Optimal Pharmacologic and Non-pharmacologic Management of Cardiac Transplant Candidates: Approaches to Be Considered Prior to Transplant Evaluation: International Society for Heart and Lung Transplantation Guidelines for the Care of Cardiac Transplant Candidates—2006

Class I:

• 1
  In patients with severe heart failure and fluid retention, loop diuretics should be used and adjusted to achieve symptom control and/or euvolemia (Level of Evidence: C).
• 2
  In cases of diuretic resistance, precipitating factors or alternative causes of fluid retention should be investigated and excluded (Table 1) (Level of Evidence: C).
  Table 1Precipitating Factors or Alternative Causes of Edema in Heart Failure

  • Non-compliance with diuretic (and other) medication

  • Non-compliance with salt and fluid restriction

  • Non-steroidal anti-inflammatory drug usage

  • Glitazones

  • Intrinsic renal disease

  • Hypoproteinemia

  • Calcium channel antagonists

  • Acute impairment of left ventricular function (new-onset ischemia, arrhythmias such as atrial fibrillation)

  Adapted with permission from Nieminen et al.

  ¹

  • Nieminen M.S.
  • Bohm M.
  • Cowie M.R.
  • et al.

  Executive summary of the guidelines on the diagnosis and treatment of acute heart failure: the Task Force on Acute Heart Failure of the European Society of Cardiology.

  Eur Heart J. 2005; 26: 384-416

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• 3
  Diuretic resistance should be treated with an increase in dose or frequency of loop diuretics, change to a loop diuretic with better bioavailability, addition of a thiazide diuretic, or intravenous administration (bolus or continuous infusion) of a loop diuretic (Level of Evidence: C).
• 4
  All neurohormonal antagonists used in the management of patients with heart failure with low left ventricular ejection fraction (LVEF) should be those shown to be effective in clinical trials and they should be used at maximally tolerated or target dosages (Table 2) (Level of Evidence: A).
  Table 2Standard Drugs That Antagonize the Neurohormonal Systems

  Drug	Class	Starting dose	Target dose from clinical trial
  Captopril	ACE inhibitor	6.25–12.5 mg tid	50 mg tid
  Enalapril	ACE inhibitor	2.5–5 mg bid	10–20 mg bid
  Ramipril	ACE inhibitor	2.5 mg bid	5 mg bid
  Trandolapril	ACE inhibitor	1 mg qd	4 mg qd
  Carvedilol	α1 non-selective β-blocker, anti-oxidant properties	3.125 mg bid	25 mg bid (50 mg bid, if weight >85 kg [187 lb])
  Metoprolol succinate	β1-selective β-blocker	12.5–25 mg qd	200 mg qd
  Bisoprolol	β1-selective β-blocker	1.25 mg qd	10 mg qd
  Candesartan	ARB	4–8 mg qd	32 mg qd
  Losartan	ARB	12.5 mg qd	50 mg qd
  Valsartan	ARB	20 mg bid	160 mg bid
  Eplerenone	Selective aldosterone receptor blocker	25 mg qd	50 mg qd
  Spironolactone	Aldosterone receptor blocker	12.5–25 mg qd	25–50 mg qd

  ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; bid, twice daily; d, day; qd, once daily; tid, three times daily.

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• 5
  All patients with heart failure and low LVEF should have a trial of angiotensin-converting enzyme (ACE) inhibitors unless there are unequivocal contraindications (Level of Evidence: A).
• 6
  Angiotensin receptor blockers (ARBs) should be used as an alternative to ACE inhibitors in patients who cannot tolerate ACE inhibitors due to cough or angioedema (Level of Evidence: A).
• 7
  All patients with heart failure and low LVEF should have a trial of β-blockers unless there are unequivocal contraindications (Level of Evidence: A).
• 8
  In patients with atrial fibrillation, control of the heart rate should be done and conversion may be performed (Level of Evidence: C).
• 9
  Patients with heart failure and low LVEF should be anti-coagulated with warfarin if they have a history of an embolic event, atrial fibrillation or evidence of a new left ventricular (LV) thrombus (Level of Evidence: A).
• 10
  In carefully selected advanced heart failure patients with low LVEF, aldosterone antagonists should be added to maximally tolerated ACE inhibitors and β-blockers. However, this approach requires frequent monitoring of serum potassium and renal function (Level of Evidence: B).

Class IIa:

• 1
  In patients with pre–renal azotemia or fluid retention resistant to diuretic therapy, it is reasonable to use hemofiltration or dialysis (Level of Evidence: C).
• 2
  In heart failure patients with low LVEF, it is reasonable to add ARBs to the combination of maximally tolerated ACE inhibitors and β-blockers (Level of Evidence: B).
• 3
  In heart failure patients with low LVEF, it is reasonable to continue maximal ARB therapy rather than changing to an ACE inhibitor (Level of Evidence: C).
• 4
  In patients with heart failure and low LVEF, it is reasonable to consider a combination of hydralazine and nitrates when progressive renal dysfunction or hyperkalemia limits therapy with an ACE inhibitor (ACEI) or ARB (Level of Evidence: C).
• 5
  In patients with heart failure and low LVEF, it is reasonable to consider the addition of a hydralazine and nitrate combination or nitrates alone for patients with persistent symptoms despite recommended therapy with neurohormonal antagonists and diuretics for fluid retention (Level of Evidence: B).
• 6
  In patients with persistent, severe heart failure and low LVEF, who are on maximal therapy with ACEIs, β-blockers and diuretics, it is reasonable to use digoxin therapy to reduce symptoms, decrease hospitalizations, or control heart rate in atrial fibrillation. Drug-level monitoring is strongly recommended. Target trough levels should be <1.0 ng/ml (Level of Evidence: C).

Class I:

• 1
  In heart failure patients with fluid retention, salt and fluid intake should be restricted (Level of Evidence: C).
• 2
  In addition to optimal medical therapy, regular exercise should be advised in patients with chronic stable heart failure to improve functional capacity (Level of Evidence: A).
• 3
  Patients with advanced heart failure should be cared for by a multidisciplinary team, and seen at regular intervals (Level of Evidence: A).
• 4
  Right heart catheterization should be performed to assess pulmonary vascular resistance (PVR) in heart transplant candidates (Level of Evidence: B).
• 5
  Hemodynamic assessment using an indwelling pulmonary catheter should be used for assessment and management in patients with cardiogenic shock (Level of Evidence: C).
• 6
  Patients with heart failure should be approached regarding their wishes for resuscitative care and their wishes should be documented in a living will or other advanced medical directive (Level of Evidence: C).

Class IIa:

• 1
  It is reasonable to consider a formal sleep evaluation for all patients with a history suggestive of sleep apnea prior to consideration of cardiac transplantation (Level of Evidence: C).
• 2
  In patients with ischemic heart failure and low LVEF, it is reasonable to consider coronary artery bypass grafting (CABG) (Level of Evidence: C).
• 3
  It is reasonable to use brain natriuretic peptide (BNP) or N-terminal pro–B-type (NT-pro-BNP) levels and trends over time in the management of patients with heart failure (Level of Evidence: B).
• 4
  Short-term hemodynamic monitoring with a pulmonary artery catheter may be used to assess and manage patients with advanced heart failure (Level of Evidence: B).

Class IIb:

• 1
  In patients with heart failure and low LVEF, ventricular restoration surgery or mitral valve repair may be considered (Level of Evidence: C).

Class III:

• 1
  Candidacy for transplantation must not be contingent upon clinical trial participation (Level of Evidence: C).

Class I:

• 1
  In patients with decompensated heart failure and adequate blood pressure, intravenous vasodilators should be considered before inotropic therapy (Level of Evidence: C).
• 2
  In patients with decompensated heart failure and hypoperfusion in spite of adequate filling pressures, inotropic or pressor therapy should be used (Level of Evidence: C).
• 3
  The need for continued inotropic therapy should be frequently re-assessed (Level of Evidence: C).
• 4
  Long-term use of inotropic therapy should only be used as a pharmacologic bridge to transplantation or for palliation (Level of Evidence: C).
• 5
  The use of vasoconstrictive agents should be reserved for those patients who are in refractory cardiogenic shock (Level of Evidence: C).

In chronic heart failure, neuroendocrine systems are activated to compensate for reduced perfusion of vital organs (e.g., activation of the sympathetic nervous system and renin–angiotensin–aldosterone system [RAAS] and secretion of vasopressin, cytokines and endothelin). Activation of these systems leads to fluid retention. Clinical correlates to fluid retention in heart failure are dyspnea and pulmonary edema (LV failure) as well as peripheral edema and ascites (right ventricular [RV] failure). Repeated decompensation or failure to control fluid retention are important symptomatic criteria for the decision to list a patient for heart transplantation.

Measures to control or avoid fluid retention in patients with heart failure include fluid and salt intake restriction and the use of diuretic drugs. Fluid status should be monitored roughly by daily weights. Limited fluid intake (1.5 to 2 liters/day for severe heart failure) limits edema formation and avoids hyponatremia. Diuretic drugs improve dyspnea, exercise tolerance and cardiac performance by reducing LV filling pressures and decreasing dynamic mitral regurgitation. Insufficient diuresis may impair the efficacy of ACEIs. Excessive dehydration should be avoided because it may lead to hypotension, further activation of RAAS, and renal insufficiency. Thiazide diuretics, which block sodium and water re-absorption in the distal convoluted tubule, cause only mild water diuresis; their primary effect in heart failure is sodium excretion with a subsequent effect on hypertension. Loop diuretics (furosemide, bumetanide or torsemide) inhibit sodium uptake in the ascending loop of Henle by blocking the sodium–potassium–chloride transporter. Loop diuretics are the most potent diuretics, have a short duration of action, and are used in the treatment of patients with chronic heart failure or an acute exacerbation of heart failure, as well as in the setting of renal failure in patients with heart failure. As diuretics may induce further activation of the RAAS, diuretics should always be combined with an ACEI or ARB.

In advanced stages of heart failure (New York Heart Association [NYHA] Class III or IV) diuretics form the mainstay of symptomatic therapy, affording unquestionable relief from dyspnea, peripheral edema and ascites. Although the effects of diuretics on symptom control are well established, the impact of diuretic therapy on prognosis (mortality) in heart failure is far less clear as large, placebo-controlled mortality trials have not been performed with diuretics. In the Torsemide in Congestive Heart Failure (TORIC) trial, a significant survival advantage was demonstrated for patients treated with torsemide vs furosemide, possibly due to additional anti-aldosterone action and better absorption of torsemide.

In advanced heart failure, diuretic resistance, defined as failure to induce clinically sufficient diuresis even with large doses of loop diuretics, may develop. Diuretic resistance is associated with an adverse prognosis, and it may be caused by delayed absorption of the diuretic, reduced secretion into the renal tubule, post-diuretic (rebound) salt retention, and compensatory hypertrophy of the distal tubule. Management includes: exclusion of precipitating factors (Table 1); salt and volume restriction; increased dosing of diuretics; intravenous application of diuretic; combination therapy of loop diuretic with thiazide or metolazone^,  ; and institution of inodilatory therapy with dopamine, dobutamine or milrinone.

Acute exacerbation of fluid retention represents the most common form of acute decompensation (“wet” decompensation) in patients with heart failure, leading to increased hospitalization, morbidity and cost. Diuretic resistance, further compromise of LV function, or intercurrent illness may represent precipitating factors. Rapid restoration of euvolemia, usually via intensified diuretic therapy, achieves symptomatic relief. In therapy-resistant cases hemofiltration or hemodialysis may be required.

Activation of the RAAS and the adrenergic system has a pivotal role in the progression of heart failure.^{,  ,}  These systems are activated by increased myocardial stretch and peripheral hypoperfusion and cause vasoconstriction, hydrosaline retention, myocardial hypertrophy and fibrosis, fetal gene expression and accelerated cell death. Their importance is shown by their independent prognostic value and, more importantly, by the beneficial effects of their long-term pharmacologic inhibition. Hence, the administration of neurohormonal antagonists is the basis of the current medical treatment of chronic heart failure.^{,  ,}  The impact of neurohormonal antagonists on prognosis is so important that no patient should undergo heart transplantation if not previously treated with or shown to be intolerant of neurohormonal antagonists. As the beneficial effects of neurohormonal antagonists are progressive and may need at least 4 months to become significant, it is recommended to wait for such a time interval, if possible, before making a decision regarding heart transplantation candidacy in a patient not previously treated.

It is also important to note that neurohormonal antagonists are not short-term life-saving agents. They are administered for their long-term beneficial effects on outcome. In the short term, their administration may be associated with worsening of symptoms and hemodynamic variables, so that their initiation may be poorly tolerated or even contraindicated in patients with unstable clinical conditions.^{,  ,  ,} 

1.2.1. Angiotensin-converting enzyme inhibitors. The main mechanisms of action of the ACEIs include inhibiting LV remodeling and myocardial dysfunction, as well as reducing ischemic events in patients with concomitant coronary artery disease (CAD). The beneficial effects of ACEIs on symptoms, hospitalization rate and mortality have been consistently shown in large, placebo-controlled, randomized trials.^,  These effects are independent from the baseline characteristics of the patients, except that they are of greater magnitude in patients with more severe LV dysfunction and symptoms.^{,  ,} 

Patients with severe heart failure have a lower tolerance to ACEI administration. Lower cardiac output and peripheral hypoperfusion are associated with a greater activation of the RAAS, with a corresponding increased likelihood of renal failure and hypotension when this system is blocked.^,  However, a mild 10% to 20% increase in serum creatinine after the initiation of ACEI therapy should not be considered a contraindication to the continuation of treatment. Similarly, hypotension should be a contraindication to treatment only if symptomatic.^{,  ,  ,  ,} 

Even if initiation and titration of ACEI therapy may be more difficult in patients with advanced heart failure, it must be pointed out that the beneficial effects of ACEIs on prognosis are similar in patients with renal failure and greater in those with more severe heart failure.^,  Conversely, hemodynamic intolerance to ACEIs is associated with a worse prognosis.

1.2.2. ARBs. ARBs block the effects of angiotensin II on Type I angiotensin II receptors. These receptors mediate most, if not all, of the untoward effects of angiotensin II. Thus, as opposed to ACEIs, their efficacy cannot be decreased by the activation of non–ACE-dependent angiotensin II synthetic pathways. Hence, ARBs provide a more effective blockade of the Type I angiotensin receptors. Unlike the ACEIs, ARBs do not increase kinin levels. This property accounts for the increased tolerability of ARBs (lack of kinin-mediated side effects), but it may also lower their efficacy, because kinins have been associated with beneficial effects such as peripheral vasodilation and inhibition of myocardial hypertrophy and fibrosis.^,  The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Alternative Trial has shown that the administration of an ARB improves prognosis in those heart failure patients who are intolerant of an ACEI. These data are consistent with previous studies in patients with chronic heart failure or with post-infarction LV dysfunction or heart failure.

The major trials addressing the issue of combined therapy with ARBs and ACEIs in heart failure have been the Valsartan Heart Failure Trial (Val-HeFT) and CHARM. In the Val-HeFT trial, the administration of valsartan to patients receiving ACEI therapy was associated with an 18.2% lower incidence of hospitalizations for heart failure; however, there was no effect on mortality. The CHARM-Added trial showed that the administration of candesartan to patients with severe heart failure (NYHA Class III or IV) or moderately symptomatic heart failure (NYHA Class II), but with a recent (<6 months) cardiovascular hospitalization, was associated with a reduction in the primary end-point (cardiovascular death or heart failure hospitalization) and a reduction in both cardiovascular death and heart failure hospitalizations. In contrast to the Val-HeFT trial, the beneficial effects of ARB use in the CHARM-Added trial were also observed in the patients on concomitant ACEI and β-blocker therapy. The differences between the two studies are likely influenced by the inclusion of patients with more advanced heart failure and poorer prognosis in the CHARM trial.

ARBs should be administered with the same precautions as ACEIs. They lack the kinin-mediated effects of ACEIs, but may cause renal failure and hypotension by the same mechanism as ACEIs.^, 

1.2.3. Aldosterone antagonists. In the Randomized Aldactone Evaluation Study (RALES), administration of spironolactone 25 to 50 mg/day was associated with a 35% reduction in mortality, a concomitant decrease in heart failure hospitalizations, and an improvement in symptoms. The Eplerenone in Patients with Heart Failure Due to Systolic Dysfunction Complicating Acute Myocardial Infarction (EPHESUS) trial showed the beneficial effects of the selective aldosterone antagonist eplerenone in patients with recent myocardial infarction (MI) and LV dysfunction or heart failure. Aldosterone antagonists should therefore be considered in all candidates for heart transplantation.

To minimize the risks of hyperkalemia and renal failure, aldosterone antagonists are generally contraindicated in patients with renal insufficiency (serum creatinine >2.5 mg/dl) or hyperkalemia (serum potassium >5.5 mEq/liter). Careful and frequent monitoring of these laboratory evaluations is required after the initiation of an aldosterone antagonist, and then periodically, at least every 1 to 3 months.^{,  ,} 

1.2.4. β-blockers. Large, randomized trials have consistently shown that β-blocker therapy is associated with a significant reduction in mortality and hospitalization rate. The magnitude of this effect is greater than that found in ACEI trials, with a 34% to 35% reduction in mortality, a 33% to 35% reduction in the heart failure hospitalization rate, and an 18% to 20% reduction in all-cause hospitalizations.^{,  ,}  These beneficial effects have been observed in patients with more advanced heart failure^{,  ,}  and become evident relatively early, 1 to 2 months after initiation of therapy, as soon as minimal effective doses of the β-blockers are reached.

The incidence rates of worsening heart failure and intolerance to β-blocker administration are higher in patients with more severe heart failure.^{,  ,}  However, these patients may benefit even more from β-blockade as they also have higher levels of cardiac sympathetic stimulation. Therefore, it is mandatory that β-blocker therapy be attempted even in patients with more advanced heart failure. Treatment should always be initiated at the lowest possible dose, with very slow and careful dose increases. The failing heart is critically dependent on adrenergic stimulation, and is therefore particularly sensitive to the negative inotropic effects of β-blockade.^{,  ,  ,} 

β-blockers are a heterogeneous class of agents.^{,  ,}  Differences in their pharmacologic characteristics may have an effect on outcome. Therefore, only the agents shown to be clearly beneficial for survival in placebo-controlled trials should be administered. These include bisoprolol, carvedilol, metoprolol succinate, and, in the elderly, nebivolol.^{,  ,} 

β-blocker therapy may worsen the symptoms and signs of congestion in patients with acute decompensated heart failure (ADHF). Therefore, starting β-blocker therapy in these patients is contraindicated.^{,  ,}  However, if acute decompensation develops in patients already on long-term β-blocker treatment, retrospective analyses have shown that the permanent reduction or withdrawal of β-blocker therapy may be an independent predictor of poor outcome.^,  The β-blocker dose should, therefore, be reduced or withdrawn only temporarily, if ever, with treatment restarted at the previous maintenance doses as soon as the patient’s condition stabilizes.

1.3.1. Hydralazine and nitrates. The major benefit of ACEIs in preventing disease progression is attributed to their neurohormonal inhibition rather than to direct hemodynamic effects. However, ACEIs do have vasodilatory activity, both through inhibition of angiotensin II production and through increase of bradykinin levels. This action may be increasingly important as the disease progresses and systemic vasoconstriction and mitral regurgitation increase. During mild or moderate heart failure, the mortality benefit of ACEIs is greater than that achieved by the combination of the direct vasodilators hydralazine and nitrates. For therapy in patients with hemodynamic compromise undergoing evaluation for transplantation, a regimen containing ACEIs was associated with better survival than a regimen containing hydralazine and nitrates without ACEIs, although nitrates were frequently added to the ACEI regimen to produce hemodynamic stabilization. The hydralazine and nitrate combination is a reasonable alternative to ACEI use in patients who no longer tolerate ACEIs due to circulatory–renal limitations of hypotension, progressive renal dysfunction or hyperkalemia, for which risk increases as heart failure becomes more severe. In patients with mild-to-moderate heart failure who cannot take ACEIs due to cough or angioedema, ARBs provide the more convenient alternative.

Addition of the hydralazine and nitrate combination to ACEIs and β-blockers has been shown to decrease mortality and hospitalizations and improve survival in an ambulatory population of self-described African Americans with moderate to severe symptoms of heart failure. Previous smaller studies indicated improved exercise capacity and symptoms from nitrates added to ACEIs in patients with moderately symptomatic heart failure. Therefore, it is reasonable to consider addition of the hydralazine and nitrate combination for any patient with persistent symptoms despite optimization of other therapies.

Hypertension should be vigorously treated at all stages of heart failure, including refractory heart failure. Reversible causes of secondary hypertension should be investigated when hypertension is severe. After ACEIs, β-blockers and ARBs, hydralazine and nitrates are reasonable agents to consider for further blood pressure control. Thiazides can also be useful as added agents for control of hypertension, but care is needed to avoid excessive diuresis in combination with loop diuretics. Although an excess risk of cardiac disease has been associated with most calcium channel blockers, this has not been the case with amlodipine. Therefore, the use of amlodipine may be considered if hypertension cannot otherwise be controlled.

1.3.2. Digitalis. Digitalis is the oldest recognized therapy for heart failure. However, its clinical usefulness has long been controversial because studies of its efficacy have been lacking. Two trials, utilizing a withdrawal design, showed that fewer patients with NYHA Class II or III heart failure who were maintained on digoxin worsened with respect to clinical symptoms. More patients who remained on digoxin had an improvement in LVEF and exercise capacity as compared with patients having digoxin withdrawn.^,  A comparison of oral milrinone, digoxin and their combination in a trial enrolling patients with NYHA Class II or III heart failure showed that digoxin was superior to placebo and milrinone for enhanced exercise capacity and clinical status. Unfortunately, these studies provided no information about the effects of digoxin on survival.

The Digitalis Investigation Group (DIG) trial was a large, randomized, placebo-controlled study that enrolled 6,800 patients with chronic heart failure and sinus rhythm to evaluate the role of long-term digoxin on mortality and morbidity. No effects on all-cause mortality or cardiovascular mortality were observed; the treated patients demonstrated a clinical improvement and a decreased risk of death from worsening heart failure (11.6% on digoxin vs 13.2% on placebo, p < 0.06). In a further post hoc analysis of the DIG trial, gender differences in the effects of digoxin in heart failure were investigated. Women randomized to digoxin showed a worse prognosis than those randomized to placebo, with a higher risk of death related to cardiovascular causes.

Digoxin is usually considered standard therapy in patients with heart failure and atrial fibrillation, although β-blockers may be more effective in the control of ventricular response during exercise or in the presence of increased sympathetic tone. The suitability of the combined use of digitalis and β-blockers is currently an important question, as the earlier trials with digitalis were in heart failure patients who were only rarely treated with β-blockers. The Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial was designed to evaluate the role of a β-blocker in survival of patients with severe heart failure. Among 2,289 randomized patients, at baseline, 61% to 78% were treated with digitalis. Eichhorn et al assessed the effect of combined therapy with digoxin and β-blockers (carvedilol) in a retrospective analysis including 1,509 patients enrolled in the U.S. Carvedilol Heart Failure Program and Australia–New Zealand Heart Failure Research Collaborative Group Carvedilol (ANZ-Carvedilol) trials. Among the patients enrolled, 669 were taking digoxin and carvedilol, 234 carvedilol alone, and 423 patients who were sicker than those included in other groups were treated with digoxin. The combined treatment did not add benefit in terms of either hospitalization or the combined end-point of death and hospitalization. These results do not preclude the combined use of β-blockers and digitalis, but the drug combination has no clear benefit in patients doing well on β-blocker therapy.

Digitalis has narrow therapeutic range. The risk of toxicity increases in relation to worsening renal and hepatic function, reduced drug redistribution volume, and concomitant use of other drugs. It is reasonable to expect that patients with severe heart failure being considered for cardiac transplantation will obtain symptomatic benefit from digoxin. Otherwise, digitalis glycosides are not indicated in ADHF, except in the presence of atrial fibrillation, or in heart failure patients with preserved systolic function.

One of the hallmarks of chronic heart failure is the development of exercise intolerance that can lead to a more sedentary lifestyle and progressive deconditioning. Exercise intolerance is due to cardiovascular as well as peripheral abnormalities associated with the syndrome of heart failure. These include reduced cardiac output with exercise, limited stroke volume, increased resting heart rate, reduced heart rate variability, reduced β-adrenergic responsiveness, abnormal autonomic balance, endothelial dysfunction, primary skeletal muscle changes and neurohormonal abnormalities.^{,  ,  ,} 

The use of exercise training or cardiac rehabilitation is a well-accepted and recommended modality in select groups of patients, such as those with ischemic heart disease, particularly after a re-vascularization procedure.^{,  ,}  Exercise training in patients with heart failure has not been as widely used until recently. There have been many small, randomized studies that have documented the benefits of exercise training in heart failure patients. Patients with heart failure who participate in structured exercise training have shown improvement in maximal and sub-maximal exercise capacity, quality-of-life scores, inspiratory muscle strength and respiratory endurance; reversal of some of the autonomic imbalances associated with physical deconditioning; increased peak oxygen consumption; improved endothelium-dependent vasodilation of skeletal muscle vasculature; decreased plasma norepinephrine level; improved skeletal myopathy of chronic heart failure; and reduced hospitalizations for heart failure.^{,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,} 

There have been very few adverse events associated with supervised exercise training in heart failure patients.^,  Rather, studies have shown improved clinical outcomes and measures in LV remodeling, cost effectiveness, and a reduction in mortality.^{,  ,  ,  ,} 

In general, the majority of exercise training studies performed in patients with heart failure excluded patients with advanced symptoms (NYHA Class IV) from participation. Although it seems intuitive that the better conditioned a patient is when undergoing a major surgical procedure (such as heart transplantation), the fewer the complications and the better the outcome, there are, to date, no clinical trials to substantiate this association in patients with advanced heart failure awaiting transplantation.

Daytime fatigue and impaired physical performance in advanced heart failure may be an indicator of sleep-disordered breathing. There is a growing awareness of sleep-disordered breathing as a frequently occurring, often unrecognized, but potentially treatable risk factor for worsening of advanced heart failure. Sleep-disordered breathing is categorized as either obstructive sleep apnea (OSA) or central sleep apnea (CSA). OSA is characterized by intermittent episodes of partial or complete obstruction of the upper airway during sleep, which disrupts normal ventilation and is typically associated with snoring and daytime sleepiness. CSA (Cheyne–Stokes respiration) is a form of periodic breathing in which apneas and hypopneas alternate with ventilatory periods having a waxing–waning pattern of tidal volume. Unlike OSA, CSA likely arises as a consequence of heart failure, delayed circulation time, increased chemoreceptor sensitivity to carbon dioxide, input into the respiratory center from other brain centers, and from peripheral receptors that might have pathophysiologic importance.^{,  ,}  It is not clear whether CSA is simply a reflection of severely compromised cardiac function, or whether it exerts independent pathologic effects on the failing myocardium.

Both OSA and CSA are common in patients with heart failure. In the two largest case series of patients with heart failure undergoing polysomnography, OSA was detected in 166 of 450 (37%) and 9 of 81 (11%) patients studied. CSA is also highly prevalent in patients with chronic heart failure, present in 30% to 40% of patients in the largest reported series.^, 

In patients with heart failure, the presence of OSA has the potential to worsen ventricular dysfunction. Inspiration against an occluded upper airway generates exaggerated negative intrathoracic pressure, leading to both an increase in LV after-load and a decrease in pre-load, resulting in reduction of stroke volume.^,  Sympathetic outflow produces intermittent hypertension, further increasing after-load. These hemodynamic effects as well as activation of adrenergic, inflammatory and other mechanisms induced by repetitive nocturnal hypoxia would reasonably be expected to worsen prognosis in heart failure. However, definitive data about the effects of OSA on the natural history of treated or untreated heart failure are lacking. In contrast, CSA has been shown to be associated with an increased risk of death or cardiac transplantation.^,  However, it remains uncertain whether it is because Cheyne–Stokes respiration is a reflection of very poor cardiac function or whether its presence constitutes an additive adverse influence on outcomes via neurohormonal activation, surges in blood pressure and heart rate, and a greater propensity to lethal arrhythmia.^, 

Currently, the standard method for the diagnosis of sleep apnea is polysomnography conducted in a sleep laboratory, which is an expensive and not universally available procedure. However, the development and validation of less expensive and more readily available techniques, such as ambulatory monitoring, may make widespread screening for sleep apnea feasible in patients with heart failure.

Therapeutic approaches have focused on correction of the pathologic breathing pattern. Various respiratory interventions during sleep have been tried, including nasal oxygen, continuous positive airway pressure (CPAP),^{,  ,  ,  ,  ,  ,  ,  ,}  bi-level positive airway pressure (BIPAP) and adaptive pressure support servo-ventilation.^{,  ,}  In patients with OSA, CPAP decreases LV after-load by increasing intrathoracic pressure, augments stroke volume, and reduces cardiac sympathetic activity.^{,  ,}  It also decreases pre-load by impeding venous return and reduces LV end-diastolic volume.^{,  ,}  A substantial improvement in both LVEF and functional class after treatment with CPAP has been demonstrated.^, 

In studies on patients with CSA, the long-term nightly use of CPAP over a period of 1 to 3 months has been shown to increase LVEF as well as reduce mitral regurgitation, atrial natriuretic peptide (ANP)^,  and nocturnal and daytime sympathetic nervous system activity.^,  It has also been shown to improve quality of life. A randomized, controlled clinical trial was conducted in 66 patients with chronic heart failure with and without CSA. The patients were randomized to nightly CPAP or control. The results showed that, over a 5-year follow-up period, patients in the CSA group who complied with CPAP had a significant reduction in the combined rate of mortality and cardiac transplantation. However, in the largest trial to date (>250 patients), there was no improvement in mortality in those randomized to CPAP. In fact, early mortality was observed.

In patients with acute exacerbation of chronic heart failure, intravenous therapy remains a cornerstone of current therapeutic regimens. Selection of treatment should be based on the patient’s volume status and cardiac output. If volume overload with peripheral or pulmonary congestion is predominant, diuretics and vasodilators are the first line of therapy. If hemodynamic compromise with hypoperfusion and hypotension, despite optimal dosing of diuretics and vasodilators, is predominant, institution of positive inotropic support is generally indicated to achieve symptomatic relief.

1.6.1. Intravenous vasodilators. 1.6.1.1. Nitrates/sodium nitroprusside. At low doses, nitrates induce only venodilation, resulting in reduced pre-load. At higher doses, nitrates also induce dilation of arteries, with consequent reduction of after-load. Their effectiveness in the treatment of acute heart failure, when combined with diuretics, has been well established. The major drawbacks of intravenous nitrate use include the rapid development of tolerance and the potential for severe hypotension.^, 

Sodium nitroprusside is a potent vasodilator. The use of nitroprusside generally requires invasive arterial monitoring. Long-term use (>3 days) is not advisable because of the potential risk of thiocyanate and cyanide toxicity, especially in patients with renal and hepatic failure. Nitroprusside can be beneficial in patients with severely increased after-load—for example, when due to marked hypertension, or in patients with pronounced acute mitral or aortic valvular regurgitation.

1.6.1.2. Nesiritide. Nesiritide, a recombinant human brain natriuretic peptide (BNP), relaxes smooth muscle cells. This leads to venous and arterial vasodilation, thereby reducing pre- and after-load, resulting in increased cardiac output without direct (positive) inotropic effect.^{,  ,  ,}  Nesiritide has been approved in the USA for the management of ADHF. Compared with intravenous nitroglycerin, nesiritide produced faster relief of dyspnea and a quicker and more pronounced reduction in elevated pulmonary capillary wedge pressure (PCWP). This benefit was sustained over 24 hours. Nesiritide suppresses both the RAAS and the sympathetic nervous system. Therefore, the vasodilatory effect is not accompanied by pronounced neurohormonal activation. This property is one of the reasons why nesiritide is postulated to be less arrhythmogenic than dobutamine.^,  BNP has a natriuretic and diuretic effect, but in severe advanced heart failure up to 50% of patients seem to be resistant to its natriuretic effects.

Currently, there is no conclusive evidence that nesiritide improves kidney function. In fact, recent concern has focused on the possibility that nesiritide may worsen kidney function. Nesiritide is generally well tolerated and hypotension is the most common side effect. Intravenous administration of nesiritide should be done with caution and under close blood pressure monitoring. Its short-term safety relative to standard diuretic and vasodilator therapies is currently not well defined.

In a randomized, open-label, pilot study, the safety and tolerability of outpatient serial infusions of nesiritide in 210 patients with decompensated heart failure was assessed. Cardiovascular and renal adverse events were not increased in the nesiritide group compared with the usual-care group. By investigator assessment, the nesiritide group showed a significant improvement in clinical status compared with the usual-care group, but there were no statistically significant differences in deaths or hospitalizations among groups. A large, randomized trial is currently underway, but at the present time there are no compelling data to recommend the use of nesiritide in a long-term, intermittent manner for either in-hospital or out-of-hospital patients.

1.6.2. Intravenous inotropes. Most inotropes increase the intracellular level of cyclic adenosine monophosphate (cAMP), either by receptor stimulation (β-adrenergic agonists) or by decreasing cAMP breakdown (phosphodiesterase inhibitors). A new class of inotropes affects intracellular calcium mechanisms by increasing the sensitivity of contractile proteins to calcium (calcium sensitizers).^{,  ,}  The mechanism of available inotropes (with the possible exception of digoxin) appears to favor short-term hemodynamic benefit at the expense of accelerating the underlying disease progression.^{,  ,}  This effect is at least in part due to the fact that an enhancement of contractility is usually associated with an increase in myocardial oxygen consumption. To date, inotropic therapies have failed to provide a mortality or morbidity benefit.^{,  ,} 

1.6.2.1. Adrenergic agonists. The most powerful way to increase contractility in the human heart is the use of a β-adrenergic receptor agonist. Although, in the failing human heart, β-adrenergic pathways undergo desensitization,^{,  ,}  the vast majority of patients with advanced heart failure still exhibit a substantial inotropic response to β-agonists. Their administration should be carefully monitored and the lowest possible effective doses used.

1.6.2.1.1. Dopamine. Dopamine is not routinely recommended as a positive inotropic agent. Low doses of dopamine may be helpful for improving renal perfusion. Consideration should be given to using higher doses of dopamine in clinical settings where an increase in peripheral resistance is necessary, such as sepsis or iatrogenic overvasodilation.

In acute shock with critical hypoperfusion, immediate institution of inotropic therapy is mandatory until definitive therapy can be implemented. First-line therapy should usually be dopamine in medium to high doses. If this is not sufficient, epinephrine should then be used. If pronounced vasodilation is present, norepinephrine might be considered.

Dopamine mediates its effects by dose-dependent activation of different adrenergic receptors. At low doses, the activation of vascular dopamine receptors predominates, causing dilation of renal, mesenteric and coronary arteries, with a resultant increase in diuresis. This effect may be useful in promoting renal blood flow and maintaining diuresis in patients who become refractory to diuretics, especially when caused by marginal renal perfusion. At intermediate doses, the cardiac effects of dopamine are based on β₁-adrenergic receptor activation. At still higher doses, dopamine effects vasoconstriction through activation of α-receptors in the periphery.^{,  ,  ,} 

1.6.2.1.2. Dobutamine. Dobutamine is recommended for treatment of patients with low cardiac output and substantially reduced blood pressure, provided that they are not receiving concomitant β-blocker therapy. Concomitant use of β-blockers with dobutamine may attenuate the benefit of either agent.^, 

Dobutamine induces mild vasodilation in combination with a significant increase in contractility, leading to an augmentation of stroke volume and cardiac output.^{,  ,}  Dobutamine may decrease β-receptor sensitivity, and prolonged infusion over 96 hours has been associated with a decrease in hemodynamic effect by as much as 50%. It is mandatory to taper off dobutamine as opposed to abrupt discontinuation.^,  Dobutamine treatment significantly increases the number of serious ventricular arrhythmias, although this might be less pronounced for patients with normal sinus rhythm.

1.6.2.2. Phosphodiesterase inhibitors. In patients with preserved systolic blood pressure, phosphodiesterase inhibitors are preferred over dobutamine, especially in patients with concomitant β-blocker use. Phosphodiesterase inhibitors (milrinone, enoximone) increase intracellular cAMP by mechanisms not involving adrenergic receptors, producing both inotropic and vasodilatory actions.^{,  ,  ,  ,}  Because they act independent of adrenergic receptors, they are still effective despite the down-regulation of β-adrenergic receptors in patients with chronic heart failure.^,  Short-term administration of phosphodiesterase inhibitors may improve myocardial performance and the clinical condition of patients with chronic heart failure.^, 

Combining phosphodiesterase inhibitors with dobutamine results in the additive effects of myocardial performance, including a reduction in PCWP and pulmonary artery pressure.^{,  ,}  Favorable hemodynamic responses to phosphodiesterase inhibitors are enhanced by either carvedilol or metoprolol.^{,  ,}  In fact, phosphodiesterase inhibitors may permit the concomitant safe introduction of β-blockers,^{,  ,  ,}  but this approach remains to be verified in a controlled trial.

1.6.2.3. Levosimendan. Levosimendan might be helpful in patients with peripheral hypoperfusion secondary to systolic dysfunction without severe hypotension. Levosimendan enhances contractility primarily by binding to troponin C and increasing myofilament sensitivity to calcium without impairment of myocardial relaxation. Levosimendan also causes vasodilation by opening adenosine triphosphate (ATP)-sensitive potassium channels and inhibiting phosphodiesterase.^{,  ,  ,}  The hemodynamic effects of levosimendan, including significant increases in stroke volume and cardiac index and decreases in pulmonary arterial pressures, PCWP and arterial pressure,^{,  ,  ,}  were maintained during a 48-hour infusion and for at least 24 hours after discontinuation, and were not attenuated by β-blockers. Levosimendan is generally well tolerated, with the most common adverse events being rate and rhythm disorders, headache and hypotension.

1.6.3. Long-term continuous inotropic treatment. For some patients on inotropic support, weaning of inotropic support is not possible, primarily because of the recurrence of symptomatic hypotension, congestive symptoms or the worsening renal function early after discontinuation of inotropic therapy. In these acutely inotrope-dependent patients, institution of a continuous infusion of the inotropic agent may be considered. As most studies have consistently shown an increase in mortality using long-term inotropes, this treatment option is used as a pharmacologic bridge to heart transplantation or mechanical support.^{,  ,  ,  ,}  In patients with end-stage (Class D) heart failure, where no other therapeutic alternatives are feasible, long-term inotropic support may be considered for symptomatic relief at the end of life, taking into account the individual patient preferences while balancing the potential symptomatic benefit with the potential risks.^{,  ,  ,  ,  ,  ,  ,} 

1.6.4. Long-term intermittent inotropic treatment. Intermittent use of inotropic support has been described to increase quality of life and hemodynamics in observational reports, but there are no controlled studies to support the benefit of intermittent infusions of positive inotropic substances to outpatients.^{,  ,  ,  ,  ,  ,  ,  ,}  Indeed, published studies with control groups suggested that this approach may also increase mortality.^,  All oral agents with positive inotropic actions studied so far have significantly increased mortality or have been associated with a trend toward increased mortality, primarily as a result of markedly more occurrences of sudden death. Although acute hemodynamic improvement with these agents is often pronounced, evidence of sustained clinical benefit is lacking.^{,  ,  ,  ,  ,}