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Revista Española de Cardiología (English Edition) Revista Española de Cardiología (English Edition)
Rev Esp Cardiol. 2010;63:451-71 - Vol. 63 Num.04 DOI: 10.1016/S1885-5857(10)70094-3

Evidence-Based Management of Right Heart Failure: a Systematic Review of an Empiric Field

Mehdi Skhiri a, Sharon A. Hunt a, André Y. Denault b, François Haddad a

a Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, California, United States
b Department of Anesthesiology, Montreal Heart Institute and University of Montreal, Montreal, Quebec, Canada

Keywords

Heart failure. Acute heart failure. Right heart. Pulmonary hypertension. Systematic review.

Abstract

In recent years, several studies have shown that right ventricular function is an important predictor of survival in patients with congenital heart disease, pulmonary hypertension or left heart failure. Our understanding of right heart failure has improved considerably over the last two decades. In this review article, our objective was to provide a critical summary of the evidence underlying the management of right heart failure. A systematic review of the literature was performed using PubMed and the latest issue of the Cochrane Central Register of Controlled Trials to identify studies conducted between January 1975 and January 2010. The literature search encompassed observational studies, randomized controlled trials and meta-analyses. The evidence underlying the use of beta-blockade, angiotensin-converting enzyme inhibitors, inhaled nitric oxide, hydralazine, warfarin, and resynchronization therapy in right heart failure was systematically reviewed. Emerging new therapies, such as metabolic modulators, and the pearls and pitfalls of managing right heart failure are also discussed in the article.

Article

INTRODUCTION

In recent years, several studies have shown that right ventricular function is an important predictor of survival in patients with congenital heart disease, pulmonary hypertension and heart failure (HF).1-3 In 2006, the National Heart, Lung and Blood Institute identified right ventricular function and failure as a priority for research in cardiovascular disease.4 Right ventricular (RV) function may be impaired in several conditions such as right ventricular myocardial infarction (RVMI), acute pulmonary embolism, left heart disease, parenchymal lung disease, pulmonary vascular disease or congenital heart disease.5-10 Our understanding of right heart failure (RHF) has considerably improved in the last 2 decades. In this review article, our objective is to critically present the evidence that underlies the management of RHF. We also discuss important perils and pitfalls that may help in the management of patients with RHF.

METHODS

A systematic review of the literature using PubMed and the latest issue of the Cochrane Central Register of Controlled Trials was performed for studies conducted between January 1975 and January 2010.11,12 The search was focused on both observational and randomized controlled trials with a minimum of 5 subjects. Book chapters, meta-analysis, review articles, and editorials were also scanned. The search terms used included, HF, right heart, right ventricle and specific therapies, eg, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), sildenafil, hydralazine, pacemaker, defibrillators, and cardiothoracic surgery. Searches using individual brand names of medications were also conducted.

All studies identified through our searches were assessed by 2 reviewers and consensus was required for inclusion in the review. Data extraction was done independently by the 2 investigators using a pre-defined form. The following data were extracted: methods (study design, method of randomization, concealment of allocation, blinding of the investigators, inclusion and exclusion criteria), populations (sample size, age, and sex), participant characteristics, etiology of heart disease, intervention (agent, dose, timing and duration of therapy, and other medications), control (participants, agent, and dose), and outcomes measures. The main studies relevant to the management of RHF are summarized in table format that summarize study design and main outcome measures. When relevant, we also report recommendations based on the most recently published consensus or guideline statement.1,3,13 When appropriate, we also quote in parenthesis the recommendations of the American College of Cardiology (ACC)-American Heart Association (AHA) or European Society of Cardiology (ESC). The recommendations are classified according to the strength of the recommendation (I, IIa, IIb, III [contraindicated]) and the level of evidence (A, B, C [expert consensus]).

DEFINITION OF RHF AS A SYMPTOMATIC AND PROGRESSIVE DISORDER

RHF is defined as a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the right heart to fill or eject appropriately.1 The cardinal clinical manifestations of RHF are: a) fluid retention manifested as peripheral edema or ascites; b) decreased systolic reserve or low cardiac output syndrome, which may present as exercise intolerance, fatigue or altered mentation; and c) atrial or ventricular tachyarrhythmias. Functionally, the affected right ventricle may be in the subpulmonary (usual) or systemic position (in congenitally corrected transpositions of great vessels (L-TGV) or D-TGV following an atrial-switch repair). Patients may present with a clinical picture of biventricular failure or predominantly RHF.

When considering RHF as a progressive disorder, patients with asymptomatic ventricular dysfunction are considered to be in the early stages of RV failure.1 Analogous for the staging proposed for left heart failure (LHF), patients may progress from being at risk of RHF (stage A), to asymptomatic RV dysfunction (stage B), to RHF (stage C) and finally refractory RHF (stage D).1 It is also practical to divide RHF as to whether it is acute or chronic.

ETIOLOGY AND PATHOPHYSIOLOGY OF RHF

The clinical syndrome of RHF may result from disorders of the myocardium, the pericardium, endocardium, pulmonary vasculature and pulmonary parenchyma (Table 1). LHF represents the most common cause of RHF. Table 2 summarizes the classification of pulmonary hypertension, a common cause of RHF.

TABLE 1. Etiology and Mechanisms of Right Heart Failure

TABLE 2. Revised World Health Organization Classification of Pulmonary Hypertension

Following initial myocardial stress or injury, several factors may contribute to progression of RV failure, including the timing of myocardial stress (adult period > pediatric), type of stressor (pressure overload > volume overload), and myocardial ischemia, as well as neuro-hormonal and immunologic activation.7,8 At a molecular level, maladaptative RV remodeling has been associated with a switch in contractile protein isoforms, alteration in cardiac metabolism, alterations in enzymes and ion channels involved in myocyte excitation-contraction coupling, matrix remodeling and neurohormonal and cytokine activation.14-21 Among the neurohormones involved in RV failure, evidence is stronger for angiotensin-II, catecholamines and natriuretic peptides.19-21 Recent studies also demonstrate that specific pathways may be selectively involved in RV remodeling. Urashima and colleagues have shown that genes may be differentially regulated in the pressure overloaded RV as compared to the pressure overloaded left ventricle (LV). The differentially expressed genes were involved in the Wnt signaling pathway, apoptosis, migration of actin polymerization and processing of the ubiquitin system.22 The differential expression of genes in the right heart and left heart is not surprising in view of the different embryological origin of the RV and LV and their different physiological environments.23,24

Ventricular interdependence also plays an essential part in the pathophysiology of RHF. Although always present, ventricular interdependence is most apparent with changes in loading conditions such as those seen with volume loading, respiration or sudden postural changes.25 Ventricular interdependence helps maintain hemodynamics in early stages of RHF. Experimental studies have shown that in the absence of a dilated RV, LV systolic contraction contributes 20%-40% of RV systolic pressure generation.25,26 Diastolic ventricular interdependence contributes to the development of LV systolic dysfunction in patients with RHF. RV enlargement or increased afterload may shift the interventricular septum and increase pericardial constraint on the left ventricle; both of these changes may alter left ventricular geometry and decrease LV preload and contractility (Figure 1).25,27 Compression of the left main coronary artery by a dilated main pulmonary artery, which is occasionally observed in pulmonary arterial hypertension (PAH), may contribute to LV dysfunction.28 Tricuspid regurgitation and ongoing ischemia may also contribute to the progression of RHF.

Figure 1. Pathophysiology of right heart failure. LM: left main coronary artery; LV: left ventricular; R to L: right to left; TR: tricuspid regurgitation; V interdepend.: ventricular interdependence; V/Q: ventilation-perfusion. Adapted from Haddad et al.8

Figure 1. Pathophysiology of right heart failure. LM: left main coronary artery; LV: left ventricular; R to L: right to left; TR: tricuspid regurgitation; V interdepend.: ventricular interdependence; V/Q: ventilation-perfusion. Adapted from Haddad et al.8

DIAGNOSTIC EVALUATION OF PATIENTS WITH RHF

The goals of the initial evaluation of patients with RHF are to better characterize its etiology, severity and functional status, the presence and extent of end-organ damage (renal dysfunction, liver dysfunction) and the presence of associated conditions. In patients with RHF, physical examination often reveals lower extremity edema, jugular venous distension and a parasternal holosystolic murmur compatible with tricuspid regurgitation. Cyanosis may be observed in patients with right to left shunting or severe low cardiac output.

Echocardiography plays a key role in the diagnosis of right heart disease. Signs of right heart disease on an echocardiogram can include RV enlargement, RV systolic dysfunction, tricuspid regurgitation, and pulmonary hypertension, congenital heart defects, valvular heart disease, or left heart disease. Magnetic resonance imaging (MRI) is becoming the gold standard for evaluating right heart structure and function and is particularly useful in patients with complex congenital heart defects (eg, Ebstein's anomaly, hypoplasic RV), in patients in whom precise quantification of valvular regurgitation is important, and for planning of a complex surgery or procedure or for research purposes.8 Recent studies using MRI have also demonstrated the prognostic value of RV end-diastolic volumes and pulmonary compliance assessed by MRI in pulmonary arterial hypertension.29,30 Angiography by MRI, computed tomography-angiography or heart catheterization may be of particular value in excluding chronic thromboembolic pulmonary disease, in assessing complex arterio-venous malformations or congenital heart defects. Right heart catheterization is an important part of the evaluation of right heart disease. Indications for right heart catheterization include assessment of pulmonary vascular resistance or impedance, pulmonary pressures, cardiac output shunt fraction, and pulmonary vasoreactivity. Exercise testing is also very useful in objectively assessing clinical deterioration in patients with PAH or congenital heart disease. Caution is, however, advised in performing maximal exercise testing in patients with severe pulmonary vascular disease (contraindicated in the recent AHA consensus on congenital heart disease).3

Obtaining baseline renal and liver function tests, albumin, uric acid levels as well as B-type natriuretic peptide levels may be of particular interest in determining prognosis of right heart disease.31-37 In patients with severe hypoalbuminemia, protein losing enteropathy should be excluded with the assay of stool alpha-1 antitrypsin. Electrocardiography is part of the routine evaluation and allows assessment of cardiac rhythm, QRS duration or the presence of atrio-ventricular conduction block.

Other studies should be individualized depending upon the suspected etiology of RHF. In patients with PAH, a ventilation perfusion scan, pulmonary function tests, overnight oximetry, serologies for HIV and connective tissue disease (eg, antinuclear antibody test, ANA) are often routinely obtained. Stool alpha-1 antitrypsin are often obtained to rule out protein losing enteropathy. Lung or heart biopsy is rarely indicated in patients with isolated right heart disease. Genetic counseling should be pursued in patients with congenital heart disease or arrhythmogenic right ventricular dysplasia (ARVD). Depending on the etiology and severity of RHF, patients are followed at varying intervals (usually 3 months to 1 year). The recent guidelines for congenital heart disease and PAH offer individualized timing for follow-up depending on conditions.3

MANAGEMENT OF RHF

Overview of the Management of RHF

The most important aspect of managing RHF is tailoring therapy to its specific cause. In contrast to patients with chronic ischemic or nonischemic cardiomyopathy, patients with RHF often have significantly abnormal afterload (eg, pulmonary hypertension) or valvular heart disease (acquired or congenital pulmonary or tricuspid disease). It is therefore not surprising that the selected therapy should primarily target the cause of RHF. In managing patients with RHF, it is also useful to divide the syndrome into 4 clinical categories: biventricular failure, systemic RV failure, predominant sub-pulmonary RV failure, and hypoplasic RV syndrome.3 The management of patients with hypoplasic RH is beyond the scope of this review and the reader is referred to the recent consensus statement of Warnes and colleagues.3

The physiological goals of RHF treatment include optimization of preload, afterload and contractility. Sodium and fluid restriction and judicious use of diuretics all help optimize RV preload. Clinically, optimal preload may be defined as the preload that results in optimal cardiac output without causing renal dysfunction. Although it is often perceived that patients with RHF require higher levels of filling pressure, the majority of patients may have an optimal preload with normal right atrial pressure (<6 mmHg). Small clinical studies also suggest that resynchronization therapy may be beneficial in selected patients with RHF.38-41 As will be discussed, only small studies suggest a beneficial role for beta blockade or ACE inhibitors in RHF; these results have not been confirmed by larger studies. Primary prevention of sudden death using defibrillators is mainly recommended in patients with arrhythmogenic RV dysplasia and tetralogy of Fallot.42,43 In the setting of acute RHF, every effort should be made to avoid systemic hypotension, as this could lead to myocardial ischemia and further hypotension. Figures 2, 3, and 4 summarize the management of chronic and acute RHF and PAH.

Figure 2. Management of chronic right heart failure syndrome. CDP: continuous distending pressure; C-PAP: continuous positive airway pressure; CTEPH: chronic thomboembolic pulmonary hypertension; Defib.: defibrillator; ERB: endothelin receptor blockers; PAH: pulmonary arterial hypertension; PDE5: phosphodiesterase-5; PVR: pulmonary valve replacement or repair; RV: right ventricle; TV: tricuspid valve; TOF: tetralogy of Fallot. Adapted with permission from Haddad et al.9

Figure 2. Management of chronic right heart failure syndrome. CDP: continuous distending pressure; C-PAP: continuous positive airway pressure; CTEPH: chronic thomboembolic pulmonary hypertension; Defib.: defibrillator; ERB: endothelin receptor blockers; PAH: pulmonary arterial hypertension; PDE5: phosphodiesterase-5; PVR: pulmonary valve replacement or repair; RV: right ventricle; TV: tricuspid valve; TOF: tetralogy of Fallot. Adapted with permission from Haddad et al.9

Figure 3. Management of acute right heart failure. ECMO: extra corporeal membrane oxygenation; Endoc.: endocartidis; PE: acute pulmonary embolism; PH: pulmonary hypertension; PR: pulmonary regurgitation; RHF: right heart failure; RV: right ventricle; RVAD: right ventricular assist device; RVMI: right ventricular myocardial infarction; TR: tricuspid regurgitation; WHO: World Health Organization. Adapted with permission from Haddad et al.9

Figure 3. Management of acute right heart failure. ECMO: extra corporeal membrane oxygenation; Endoc.: endocartidis; PE: acute pulmonary embolism; PH: pulmonary hypertension; PR: pulmonary regurgitation; RHF: right heart failure; RV: right ventricle; RVAD: right ventricular assist device; RVMI: right ventricular myocardial infarction; TR: tricuspid regurgitation; WHO: World Health Organization. Adapted with permission from Haddad et al.9

Figure 4. Management of pulmonary arterial hypertension. Treatment of patients with pulmonary arterial hypertension depends on pulmonary vasoreactivity, risk stratification and selected etiology. AC: anticoagulation; CCB: calcium channel blockers (amlodipine, felodipine or diltiazem); CHD: congenital heart disease; CI: cardiac index; CTD: connective tissue disease; ERB: endothelin receptor blockers; NYHA: New York Heart Association; PAH: pulmonary arterial hypertension; PPHT: porto-pulmonary hypertension; RAP: right atrial pressure. Adapted from McLaughlin et al.2

Figure 4. Management of pulmonary arterial hypertension. Treatment of patients with pulmonary arterial hypertension depends on pulmonary vasoreactivity, risk stratification and selected etiology. AC: anticoagulation; CCB: calcium channel blockers (amlodipine, felodipine or diltiazem); CHD: congenital heart disease; CI: cardiac index; CTD: connective tissue disease; ERB: endothelin receptor blockers; NYHA: New York Heart Association; PAH: pulmonary arterial hypertension; PPHT: porto-pulmonary hypertension; RAP: right atrial pressure. Adapted from McLaughlin et al.2

Evidence Underlying the Management of RHF

Compared to the evidence supporting the management of LHF, the management of RHF is not well supported by randomized controlled trials. Furthermore, clinical trials in patients with RHF have not been powered for mortality endpoints. Among patients with RHF, the evidence is best established for patients with PAH.1-3 In PAH it may, however, be difficult to distinguish whether the beneficial effects of therapy are due to changes in pulmonary vasculature or RV specific effects; we therefore often consider the effects of PAH therapy in the context of the cardiopulmonary unit. In patients with congenital heart disease, the effects of therapy have not been consistently studied across functional class severity (New York Heart Asssociation [NYHA] functional class).

Because the prevalence of RHF is relatively small compared to the prevalence of LHF, finding appropriate surrogate end-points has been an important focus of research.44,45 Surrogate end-points being considered include exercise capacity, clinical worsening, ventricular remodeling or measures of vascular impedance in pulmonary hypertension.

General Preventive Measures

Referral to a congenital heart disease or pulmonary hypertension specialist when appropriate is recommended in patients with pulmonary arterial hypertension or complex congenital heart disease.2,3 This measure will help avoid any delay in timely intervention such as cardiac surgery, percutaneous closure of a cardiac defect or percutaneous valve replacement or initiation of PAH specific therapy.2,3

Prevention or early recognition of RHF decompensation is key in managing RHF. Factors that may lead to volume overload include non-compliance with sodium (<2 g daily) or fluid restriction, non-compliance with medications or use of nonsteroidal anti-inflammatory drugs or nondihydropyridine calcium channel blockers. Patients with significant PAH or severe RHF should also be advised against pregnancy, as it is associated with increased maternal and fetal mortality rate.2,3 Prevention of infection with influenza and pneumococcal vaccination is also recommended, as is prophylaxis against bacterial endocarditis in patients with mechanical valves, previous infectious endocarditis or in patients with selected congenital heart defects.2,3

Recent studies have shown that supervised cardiac rehabilitation for 8 weeks led to a significant improvement in 6 minute walk test (6MWT) in patients with PAH (mean difference of 111 m compared to placebo).46 Interestingly, the absolute improvement was greater than any change in 6MWT with PAH targeted therapy. Patients are however still advised against intense exercise or travel to altitudes above 5000 feet.

ETIOLOGY-BASED MANAGEMENT OF RHF, THE MAIN TARGET

Biventricular failure is managed following the guidelines of the AHA/ACC or ESC for managing patients with chronic HF.1 Patients with biventricular failure benefit from beta blockade and ACE inhibition or angiotensin receptor blockers. Recent studies have shown that sildenafil may improve pulmonary hemodynamics, exercise capacity and endothelial function in patients with chronic systolic HF (Table 3).47-51 Whether patients with left HF and evidence of right heart dysfunction may derive greater benefits from sildenafil still remains to be proven.

TABLE 3. Selected Studies on Phosphodiesterase-5 Inhibition in Patients With RHF or Pulmonary Hypertension

In patients with ST elevation myocardial infarction involving the right ventricle, early reperfusion should be achieved as early as possible.52 Although the RV usually recovers following acute myocardial infarction, reperfusion therapy has also been shown to improve RVEF and reduce the incidence of complete heart block.53,54 Maintenance of atrioventricular synchrony, correction of bradycardia and maintenance of hemodynamic stability with appropriate volume loading or inotropic support are also recommended.52

In patients with acute hemodynamically compromising pulmonary embolism (systolic blood pressure <90 mmHg or a drop in systolic blood pressure of ≥40 mmHg from baseline), evidence supports the use of thrombolytic agents (alteplase).55,56 Although many clinicians advocate thrombolytic therapy in patients with evidence of RV dilatation and dysfunction without systemic hypotension, the indication has not gained widespread acceptance and remains highly controversial.55,56 The controversy arises from the fact that clinical trials did not stratify patients according to RV size and function, although isolated RV dysfunction is a clear prognostic factor of outcome. In patients with chronic thromboembolic disease, pulmonary endarterectomy may decrease pulmonary pressures to near normal and reverse RHF.57,58 Because pulmonary endarterectomy may be life saving, pulmonary angiography, usually using computed tomography scan, is a routine part of clinical investigation.

The treatment of PAH has evolved tremendously in the last 20 years. The ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension has recently summarized its recommendations on pulmonary hypertension.13 Figure 4 summarizes the current management of PAH. The majority of treatments for PAH were approved on the basis of an improvement in 6MWT. Because of the small number of patients with PAH, powering the studies for mortality outcomes will prove to be difficult. Also, more attention is being focused on the effects of therapy on both the pulmonary vasculature and the heart (cardio-pulmonary unit). For example, while both endothelin receptor blockers (bosentan) and sildenafil improve 6MWT, recent studies suggest that sildenafil may also have positive inotropic effects on the RV.59 Whether these differences will translate in to beneficial long-term effects remains to be proven. Anticoagulation is also recommended in patients with PAH based on several observational studies or sub-analysis of randomized trials (Table 4).60-63 Digoxin may lead to clinical improvement, but the evidence favoring its use is based on improvement in acute hemodynamic profile and not long-term effects (Table 5).61,63-66 An interesting recent advance is the demonstration that prostanoid therapy may allow sufficient reversal of pulmonary vascular disease to allow closure of an atrial septal defect.13

TABLE 4. Warfarin Therapy in Pulmonary Arterial Hypertension

TABLE 5. Digoxin Therapy in Right Heart Failure

In patients with tetralogy of Fallot following initial repair, pulmonary valve replacement is recommended in patients with symptomatic pulmonary regurgitation (I, B) or in asymptomatic patients with moderate to severe RV enlargement (IIa, C), moderate to severe RV dysfunction (IIa, C), or moderate to severe tricuspid regurgitation (IIa, C). Other indications include new onset sustained atrial or ventricular arrhythmias or residual significant stenosis (peak RV outflow track gradient >50 mmHg by echocardiography or 70% systemic values; (IIa, C)) or residual ventricular septal defect, with a left-to-right shunt greater than 1.5:1 (IIa, B).3 Coronary artery anatomy, specifically the possibility of an anomalous anterior descending coronary artery across the RV outflow track, should be ascertained before any operative intervention (I, C).3

In patients with congenitally corrected transposition of great arteries (L-TGA) or dextro-transposition of great arteries (D-TGA), the RV functions as the systemic ventricle. In both these conditions, surgery or intervention is often considered in the presence of significant atrio-ventricular (morphologically tricuspid) valve regurgitation, significant baffle leaks (D-TGA), significant or unrepaired defects, or conduit stenosis (please refer to the recent guidelines of Warnes and colleagues for more complete information).3 The benefits of ACE-inbition or beta-blockade in patients with D-TGA or L-TGA is not well established (Tables 6 and 7). The studies addressing the question are small and underpowered for mortality or clinical outcome. If beta-blockade is given, caution must be used because of the risk of precipitating advanced atrioventricular block (especially in patients with preexisting sinus or AV nodal dysfunction).

TABLE 6. Angiotensin Converting Enzyme Inhibitors or Angiotensin Receptor Blockers in Right Heart Failure

TABLE 7. Beta Blockade in Patients With Right Heart Failure

In patients with Ebstein's anomaly, surgery should be considered in the presence of symptoms with deteriorating exercise capacity, (I, B), cyanosis (oxygen saturation less than 90%) (I, B), paradoxical embolism, (I,B) or progressive RV dilatation or ventricular dysfunction (I,B). The primary operation generally consists of closure of any interatrial communications; antiarrhythmia procedures such as surgical division of accessory conduction pathways, cryoablation of atrioventricular node reentry tachycardia, or Maze procedure; and tricuspid valve surgery. The tricuspid valve is repaired when feasible, and tricuspid valve replacement is performed with a mechanical or heterograft bioprosthesis when repair is not feasible or the repair result is not satisfactory. A right reduction atrioplasty is often performed.3

In patients with valvular pulmonary stenosis, percutaneous valvotomy is recommended in asymptomatic patients with a peak instantaneous gradient by Doppler greater than 60 mm Hg or a mean Doppler gradient greater than 40 mm Hg or a symptomatic patient with a peak instantaneous Doppler gradient greater than 50 mm Hg or a mean Doppler gradient greater than 30 mm Hg. The RV usually remodels well after intervention, in the absence of severe RV enlargement.

Recent studies also suggest that patients with flail tricuspid valves may benefit from earlier repair. Messika-Zeitoun and colleagues have demonstrated that flail tricuspid valve is associated with a decreased survival and a high incidence of HF, atrial fibrillation and need for valve replacement.67 At this time, centers with low surgical mortality consider early intervention for asymptomatic patients with flail tricuspid valve.

EVIDENCE UNDERLYING ACE INHIBITION, BETA-BLOCKADE, DIGOXIN AND HYDRALAZINE THERAPY IN RHF

With the success of medical management of patients with LHF, several researchers have investigated whether therapies proven to be beneficial in LHF may be applied to RHF.68-80 Because most of these studies are underpowered for mortality outcomes and commonly underpowered for exercise capacity, definite conclusions are difficult to make at this time.

A small study supports the use of digoxin therapy in patients with idiopathic pulmonary hypertension.64 In the study of Rich and colleagues, intravenous digoxin therapy produced a modest increase in cardiac output, as well as a significant reduction in circulating norepinephrine.64 At this time, no evidence clearly supports the use of digoxin therapy in patients with chronic obstructive pulmonary disease and associated RHF.65,66,81

Following initial enthusiasm associated with the use of beta blockade in patients with systemic RV,73,74 a larger randomized controlled trial in pediatric patients with HF did not demonstrate a beneficial trend.71 A multicenter prospective trial on beta blockade in patients with PAH is currently ongoing. In patients with tetralogy of Fallot, no benefit of the beta-blocker bisoprolol on exercise capacity was demonstrated, although this was only studied in patients with NYHA functional class 1 or 2.82 Finally in patients with pulmonary hypertension associated with liver disease (porto-pulmonary hypertension), a detrimental effect on hemodynamics was noted in a small study of 10 patients.70 The use of ACE inhibitors or angiotensin receptor blocker was also not associated with any significant beneficial effects on exercise capacity or hemodynamics in patients with systemic RV.75-80 Although the hydralazine and nitrate combination showed beneficial effects in some patients with LHF, the use of hydralazine in PAH was associated with either detrimental effects or less beneficial effects than prostacyclin therapy (Table 8).83-89

TABLE 8. Hydralazine Therapy in Patients With Right Heart Failure

NITRIC OXIDE THERAPY AND RHF

Initially, there was a lot of enthusiasm surrounding the use of inhaled nitric oxide (iNO) in patients with RHF or pulmonary hypertension. This was based on the fact that iNO could provide selective pulmonary vasodilatation without causing systemic hypotension or worsening ventilation-perfusion mismatches. This enthusiasm was, however, curbed by the practical difficulties associated with its administration, the development of alternative therapies, and the failure of studies to show consistent benefits of iNO (Table 9). An interesting recent study has, however, showed that iNO could lead to acute hemodynamic improvement when administrated to patient with RV myocardial infarction complicated by cardiogenic shock.90 At this time, iNO is primarily used for acute vasoreactivity testing in PAH, and treatment of patients with acute RHF or severe hypoxemia following lung transplantation (Table 9).49,90-101 Small reports also suggest that iNO may increase left filling pressures and precipitate pulmonary edema in patients with concominant LHF.92

TABLE 9. Nitric Oxide in Patients With Right Heart Failure or Pulmonary Hypertension

The role of prophylactic iNO in patients with pulmonary hypertension undergoing cardiac surgery remains controversial. Ongoing studies are investigating the role of inhaled vasodilators such as milrinone or sildenafil in preventing post-operative RHF following cardiac surgery.102,103

PHOSPHODIESTERASE 5 INHIBITORS IN PATIENTS WITH RHF OR PULMONARY HYPERTENSION

The use of phosphodiesterase-5 inhibitors in the treatment of PAH has received much attention in the last few years.47-51 PDE5 inhibitors have beneficial effects on pulmonary vascular remodeling with minimal effects on the systemic vasculature (other than the penile circulation). Sildenafil has also been shown to improve RV remodeling and contractility. While expression of phosphodiesterase 5 (PDE5) is minimal in the normal RV (where it is only expressed in the smooth muscle cells of the coronary arteries), its expression is markedly increased in the hypertrophied RV (as well as in the neonatal RV).59,104 Ongoing multicenter studies are currently underway to assess the effects of sildenafil in patients with diastolic HF.

INOTROPIC THERAPY

Inotropic therapy is indicated in patients with acute RHF and signs of low cardiac output. Among the inotropic or vasopressor agents, dobutamine has been the most extensively studied in RHF.105,106 In RVMI, dobutamine increased cardiac index and stroke volume while maintaining preload.105 In PAH, dobutamine at doses of 2-5 mcg/kg/min increase cardiac output while decreasing pulmonary vascular resistance.106 The combination of dobutamine and iNO in pulmonary hypertension has also been shown to increase cardiac index, decrease pulmonary vascular resistance and significantly increase PaO2/ FiO2 ratio.106 Dopamine use is often reserved for hypotensive patients, while milrinone is preferred in the presence of tachyarrythmias. While epinephrine infusion is commonly used in the intensive care unit, its specific effects in pulmonary hypertension have not been well studied.

Levosimendan is a calcium sensitizer with inotropic properties. Recent studies suggest that levosimendan could improve RV function or pulmonary hemodynamics in patients with biventricular failure or ARDS.107-109 Future studies will determine its role in managing patients with acute RHF.

MAINTENANCE OF SINUS RHYTHM RESYNCHRONIZATION THERAPY

Maintenance of sinus rhythm and heart rate control is important in RHF. Advanced AV block or atrial fibrillation can have profound hemodynamic effects in patients with acute RHF or severe RV dysfunction. In patients with LHF, cardiac resynchronization therapy (CRT) has been shown to improve both survival and exercise capacity and is currently indicated in patients with a QRS>120msec and evidence of LV systolic dysfunction (LVEF<35%).1 Recent studies also suggest that resynchronization may be beneficial in patients with RHF (Table 10).38-41 In a multicenter international study, Dubin and colleagues demonstrated that CRT in patients with RV dysfunction was associated with improvement in RV ejection fraction (RVEF) in patients with either systemic or pulmonic RV (Table 10).38 Dubin and colleagues had previously shown that atrioventricular pacing in patients with RBBB and RV dysfunction augments RV and systemic performance.40 Multicenter studies of resynchronization in patients with PAH are currently planned.48

TABLE 10. Resynchronization Therapy in Patients with RHF38-41

PREVENTION OF SUDDEN DEATH AND DEFIBRILLATOR THERAPY

The mechanisms of sudden death in patients with RHF vary depending on its etiology. Ventricular tachycardia/RV fibrillation, pulmonary embolism, pulmonary hemorrhage or mechanical or electrical complications in RVMI may all contribute to sudden death. Optimal management such as revascularization, treatment of pulmonary hypertension, and correction of congenital defects can decrease the incidence of sudden death.

Prediction of sudden death in RV failure is difficult and criteria have mainly been developed in patients with arrhythmogenic RV dysplasia and tetralogy of Fallot.42, 43 The incidence of sudden death for the adult tetralogy population can be estimated from several large series to be on the order of 2.5% per decade of follow-up.3 Risk factors for sudden death in tetralogy of Fallot include prolonged QRS duration (QRS>180 ms), or inducible ventricular arrhythmias using programmed ventricular stimulation during electrophysiology study.3 Because of the absence of long-term outcome studies, primary prevention of sudden death using implantable defibrillators in tetralogy of Fallot remain center-specific.3 In patients with ARVD, primary prevention of sudden death is considered (IIa, C) in the presence of extensive disease, a family history of sudden cardiac death or undiagnosed syncope when ventricular tachycardia or ventricular fibrillation has not been excluded as the cause of syncope.110 In patients with PAH, prophylactic antiarrhythmic therapy is contraindicated and the role of defibrillator therapy for primary prevention of sudden death not defined.110

TRANSPLANTATION, ATRIAL SEPTOSTOMY, AND MECHANICAL SUPPORT

In patients with advanced refractory RHF, transplantation can be considered after exclusion of all reversible causes and careful consideration of contraindications. In appropriate patients with severe pulmonary vascular disease, heart-lung or double lung transplantation are considered.111 Because of scarcity of organs, heart-lung transplantation is usually considered only in patients with congenital heart defects and in patients in whom the physician considers recovery of right heart function unlikely. Predictors of persistent RV failure after double lung transplantation have, however, not been well established at this time.

The observation of improved survival of patients with pulmonary hypertension and patent foramen ovale has led to the hypothesis that atrial septostomy, which "decompresses" the RV and increases right to left shunting, could be helpful in severe RV failure. The response to atrial septostomy in pulmonary hypertension is variable. At this time, atrial septostomy should be considered palliative.112

In patients with acute RHF refractory to medical treatment, mechanical support of the RV is sometimes used as a bridge to transplantation or a bridge to recovery. The most common indications for RVAD use are severe RV failure after LV assist-device, RV failure after heart transplantation or RV failure after massive pulmonary embolism.113 Permanent implantation or "destination therapy" for chronic advanced RV failure has not been studied. Future studies will determine whether mechanical support using axial flow devices could be of benefit in patients with refractory RHF with a contraindication to transplantation.

PERILS AND PITFALLS

Management of RHF may be at the same time simple and complex. In order to optimize patient care, several pitfalls should be avoided. Among them, the most common ones include: a) ordering maximal exercise testing in patients with severe pulmonary vascular disease; b) failure to exclude chronic thromboembolic disease as a cause of pulmonary hypertension; c) delaying referral to a specialized center for appropriate surgical, interventional or medical therapy; d) excessively volume loading a patient with acute RHF; or e) closing an atrial septal defect in a patient with severe pulmonary vascular disease. Caution should also be advised when using inhaled nitric oxide or sildenafil in patients with severe left ventricular filling pressures as increased cardiac output can precipitate pulmonary edema.

EMERGING THERAPIES FOR RHF

In the next few years, several specific therapies for RHF are potentially emerging. Among therapies that improve energy utilization of the heart, metabolic modulators are probably the most promising at this time. Recent experimental studies show that metabolic modulation reverses maladaptative RV remodeling in rats with monocrotaline induced PAH.16,114-117 Other potential new therapies include myosin activators, Na/K-ATPase inhibitors, adenosine or vasopressin antagonists or micro-RNA modulators.118 An interesting case report also suggests that tricuspid annuloplasty could play a role in managing patients with severe PAH.119

CONCLUSION

RHF is a complex clinical syndrome that presents with lower extremity edema, ascites, decreased exercise tolerance, or arrhythmia. Common causes of RHF include right ventricular myocardial infarction, pulmonary embolism, congenital heart disease, and pulmonary hypertension from a variety of causes. At this time, advances in therapy have mainly been made in treatment of pulmonary arterial hypertension and surgical repair of complex congenital lesions. Ongoing studies will investigate the role of betablockade or cardiac resynchronization therapy in patients with PAH. Emerging new therapies may include metabolic modulators or myosin activators.

ACKNOWLEDGMENTS

We want to acknowledge the educational support of the Vera Moulton Wall Center for Pulmonary Vascular Disease at Stanford as well as the support of the Division of Cardiology of Stanford University.

ABBREVIATIONS
6MWT: 6-minute walk test
ARVD: arrhythmogenic right ventricular dysplasia
CO: cardiac output
CTEPH: chronic thromboembolic pulmonary hypertension
ERB: endothelin receptor blockers
HF: heart failure
iNO: inhaled nitric oxide
LV: left ventricular
LHF: left heart failure
LVEF: left ventricular ejection fraction
MPAP: mean pulmonary arterial pressure
NYHA: New York Heart Association
PAH: pulmonary arterial hypertension
PCWP: pulmonary capillary wedge pressure
PDE5: phosphodiesterase-5
PVR: pulmonary valve replacement or repair
PVRI: pulmonary vascular resistance index
RAP: right atrial pressure
RBBB: right bundle branch block
RCT: randomized placebo controlled trial
RHF: right heart failure
RV: right ventricular
RVEDP: right ventricular end-diastolic pressure
RVEF: indicated right ventricular ejection fraction
RVMI: right ventricular myocardial infarction
TGA: transposition of the great arteries
TOF: tetralogy of Fallot
TTPG: transtricuspid pressure gradient


Correspondence: F. Haddad, M.D.
Division of Cardiovascular Medicine, Stanford University School
of Medicine, Palo Alto, California, United States of America, 94305.
E-mail: fhaddad@stanford.edu">fhaddad@stanford.edu

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