heart disease for the prevention of myocardial infarction and death. However, lower doses of aspirin (81 mg) may be preferable due to the concern of worsening of heart failure at higher doses.

A study performed on female rats suggested that digitalis glycosides may prolong survival in certain circumstances [55]. The study indicated two possible scenarios in which digitalis glycosides may provide a benefit: in the early onset of digitalis treatment after myocardial injury and in the treatment of patients with more accentuated ventricle dysfunction. Another study performed on 72 rats found that long-term treatment with digitoxin attenuates congestive heart failure, mitigates myocardial remodeling, and preserves calcium-binding myocardial proteins [56].

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].

Nesiritide is the generic name assigned to recombinant human BNP. The physiologic effects of BNP are very similar to those of ANP. Both peptides result in increased venous capacitance, decreased vascular tone due to decreased sympathetic stimulation, and inhibition of the RAAS. The intravenous administration of nesiritide has been shown to produce favorable hemodynamic effects, including balanced vasodilatation associated with a rapid improvement in heart failure clinical symptoms. It also reduces levels of deleterious neurohormones, such as norepinephrine, aldosterone, and endothelin-1 [59].

Nesiritide emerged in 2000 in the Nesiritide Study Group trial, which enrolled patients hospitalized due to heart failure in either an efficacy trial or a comparative trial. The efficacy trial included 127 patients randomly assigned to double-blind treatment with placebo or nesiritide. The comparative trial included 305 patients randomly assigned to open-label therapy with standard agents or nesiritide for up to seven days. Nesiritide was found to improve both hemodynamic function and clinical status in both groups [60]. Nesiritide was subsequently approved by the FDA in 2001 [59].

In 2002, results of the Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) trial were published [61]. VMAC evaluated the hemodynamic and clinical effects of nesiritide in addition to standard care compared with standard care plus IV nitroglycerin or placebo in 489 patients with acute decompensated heart failure and dyspnea at rest. This trial demonstrated that a 2 mcg/kg intravenous bolus given over one minute followed by a fixed infusion of 0.01 mcg/kg/min, rapidly, efficiently, and safely reduced pulmonary capillary wedge pressure while improving self-reported dyspnea index scales in patients with and without pulmonary artery catheters to monitor their central hemodynamics. In this trial, nesiritide was added to standard therapy (including dobutamine, dopamine, and parenteral diuretics) in patients hospitalized with acutely decompensated heart failure due to a wide variety of causes. Results indicated that nesiritide achieved greater hemodynamic and clinical benefits compared with intravenous nitroglycerin, with fewer adverse effects [30].

In 2005, two meta-analyses were published that raised questions about the safety and efficacy of nesiritide. In the first analysis, nesiritide use in 862 patients hospitalized for acute decompensated heart failure was associated with a 74% increased risk of 30-day mortality [62]. In the second, nesiritide use in 862 patients hospitalized for acute decompensated heart failure was associated with a 54% increased risk of worsening renal function [63]. A few months following publication of these analyses, the ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure included nesiritide in the section on interventions under active investigation [64]. The 2009 update to the guideline moved nesiritide from an active investigation status to a drug recommended for hospitalized patients comparative to nitroglycerin and nitroprusside [65]. The ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) study, published in 2011, found no impact of nesiritide on either death or heart failure hospitalization [66]. However, the agent was found to have little benefit over existing therapies for the treatment of acute decompensated heart failure [67,68,69]. In 2018, the FDA reported that Janssen Pharmaceuticals was discontinuing manufacture of nesiritide, and the drug is no longer available in the United States [59].

The ACC/AHA/HFSA asserts that ivabradine can be beneficial to reduce heart failure hospitalization and cardiovascular death for patients with symptomatic (NYHA class II–III) stable chronic heart failure (LVEF ≤35%) who are receiving guideline-directed evaluation and management and who are in sinus rhythm with a resting heart rate of 70 bpm or greater.

(https://www.ahajournals.org/doi/10.1161/CIR.0000000000001063 Last Accessed: November 21, 2022)

Level of Evidence: 2a (Moderate recommendation based on moderate-quality evidence from one or more randomized controlled trials)

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].

A randomized controlled trial (Prospective Comparison of ARNi with ACEi to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]) compared sacubitril/valsartan with the ACEI enalapril in symptomatic patients with HFrEF tolerating an adequate dose of either ACEI or ARB [73]. In previous trials, enalapril improved survival in such patients. In the PARADIGM-HF trial, sacubitril/valsartan significantly reduced the composite endpoint of cardiovascular death or heart failure hospitalization by 20% compared with enalapril. A similar benefit was observed for death and heart failure hospitalization and was consistent across prespecified subgroups [73]. Use of an ARNI is more frequently associated with symptomatic hypotension and a comparable incidence of angioedema when compared with enalapril [73]. The efficacy of ARNI in patients with left ventricular dysfunction and heart failure in the early post-myocardial infarction period remains uncertain [10].

Potential adverse effects include hypotension, renal insufficiency, and angioedema. Sacubitril/valsartan should not be given with any ACEI, as this increases the risk for angioedema. Sacubitril/valsartan is to be used in place of an ACEI or an ARB and in conjunction with other standard heart failure treatments (e.g., beta-blocker, aldosterone antagonist). Patients must be able to tolerate ACEI or ARB before starting on sacubitril/valsartan [74]. The drug is also contraindicated in pregnant women [59]. Use of an ARNI is recommended to reduce morbidity and mortality in patients with HFrEF and NYHA Class II–III symptoms [10].

Beginning in 2020, the FDA has approved several sodium-glucose cotransporter 2 (SGLT2) inhibitors for adults with heart failure with reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization [75,76]. These agents, including dapagliflozin, empagliflozin, and sotagliflozin, have proven efficacy in reducing the risk of death and/or hospitalization in these patients, even in those without diabetes [77,78,148]. The 2022 AHA/ACC/HFSA guideline for the management of heart failure recommends SGLT2I for treatment of patients with symptomatic chronic HFrEF to reduce heart failure hospitalization and cardiovascular mortality, irrespective of the presence of type 2 diabetes [10]. Several randomized controlled trials in patients with type 2 diabetes who either have established cardiovascular disease or who are at high risk for cardiovascular disease have shown that SGLT2I prevent heart failure hospitalizations compared with placebo. Two trials showed the benefit of SGLT2I (dapagliflozin and empagliflozin) versus placebo on outcomes. Compared with placebo, SGLT2I reduced cardiovascular death or heart failure hospitalization by approximately 25%. The benefit in reduction of heart failure hospitalization was greater (30%) in both trials. Additionally, the benefits in both trials were seen irrespective of baseline diabetes status [10]. The benefit appears independent of the glucose-lowering effects. The proposed mechanisms include reductions in plasma volume, cardiac pre- and afterload, alterations in cardiac metabolism, and reduced arterial stiffness [79,80].

One study compared the effects of SGLT2I with the effect of ARNI in heart failure with reduced ejection fraction [81]. Among the six randomized controlled trials included, SGLT2I were found to significantly reduce risk of cardiovascular death or hospitalization for heart failure by 27% and all-cause death by 16%. The reduction was similar in patients both with and without diabetes. Indirect treatment comparison showed that SGLT2I and ARNI had similar effects and that a combination of the two achieved a better prognosis compared with ARNI monotherapy [81]. Another study found that therapy with SGLT2I did not significantly lower the risk of cardiovascular death or heart failure hospitalization when compared with ARNI [82].

Primarily a disease of the elderly, heart failure continues to be an ever-increasing healthcare problem given the growth in the number of individuals older than 65 years of age. Although there have been many advances in the pharmacologic management of heart failure, there continues to be a significant number of patients with persistent symptoms despite maximal therapy, and it is likely that this group of patients will continue to increase in number.

Guidelines recommend the use of ACEIs, beta-blockers, diuretics, aldosterone antagonists, and digoxin for the treatment of patients with heart failure at various stages of the disease [83]. Despite advances in the pharmacologic management of heart failure, there remains a significant number of patients with persistent symptoms while on maximal medical therapy. Device therapies, such as ventricular synchronization, represent a promising modality in the treatment of patients with heart failure [84,85].

The myocardial conduction system is vulnerable to the same pathophysiologic processes that occur in myocytes and interstitium, with altered conduction properties observed in response to ischemia, inflammation, fibrosis, and aging. Supraventricular arrhythmias, particularly atrial fibrillation, are often the precipitating events that herald the onset of either systolic or diastolic heart failure. Elevated ventricular end-diastolic pressure in a patient with hypertension or abnormal myocardial function leads to atrial stretch, which in turn incites electrical instability. Recognition of the presence of atrial fibrillation in a patient is critical, as several studies have demonstrated the effectiveness of oral anticoagulant therapy for the prevention of stroke.

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.

The rate of sudden cardiac death among persons with heart failure is six to nine times that seen in the general population. Major innovations in medical and device-based therapy for the primary and secondary prevention of lethal ventricular arrhythmias have occurred in the past decades. Increasing use of implantable cardioverter-defibrillators (ICDs) has reduced mortality in a subgroup of patients with heart failure [12].

The presence of dysrhythmias and conduction system abnormalities is an important characteristic of heart failure. Up to 53% of patients with heart failure have an intraventricular delay that can lead to abnormal electrical depolarization and subsequent dyssynchrony between the right and left ventricle. While many efforts have focused on optimization of preload, afterload, and contractility, technologic breakthroughs have made addressing the correction of ventricular dyssynchrony a possibility [84]. Ventricular desynchronization can lead to abnormal interventricular septal wall motion, reduction in stroke volume, reduction in the rate of rise of left ventricular pressure, diminished diastolic filling times, and prolongation of mitral regurgitation. Because all of these can contribute to worsening heart failure and symptomatic deterioration, the ability to correct this dyssynchrony is a very significant step in the treatment of heart failure.

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.

Abnormal electrical signals that arise from damaged heart muscle may cause arrhythmias; therefore, arrhythmias are common in patients with heart failure. Remarkable advances in the technology and function of implanted cardiac devices have been achieved over the past 15 years. Most of these devices can be implanted with minor surgery that may be done as outpatient procedures or require only a day or two in the hospital. Leads are placed in the right upper and lower chambers of the heart. A small computer is implanted under the skin, usually near the collarbone. These "built-in" computers have enormous potential to increase survival and the quality of life for the patients with heart failure. Patients with heart failure may be treated with permanent pacemakers, hemodynamic monitors, ICDs, or resynchronization devices. ICD therapy for primary prevention of sudden cardiac disease is recommended for select patients (i.e., expectation of meaningful survival greater than one year) to reduce total mortality and hospitalizations and improve symptoms and quality of life [10]. Periodic re-evaluation of ejection fraction following myocardial infarction, revascularization, or guideline-directed medical therapy is useful to determine candidacy for ICD or cardiac resynchronization therapy (CRT) [10]. Guideline-directed medical therapy should be optimized before ICD and CRT implantation to assess whether the left ventricular ejection fraction improves [10].

CRT is a pacemaker-based approach to the treatment of patients with heart failure who have a wide QRS complex on 12-lead electrocardiography. The purpose of resynchronization is to provide electromechanical coordination and improved ventricular synchrony in symptomatic patients who have severe systolic dysfunction and clinically significant intraventricular conduction defects, particularly left bundle-branch block [12].

The European Heart Rhythm Association/Heart Rhythm Society recommend cardiac resynchronization therapy rather than standard RV pacing for patients with symptomatic heart failure (HFmrEF) and an uncontrolled heart rate who are candidates for atrioventricular junction ablation (irrespective of QRS duration).

(https://academic.oup.com/eurheartj/article/42/35/3427/6358547 Last Accessed: November 21, 2022)

Level of Evidence: IIa (Weight of evidence is in favor of usefulness/efficacy.)

Approximately 8% to 15% of patients with advanced heart failure have pacemakers implanted for symptomatic bradycardia, and an additional group of patients with heart failure have an implantable cardioverter defibrillator and use the bradycardia feature of the device to pace the right ventricle. Such patients have an increased risk of mortality or urgent transplantation due to progressive pump dysfunction. In one series, the risk at one year was 49% versus 15% in patients without a pacemaker. This difference may be due in part to the dyssynchronous contraction caused by right ventricular-based pacing. Whether such patients would benefit from the addition of a left ventricular lead is being studied. One of the most important and overlooked aspects of resynchronization therapy is its potential to allow for maximal optimization of the pharmacologic treatment of heart failure. This can be achieved by the ability of the resynchronization device to help support blood pressure and heart rate while also treating arrhythmias [84].

When CRT is added to optimal medical therapy in patients in sinus rhythm, there is a significant decrease in patient mortality and hospitalization, a reversal of left ventricular remodeling, and improved quality of life and exercise capacity [86,87,88]. CRT reduces the interventricular mechanical delay and the left ventricular end-systolic volume index and increases the ventricular ejection fraction. Similar overall results with respect to the role of CRT were observed in the Comparison of Medical Therapy, Resynchronization, and Defibrillation Therapies in Heart Failure Trial (COMPANION) and in the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) trial [88,89]. In the REVERSE trial and meta-analysis, CRT was shown to improve mortality in patients with and without ischemia, but patients with ischemia had less extensive reversal of left ventricular remodeling than those without ischemia [87,88,90].

Heart transplantation is an accepted treatment option for end-stage heart failure. Although controlled trials have never been conducted, it is considered to significantly increase survival, exercise capacity, return to work, and quality of life compared with conventional treatment. Patients who should be considered for heart transplantation are those with severe symptoms of heart failure with no alternative form of treatment and with a poor prognosis. Besides shortage of donor hearts, the main problem with heart transplantation is rejection of the allograft, which is responsible for a considerable percentage of deaths in the first postoperative year. The long-term outcome is limited predominantly by the consequences of immunosuppression [46].

Although typically considered a bridge to transplant device, left ventricular assist devices (LVADs) are extending the life of patients with heart failure as permanent or destination therapy. Additionally, survival after transplant is similar or increased when bridging with a LVAD is used. LVADs can be a good option for patients not eligible for transplantation; 80% of these individuals survive to one year and 70% survive at least two years post-implantation with a continuous-flow LVAD. Patients up to 70 years of age without cardiogenic shock, diabetes, or renal impairment have a survival of 85% at two years with a continuous-flow LVAD. Bleeding, thromboembolism, pump thrombosis, driveline infections, and device failure are still significant problems affecting long-term patient outcomes, despite technologic advances [46,104]. Additionally, an estimated 60% of patients are rehospitalized at least once by six months postimplantation [104]. Consensus-based contraindications to LVAD therapy include active malignancy or active infection; severe liver, lung, or vascular disease; significant aortic insufficiency; and inhibiting psychosocial factors [104].

Patients with heart failure of any stage who are at risk for coronary artery disease should be screened for myocardial ischemia [105]. Revascularization, through either a catheter-based or a surgical approach, often improves ischemic symptoms, improves cardiac performance, and reduces the risk of sudden death. In select patients with heart failure, reduced EF (≤35%), and suitable coronary anatomy, surgical revascularization plus guideline-directed medical therapy is beneficial to improve symptoms, cardiovascular hospitalizations, and long-term all-cause mortality [10]. Patients with Stage C or Stage D heart failure, who have been considered unacceptable candidates for surgery, may in fact derive substantial benefit from bypass surgery and additional techniques designed to reduce myocardial wall stress. Procedures to eliminate or exclude areas of infarction, repair mitral regurgitation, or support the failing myocardium are undergoing clinical trials [105]. Similarly, the role of mechanical devices that serve to support patients who are awaiting heart transplantation or are definitive therapy for end-stage (Stage D) heart failure continues to evolve, and such devices offer great hope to many patients who are not eligible for cardiac transplantation [12,104].

Results are available from at least one trial, the Surgical Treatment for Ischemic Heart Failure (STICH) trial, which compared the addition of coronary artery bypass grafting (CABG) to medical therapy versus medical therapy alone. The most common types of death—sudden and pump failure—were significantly reduced with CABG (as were severe ischemic events), but these gains were offset by an increase in post-procedure deaths (i.e., surgical therapy did not statistically reduce the primary outcome of all-cause mortality) [106]. The greatest benefit of CABG was survival at the two-year mark, and the STICH Extension study is investigating the benefit beyond 24 months.

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.

The application of TEB technology in the assessment of cardiac function is known as impedance cardiography. Impedance cardiography was originally introduced in the late 1930s. However, systematic study of TEB technology was delayed until the late 1960s when the National Aeronautics and Space Administration (NASA) considered it for use in monitoring astronauts during the Apollo manned flight into space.

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 contemporary focus of disease management is shifting from symptom management to evaluating hemodynamic performance, including cardiac output, left ventricular volumes, and ejection fraction. Objective, accurate, reproducible, and easy-to-obtain measurements of physiologic parameters that are indicators of hemodynamic function are essential for managing both predisposing conditions and heart failure itself. Heart failure represents one of the chronic disorders for which management might be improved with the use of impedance cardiography. This potential exists for three specific reasons. First, both recognizable hemodynamic abnormalities and the accumulation of thoracic fluid characterize worsening heart failure. Second, changes in hemodynamic variables and in thoracic fluid content are clinically relevant when assessing improvement or progression of the disease process and are regarded as appropriate targets for therapeutic intervention. Third, physicians are generally unable to assess hemodynamic variables and thoracic fluid content, or changes in these variables, accurately using either clinical judgment or any commonly available noninvasive technique. Therefore, it is appropriate to hypothesize that impedance cardiography may be able to identify clinically relevant changes in hemodynamic variables or thoracic fluid content earlier or more accurately than the usual clinical assessment carried out by physicians. Therefore, it might be appropriate to recommend the routine use of impedance cardiography and to expect that it may enhance patient care and improve outcomes of patients with chronic heart failure as well as other chronic cardiopulmonary disorders. To further increase the knowledge of the importance of bioimpedance data in optimizing patient management, the following case studies will be presented.

Despite compelling scientific evidence that pharmacologic therapy, such as ACEIs, beta-blockers, and aldosterone antagonists, reduces hospitalizations and mortality in patients with heart failure, these life-prolonging therapies continue to be underutilized outside the highly artificial environment of clinical trials. Indeed, numerous studies in a variety of different clinical settings indicate that a significant proportion of patients with heart failure are not receiving treatment with evidence-based, guideline-recommended therapies. Treatment gaps have also been documented in the provision of other components of care for patients with heart failure, especially in the critically important area of patient education [109,110,111]. Being unhoused, substance use, food insecurity, limited English proficiency, intimate partner violence, elder abuse, social isolation, and lack of transportation represent potential barriers to optimal disease management [10].

Numerous studies have shown that many of the challenges to delivering optimal care to patients with heart failure can be met through an integrated specialized heart failure clinic approach that utilizes nurse and physician extenders to deliver and ensure the implementation of care [112]. Although disease management strategies can lead to improved survival, it is not clear that these strategies are necessarily more cost effective [10]. Accordingly, the biggest challenge to disease management programs is to determine how to support the additional personnel required in this model of care.

Any effort at the establishment of a heart failure clinic requires a methodical process that first seeks to examine the local operative conditions that influence therapeutic interventions. There are key questions which should be prospectively tackled. First, determine which process works best. Next, define the patient population that will be treated. The next step is to determine the most effective way to modify patient behavior, because this is the key to changing outcomes in patients with heart failure. To define the economic feasibility of setting up a heart failure clinic, one must know the cost of care for heart failure as well as the average length of stay in the hospital setting. Furthermore, the 30- and 90-day readmission rates should be calculated. Other important points to consider relate to the current approach to these patients in the local emergency room. Finally, knowing about the structure of payments and payer classes is important [113].

One should understand where the important financial responsibilities and opportunities lie in the global heart failure care process. Clearly, setting up an outpatient service is associated with a cost increase. This is a result of the additional resources that are developed, the cost of increased telephone management, the cost of the education component, and the cost of increased pharmaceutical use in the outpatient setting. On the other hand, the cost savings are most noticeable in the hospital and the emergency department. Should the hospital pay the increased costs to implement outpatient care processes? The obvious answer is yes. This type of financial alignment is very important in a move to a nontraditional heart failure care process [7].

The traditional format of healthcare delivery for the patient with heart failure has centered around crisis intervention, a concept that allows patients to reach a point in their illness that requires acute care followed by a cycle of prolonged and repeated hospitalizations. Thus, of the four areas where heart failure care is provided (outpatient, home, hospital, and emergency department), the hospital and the emergency department have been the major areas of focus. The emerging paradigm for heart failure care now dictates that the traditional focus must shift to the outpatient and home settings, with an emphasis on preventative intervention designed to break away from the vicious cycle of repeated and prolonged hospitalizations. These concepts have led to the development of outpatient strategies, which have resulted in the creation of heart failure treatment centers [7,114].

In an effort to provide better care, doctors and nurses have set up special disease management programs for patients with heart failure. Hospitalizations and emergency visits for heart failure have decreased, and functional status, peak oxygen consumption, and quality-of-life scores have improved [115]. The key elements present in these programs are [113]:

Perhaps one of the critical features of a successful heart failure clinic is a core of professionals who have excellent knowledge of the concepts and will work diligently to maintain the goal of enhanced quality of life for their patients. There is no specific number of people needed to initiate a successful clinic. However, commitment is crucial, and results are usually best when clinic development is part of a plan of care that includes support by administration, nurses, physicians, ancillary personnel, and even local insurers.

The heart failure team is comprised of a number of players. The lines of authority and communication among these people should be agreed on and incorporated into the program plan. Good communication is essential among the team members and the patient.

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.

The cardiologist is important for the management of patients with particularly difficult problems, such as those with multiple hospital admissions over a short period. As cardiologists who specialize in heart failure are still relatively rare, networks should be developed that allow PCPs or general cardiologists ready access to this additional consultation resource.

The heart failure specialist can be instrumental in developing and updating the clinical practice guidelines or care pathways used in the outpatient setting by the PCP. In helping develop the protocol, heart failure specialists should assist in interpreting and communicating published guidelines and ensure that the program is research-based and aggressive and provides the best opportunity to improve outcomes. Heart failure specialists generally have much experience in the aggressive care of very advanced heart failure syndromes, as the cornerstone for their proaction is usually patient referral for heart transplantation. They are more likely to promote options such as experimental drugs or emerging surgical procedures that might be suitable for very ill patients. Patients with advanced heart failure who wish to prolong survival should be referred to a team specializing in heart failure. This team will assess suitability for advanced heart failure therapies and can use palliative care where consistent with the patient's goals of care [10].

The cardiac nurse is used in many successful programs to assist in patient management [116]. In one inpatient program, total hospital costs were significantly lowered and length of hospital stay decreased in the year after a nurse was added to the team. In two hospital-based studies, patient education that included one-on-one, one-hour heart failure education delivered by cardiac nurses decreased subsequent hospitalization compared with usual care [117,118]. Cardiac nurses have also been incorporated into programs at cardiomyopathy clinics, and reported outcomes have been good. In an aggressive, nurse-assisted management program, outpatient visits and communication increase, whereas hospital readmission rates decrease 33% [119]. Improvements in self-care knowledge and home-care behavior are credited.

Other team members include emergency medicine specialists, pharmacists, nutritionists, dieticians, cardiac rehabilitation personnel, social workers, home healthcare personnel, and palliative care specialists [120].

After the target population has been identified and the services or scope of the heart failure clinic have been decided, the next issue is how to provide these services to the patient population. One of the most common ways to manage patients with heart failure is through direct contact, predominantly by telephone. Nearly one-half of the surveyed clinics in the United States reported telephone contact as the primary method of patient management [19]. Such contact can be initiated either by the staff of the heart failure clinic or by the patient. In the former case, an initial call is usually made to patients soon after a hospital discharge, with the goals being determination of stability, understanding of medication changes, and cooperation with the current medical regime. This entails a transfer of information from the inpatient physicians and nursing staff to the heart failure clinic personnel. In some situations, heart failure clinic nurses actually visit patients in order to provide the continuity required for transition into the outpatient setting.

Beyond the initial telephone call, the role of the heart failure clinic often varies considerably. In some cases, a telephone call is made at fixed intervals, during which patient weight, symptoms, and problems are noted. These are often relayed to the appropriate physician for further action. In some instances, nurses and physicians have developed treatment algorithms or orders to be followed in various common clinical scenarios such as weight gain or leg edema. The additional follow-up actions usually depend on the teamwork and experience of the heart failure clinic staff.

Another development in telephone management has been computerized screening for patients at risk for further decompensation. In these systems, daily telephone calls may be initiated by the patient. Often, contact is initiated when a set of vital signs, such as weight, blood pressure, heart rate, and oxygen saturation, are measured at home. The home actions are transmitted via the patient's telephone line, usually to a central monitoring station. Limits for the various measurements are preset, and deviation usually triggers direct patient contact or notification of the heart failure clinic personnel for further action.

Because the average hospital has more than 500 primary heart failure admissions annually, perhaps one of the most difficult tasks is identifying which patients should be targeted for the heart failure clinic [19]. Ideally, some strategy should be directed at improving the outcome of all patients with heart failure as well as those with asymptomatic left ventricular dysfunction and those at risk for the development of heart failure. However, most clinics focus on the patient with overt, symptomatic advanced heart failure. Increasingly, patients admitted to a hospital with heart failure have very advanced symptoms and poor prognostic markers and, hence, are likely to be readmitted. In fact, readmission rates for these patients at 30 and 60 days approach 30% to 50% [121]. Also, because databases of financial information are found predominantly within medical institutions, outcomes regarding hospital length of stay and readmission are often the easiest to track. Some heart failure clinics are able to work closely with emergency departments, which are the source of most hospital admissions for heart failure. In most cases, triage, treatment, and release are arranged by the heart failure clinic. This is obviously a good opportunity to enroll patients into the clinic population.

Readmission after hospitalization for heart failure is common, estimated at 25% at one month within the Medicare population [122]. Reduction in heart failure hospitalizations is an appropriate goal for treatment modalities and quality improvement strategies because hospitalization impacts adversely on both sides of the cost-effectiveness equation. On the cost side, hospitalization is the principal component of the high cost of care for patients with heart failure, representing 70% to 75% of total costs. On the effectiveness side, hospitalization may represent a failure of treatment, a progression of disease severity, or the elusiveness of effective interventions to prevent unnecessary readmissions. All scenarios detract from the patient's overall quality of life [122,123].

As pharmacologic treatments continue to reduce mortality rates in heart failure, reduction of hospitalization frequency emerges as an increasingly important therapeutic goal. In the practice setting, physician adherence to prescription recommendations and patient compliance represent important goals in an effort to improve clinical outcomes, including reduction in heart failure hospitalizations.

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.

This study also described their process of pre-emptive hospitalization, which is any admission by the heart failure care team that avoids patient-initiated emergency room visits or home ambulance calls. Pre-emptive hospitalization was a proactive hospital admission for a patient exhibiting progressive decompensation despite a variety of measures in the outpatient setting (i.e., increased doses of diuretics, forced bed rest, urgent fluid and/or sodium restriction, more frequent clinic visits). The care team observed a marked reduction (72%) in emergency department visits [124].

Patient education was another important intervention. This study was the first that examined the pre- and post-program differences in the patient's knowledge of an adherence to self-care recommendations. At six months after referral, a significant improvement was shown in patients' knowledge regarding daily weight monitoring, importance of restricting dietary salt intake, and contacting providers if experiencing a sudden weight gain. However, the study members did not observe any changes in patients' self-reported adherence to dietary salt intake restriction and medical dosage compliance. This study showed improvement in patient quality of life after three and six months as measured by the Minnesota Living with Heart Failure Questionnaire, NYHA functional classification, fatigue and dyspnea score, and patient global assessment. There was also a reduction in risk of hospitalization, emergency department visits, and reduced expenditure [124].

In a landmark study conducted at one Veterans Affairs (VA) facility, a marked decrease in hospital days and healthcare costs was demonstrated. Total estimated outpatient cost increased 200%. However, because inpatient costs are much higher than outpatient costs, the net result was a 75% decrease in total patient cost. One large VA facility in the Midwest has had a nurse-managed clinic for patients with heart failure for the past 19 years. Successful outcomes include a dramatic reduction in readmission to the hospital at this institution [125].

At the initial visit, patients are encouraged to bring a spouse, family member, or significant other. The patient is given an explanation of his or her disease in layman's terms and has an opportunity to ask questions. The patient is also informed of the procedure for obtaining prescriptions through the clinic. Heavy emphasis is placed on obtaining a scale, the method of daily weighing, and the importance of knowing the target weight.

On subsequent visits, the patient's physical and psychosocial statuses, as well as the ability to self-monitor his or her condition, are assessed. Assessment by the nurse of the patient's ongoing ability to self-monitor is critical to the success of this model. Some questions asked of the patients on successive visits are:

Frequently, with the patient's help, diuretics will be titrated to treat fluid retention. It is not uncommon to give a bolus dose of a diuretic, and then have the patient closely monitor his or her weight at home. Telephone calls are made daily for a few days to check with the patient, and diuretics are prescribed accordingly. Patients are encouraged to report increased weight and symptoms at the onset to avoid hospitalizations.

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.

Jugular venous pressure should be assessed with the patient sitting up at a 30- or 45-degree angle. Although jugular venous pressure can be difficult to interpret on initial examination, it is often the only reliable indicator of volume status in patients with chronic heart failure [10]. Hepatojugular reflux can also be assessed at each visit. Application of constant pressure over the liver causes a transient rise in pressure in the neck veins for a few cycles, followed by a return to normal in most patients.

The presence of crackles in the lungs during auscultation is usually evidence of pulmonary edema, and treatment with diuretics and afterload reduction should be instituted until the cause is clearly shown to be lung disease or another disorder.

The ACC/AHA/HFSA asserts that in patients heart failure and suspicion of sleep-disordered breathing, a formal sleep assessment is reasonable to confirm the diagnosis and differentiate between central and obstructive sleep apnea.

(https://www.ahajournals.org/doi/10.1161/CIR.0000000000001063 Last Accessed: November 21, 2022)

Level of Evidence: 2a (Moderate recommendation based on moderate-quality evidence from one or more randomized controlled trials)

As noted, enrollment in heart failure clinics has resulted in a significant reduction in readmissions to the hospital, as well as emergency department visits. Despite the fact that traditional aspects of disease progression, such as mortality and readmission, are important and useful outcomes with which to judge the efficacy of a heart failure management program, patient-centered outcomes, such as functional status and quality of life, are increasingly recognized as important markers of healthcare quality. The term "quality of life" has come to be perceived as synonymous with patient-rated, nonclinical aspects of health status, whereas functional status is defined as the ability to exercise measured by NYHA classification and peak oxygen consumption. Often, these terms are used interchangeably, and progress or deterioration of one can directly affect the other.

Knowing the patient's quality of life and functional status at the onset of a new heart failure intervention, such as enrollment in the heart failure clinic, is helpful in assessing the ongoing progress of each patient. Fatigue, a major symptom of heart failure, is sometimes difficult to measure. Drugs such as ACEIs and beta-blockers can help to improve levels of fatigue. Fatigue can also be influenced by feelings of depression related to chronic illness [125].

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.

The management of heart failure in elderly persons is often made more challenging by the presence of multiple coexisting problems. These factors contribute to the increased vulnerability of elderly patients to noncompliance and rehospitalization for heart failure and include:

Clinicians who do not consider these factors when caring for elderly patients with heart failure can contribute to patient noncompliance.

A few studies have examined the role of healthcare provider compliance with heart failure practice guidelines and the impact on patient outcomes [109,110]. Despite the publication of consensus guidelines that established standards for heart failure medical therapy, many patients are still not prescribed ACEIs, do not receive them in adequate doses, and/or are prescribed drugs that may have deleterious effects on heart failure. The use of ACEIs for the treatment of heart failure in the community setting has increased, but the use has remained below recommendations in practice guidelines. More cardiologists than noncardiologists were found to conform to published guidelines for the management of patients with heart failure. Specifically, more cardiologists than generalists were likely to use ACEIs for the treatment of mild, moderate, and severe heart failure and titrated doses proved to be efficacious in clinical trials. Other studies have found that patients who were referred to heart failure specialists had fewer hospitalizations.

A major challenge is to identify the combination of interventions within a given program that is effective. Because there have been no studies that compare the relative effectiveness of different programs or that compare individual components or combinations of components within programs, there remain several unanswered questions. For example, is a truly multidisciplinary team necessary, or is it sufficient for teams of nurses and physicians to manage patients? Until there is research available, identification of the components common to successful programs that are adaptable to a variety of communities and settings can provide guidance to clinicians. Optimization of medical therapy based on consensus heart failure guidelines is an important aspect of care for heart failure programs.

In making decisions about which components to include in a heart failure program, the characteristics of the target population should be examined. For example, if the heart failure population to be targeted consists of very elderly patients, a program that includes some component of home care is likely to be more successful given the mobility and transportation difficulties experienced by many elderly patients. In addition, elderly patients are a more vulnerable population due to often unresolved social and financial issues. The inclusion of mechanisms to address these issues is important to the success of a program.

Another challenge is determining how to implement a heart failure clinic outside an academic center, as most research has been done in academic medical centers. Many of the heart failure programs were formed in academic medical centers to conduct pharmaceutical trials or to manage patients before and after heart transplantation. Community-based programs are trying to provide the intensive care these patients require, although reliable sources of reimbursement for the commitment of specialized nursing are just beginning to become available. Implementation of a heart failure clinic in a community setting not associated with an academic medical center depends on guidance from committed, experienced clinicians. Cardiologists and experienced cardiovascular advanced practice nurses manage many successful heart failure programs in a variety of communities across the United States.

An integral part of any heart failure program is evaluation, and every program should include a plan for evaluation of its effectiveness. Evaluation of the impact of a program allows for refinement to improve program effectiveness and provides data when seeking reimbursement for a program from managed care organizations and insurance companies [131].

Heart failure clinics managed by nurses can take a variety of approaches. Nurses can manage these patients in close collaboration with a physician, as part of an interdisciplinary team, or as primary care providers. Outcomes in these clinics are significant and include a dramatic cost savings. Despite increased outpatient costs, initial time spent with the patient and his or her family in the outpatient setting can result in a decrease in inpatient admissions. Nurses, by their ability to address the myriad concerns of this population, have demonstrated that the total care given to the patient ultimately has the potential to increase patient quality of life and to decrease unnecessary readmission for heart failure.

The term "heart failure" has a negative connotation. It is important for the nurse caring for patients with heart failure to convey an attitude of hopefulness, even during the advanced stages of the disease. It is imperative that nurses remember that their beliefs about adherence will influence the way they interact with the patient. If a nurse believes that older persons or those with little education will not comply with their treatment, that belief will be conveyed nonverbally to the patient and may influence the patient's comprehension. Change is always possible, but it is built on honesty. Finally, the care of patients with heart failure should include those close to them. Including these significant others not only identifies potential problems before they occur but gives the patient a broader base of support. In essence, to treat heart failure effectively, a team and a plan are necessary. Although some may say such an approach is "cookbook medicine," the proof is in the outcomes. Studies have shown that patients treated in formal programs have lower hospitalization rates, fewer emergency visits, and a higher quality of life, functional status, and level of satisfaction with their care. With a team in place, work may be delegated. Nurses keep in contact with the patients at home on a regular basis, heading off problems before they become crises. Heart failure specialists and others are available if their input is necessary. With a formal plan, adherence to evidence-based guidelines can be guaranteed. A program can, therefore, be proactive instead of reactive, concentrating on keeping patients healthy, instead of dealing with acute exacerbations. A team approach to heart failure management can be implemented in most traditional or managed-care outpatient settings [120].

Regardless of the methods utilized in identifying, communicating with, and treating patients with heart failure, some indicators of the success of interventions are required. Financial outcomes are frequently the easiest to obtain and measure. Seventy-two percent of heart failure clinics employ outcome measures other than financial data for their patients. Additionally, quality of life is measured in 58% of patients attending heart failure clinics, as this is perceived to be an important goal of a program treating patients with advanced disease [19].

Perhaps one of the most important requirements of a heart failure clinic is a suitable medical information system to allow tracking of key measurement parameters. The data set should also serve as an electronic medical record capable of monitoring frequent changes in medications and adverse reactions. A reporting feature of the software is also important to provide an up-to-date summary of information and testing should patients present to the emergency department or require hospital admission. Remote access enhances the value of the data set, particularly when the clinic personnel are limited. Few of the commercially available electronic records are ideal for the management of chronic heart failure, but this will probably change as the need becomes more apparent.

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.

Treatment of risk factors for coronary artery disease should be a high priority. Use of a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, simvastatin, in the 4S trial not only improved survival but also significantly reduced the future risk of developing heart failure. Another area of concern is the treatment of hypertension. When hypertension is treated, the impact on preventing heart failure is substantial. In the Systolic Hypertension in the Elderly Program (SHEP), treatment of elderly patients with systolic hypertension resulted in a 49% reduction in the likelihood of developing heart failure [136]. Many trials have shown that control of hypertension reduces the risk of heart failure. Although the magnitude of the benefit varies with the patient population, target blood pressure reduction and effective hypertension treatment invariably reduces heart failure events [10]. The AHA/ACC/HFSA guideline provides recommendations for the management of other risk factors for heart disease including, iron deficiency, anemia, sleep disorders, and type 2 diabetes [10]. These chronic conditions complicate the management of heart failure and can have a significant impact on its prognosis [10]. For select interventions, the AHA/ACC/HFSA guideline includes value statements with high-quality published economic analysis [10].

It will take a concerted and sustained effort by numerous parties, including the government, pharmaceutical companies, consumer and physician groups, and enlightened health maintenance organizations, to bring about change in this area. If risk factor management can be improved, it would have a substantial effect on the incidence of heart failure and its clinical sequelae.

What is needed is a means of reliably and inexpensively screening a population at risk for early indicators of cardiac dysfunction. Some evidence suggests that the family of natriuretic peptides (i.e., ANP and BNP) that are released from the heart in response to stretch may be useful to detect evidence of incipient heart failure. One study found that among patients at risk of heart failure, BNP-based screening and collaborative care reduced the combined rates of left ventricular systolic dysfunction, diastolic dysfunction, and heart failure [137]. Results such as these could potentially lead to routine screening of populations at risk with a blood test to help select patients for early initiation of neurohormonal blockade. The ACC/AHA/HFSA 2022 update supports the use of BNP-based screening for initial diagnosis, risk stratification, early intervention, and prevention [10].

In addition to earlier initiation of neurohormonal blockade during the preclinical phase of heart failure, there are several promising neurohormonal blockers that are currently under investigation. Endothelin is an extremely potent vasoconstrictor. It also promotes hypertrophy of cardiac myocytes and stimulates other neurohormonal systems. Circulating endothelin levels have been shown to be elevated in patients with heart failure [138,139]. In experimental animal models of heart failure, the chronic administration of endothelin receptor blockers improves cardiac function and hemodynamic variables. Other endothelin blockers are in development and clinical trials are either planned or under way with several of these drugs.

New surgical techniques and improvements of more established therapies designed to improve or replace cardiac function have been developed over the past decades. These techniques fall into three major categories: conventional surgical treatment applied to patients not previously approached, attempts to augment intrinsic cardiac function, and cardiac replacement strategies.

In the first category are revascularization and mitral valve surgery. The major emphasis in the former has been to better define which patients with severe left ventricular dysfunction are likely to respond to aggressive and complete revascularization.

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].

The expanded use of permanent mechanical VADs is becoming an important part of the treatment of heart failure. According to the Organ Procurement and Transplantation Network, improvements in VAD technology have led to one-year survival rates approaching those of heart transplant [141]. Devices have been extensively studied in the setting of bridging to transplantation. Current devices are still bulky, require a sternotomy, and are energy inefficient given the assumed need of pulsatile flow.

In the last several years, the understanding that regenerative processes exist at the level of the myocardium has placed stem cell research at the center stage of cardiology. Through cellular therapies, the concept of "growing" heart muscle and vascular tissue and manipulating the myocardial cellular environment has revolutionized the approach to treating heart disease.

Cell transplantation is the first therapy designed to treat the underlying injury in heart failure—cardiomyocyte and vessel cell death—and bring us closer to the ambitious goal of myocardial regeneration. Since 1998, when functional repair after injection of autologous skeletal myoblasts into the injured heart was first reported, a variety of cell types have been proposed for transplantation in different stages of cardiovascular disease. It now appears clear that cell-based cardiac and vascular repair is feasible, both early and later in the disease process. However, many questions about the technology remain. Cardiac regeneration, literally regenerating contractile cardiac muscle, functional vasculature, and electrical conductance in a fibrous, dilated, and underperfused scar, is the ultimate goal. In summary, cell-based cardiovascular repair offers unprecedented potential to treat the underlying injuries associated with cardiovascular disease and ultimately perhaps reverse the disease process [142,143].

Using modern techniques of linkage analysis, investigators have uncovered genetic mutations that result in a number of inherited cardiovascular diseases, including hypertrophic cardiomyopathy. Genetic variants have been implicated in 25% to 40% of patients with dilated cardiomyopathy with a positive family history but also in 10% to 30% of patients without a recognized family history [10]. Progress in uncovering point mutations that lead to dilated cardiomyopathy should help reveal intracellular pathways and mechanisms that give rise to the heart failure phenotype. Phenotype and family history are important for identifying patients for whom genetic testing is most likely to yield clinically relevant information [10].

Progressive changes in response to injury lead to structural and functional changes that are the cause of heart failure in most patients. The likelihood and rapidity of the development of heart failure appears to vary greatly among patients, suggesting that there may be genetic modifiers of the rate of progression. The AHA/ACC/HFSA 2022 guideline recommends genetic screening and counseling in first-degree relatives of select patients with either genetic or inherited cardiomyopathies. The goals of such screening are early detection and intervention to decrease heart failure progression and sudden death [10].

The use of polymerase chain reaction amplifications of DNA obtained from white blood cells makes analysis of the presence of various polymorphisms relatively easy to accomplish. The application of this technique prospectively in a large population should help uncover associations between polymorphisms and changes in the rate of progression of disease. This information will help to not only provide insights into mechanisms of heart failure but also provide therapeutic targets for intervention [136].