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Management of acute and chronic RV dysfunction

Irene M. Lang

Department of Internal Medicine II, Division of Cardiology, Vienna General Hospital, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria

Corresponding author. Tel: +43 1 40 400 4614; fax: +43 1 408 11 48. E-mail address: irene.lang{at}meduniwien.ac.at

	Abstract

Top Abstract Definition Spectrum of disorders causing... Correction of RV volume... Correction of RV pressure... Treatment of RV contractility Ventilation and correction of... Physical and respiratory... Acknowledgements References

 
The aim of this article was to outline contemporary treatments of right ventricular (RV) dysfunction and failure. Despite the heterogeneity of disorders underlying RV failure, RV function is a main determinant of long-term prognosis. Therefore, the unique therapeutic goal is to preserve or ameliorate RV function. Although, in advanced stages of RV failure, there is a considerable overlap of pathophysiological mechanisms, the principle targets of treatment are RV contractility, RV pressure overload, and RV volume overload. Apart from surgical strategies such as pulmonary endarterectomy, lung transplantation, closure of shunt lesions, and interventional structural cardiology procedures such as closure of abnormal communications and defects, or graded blade balloon atrial septostomy, targeted pharmacological treatments have become available over the past years. In addition, global strategies such as exercise training, arrhythmia correction, and synchronization treatments may become a new standard of care in the near future.

Key Words: Right ventricular dysfunction • Right ventricular failure

	Definition

Top Abstract Definition Spectrum of disorders causing... Correction of RV volume... Correction of RV pressure... Treatment of RV contractility Ventilation and correction of... Physical and respiratory... Acknowledgements References

 
Right ventricular (RV) dysfunction has been defined as a state where stroke volume still increases in the presence of increased RV end-diastolic volume. In contrast, RV failure is present when stroke volume cannot increase any further in parallel to increased RV end-diastolic volume. The compromise of the systemic circulation by the septal shift and interventricular dependence causing a severe left ventricular (LV) filling disorder, offsets a vicious cycle. On a molecular basis, it appears that there is a recapitulation of the fetal gene pattern with a decrease in the -myosin heavy chain gene and an increase in the expression of the fetal β-myosin heavy chain in dysfunctional or failing RV myocardium.¹ Although excessive and longstanding elevation of RV afterload is a major and prevalent cause of RV dysfunction/failure, evidence accumulates that RV ischemia,² excessive sympathetic and renin-angiotensin system stimulation,³ and volume overload that is accelerated by tricuspid regurgitation⁴ contribute. This transition from dysfunction to failure may be ongoing fast or slowly over years, with an unknown genetic component underlying the ability of the RV to resist pressure and volume overload and to maintain stroke volume. RV hypertrophy is a mechanism accounting for preserved RV function. Recent work has demonstrated that in COPD, concentric RV hypertrophy is the earliest sign of RV pressure overload. However, this early structural adaptation of the heart does not yet compromise RV and LV systolic function.⁵

In practice, the distinction between RV dysfunction and failure can be revealed by a short-time inhalation of NO which, because of its high pulmonary vascular selectivity,⁶ will increase RV stroke volume only in the case of a predominantly pulmonary vascular alteration, i.e. in the presence of RV dysfunction.

Taken together, pressure, volume, and contractility are main determinants of RV function, and as such, are analysed in this article as independent targets for treatment (Figure  1).

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	Spectrum of disorders causing RV-dysfunction/failure

Top Abstract Definition Spectrum of disorders causing... Correction of RV volume... Correction of RV pressure... Treatment of RV contractility Ventilation and correction of... Physical and respiratory... Acknowledgements References

 
Although very different diseases, e.g. cardiomyopathy, pulmonary embolism (PE), myocardial infarction (MI), perioperative injury, sepsis, transplantation, congenital heart disease, pulmonary hypertension (PH), cardiac and peripheral shunts, and pericardial and valvular diseases, impact on RV function, survival is highly dependent on RV function in any of those conditions. For example, in the NIH registry on pulmonary arterial hypertension (PAH), parameters of RV function were significant predictors of survival.⁷ Further evidence comes from the studies of prostacyclin in PH where, in patients receiving long-term treatment, a significantly increased cardiac output (CO) was positively correlated with improved survival.⁸

	Correction of RV volume overload – decreasing preload

Top Abstract Definition Spectrum of disorders causing... Correction of RV volume... Correction of RV pressure... Treatment of RV contractility Ventilation and correction of... Physical and respiratory... Acknowledgements References

 
Standard medical treatments
Diuretics are very useful in decreasing and preventing fluid overload that manifests as generalized oedema, liver congestion, and ascites. Fluid accumulation may occur gradually and clinically inapparently.^9,10 Pressure overload of the atria and the kidney elicits activation of the sympathetic nervous system and the rennin–angiotensin–aldosterone axis. Although the use of aldosterone antagonists and loop diuretics is extremely efficient, care has to be taken to not aggravate RV dysfunction by impairing systemic pressure, and coronary and renal perfusions. A similar deleterious effect may be achieved with a vast ascites tap. Generally, in RV failure, inotropic support (see below) is required in parallel with diuretic therapy and combined with digoxin for its mild inotropic, anti-adrenergic,¹¹ and anti-arrhythmic properties.¹²

Prevention of arrhythmia and treatment of asynchrony
Arrhythmia is an important therapeutic target.¹³ In our experience, both amiodarone and classical interventional ablation techniques can be used to prevent and treat atrial arrhythmias, for example, typical atrial flutter, in atrial arrhythmic patients.

Significant asynchrony has been demonstrated in patients with chronic RV dysfunction. Simultaneous pressure curves of both ventricles in control subjects and patients with PAH have demonstrated asynchrony, and thus providing an explanation for septal bowing in PH.¹⁴ Synchronization therapy may be a possible treatment option for RV failure, because delayed RV contraction critically impairs LV filling.¹⁵ Studies are prepared to study the effects of resynchronization therapy on cardiac function in end-stage RV failure.

Closure of shunt lesions
In the presence of inter-atrial or inter-ventricular communications, left-to-right shunting results in elevated flow and pressure in the RV. Approximately 5% of patients with congenital heart disease suffer endothelial damage through elevated sheer stress, setting off a cascade of negative vascular remodelling resulting in PH. Currently, a few interventional techniques in congenital heart disease have become unequivocally established as first choice over their surgical counterparts to prevent RV overload. The decision to perform an intervention should therefore undergo a process of peer-review and interdisciplinary discussion including surgeons.

Balloon dilatation of a congenital pulmonary valve stenosis has been very successful. In contrast to aortic valvuloplasty, a balloon to annulus ratio of <1.1:1 should be adhered to. Acquired arterial and venous collaterals and fistulous communications are readily closed using coil embolization techniques. Similarly, a small arterial duct can be closed using detachable coils, or for defects between 4 and 16 mm, detachable plug devices can be employed. Transcatheter closure of atrial septal defects has become standard of care for the majority of cases. Given a suitable anatomy, defects up to 40 mm in diameter can be closed with various devices. The degree of acceptable PH prior to interventional and surgical closure is still a matter of debate. As a thumb rule, mean pulmonary arterial pressure (mPAP) should be below two-thirds of mean systemic pressure, or pulmonary vascular resistance (PVR) should be below two-thirds of systemic vascular resistance. We perform complete closure of a defect causing a >1:1.5 systemic-to-pulmonary shunt only when PVR is <400 dynes cm^–5 s. The closure of further intra- and extracardiac communications causing shunt (e.g. baffle leaks, systemic arterial, and venous and coronary fistulas) can also be achieved using the prototypic ‘ASD occluders’.

Atrial septostomy
Survival in PH is largely determined by the functional status of the right ventricle.⁷ Both animal experiments¹⁶ and human studies¹⁷ have revealed that intra-cardiac shunting at the level of the atria had a favourable impact on survival in patients with severe PH. As an explanation, it is assumed that deterioration in chronic right heart failure is mainly the result of compromised systemic flow. Therefore, interventional blade balloon atrial septostomy has been developed.¹⁸ Subsequent clinical series^19,20 have established the procedure, and modified it as graded balloon dilation atrial septostomy (BDAS), with similar favourable outcomes,^21,22 albeit when performed in an expert centre.^23,24 It is important to note that patients undergoing BDAS are very ill, and there is hardly room to explore a learning experience with these individuals. To ensure preservation of systemic oxygen transport, BAS candidates must have an arterial saturation of at least 90%, a haematocrit level of >35%, and preserved LV function with an ejection fraction of >45%. The technique is a standard transseptal approach over a 6F femoral vein sheath, using a Mullins support catheter and Inoue equipment similar to classic mitral commissurotomy.²⁵ In contrast, special care has to be taken to prevent left atrial perforation as the left atrial size is small in PAH patients. Graded balloon dilations are performed until LVEDP rises to about 18 mmHg, arterial oxygen saturation has declined to 80%, and a 16 mm septal orifice has been created. Long-term favourable results of the procedure have been reported elsewhere.^20,26

Treatment of RV infarction
Right ventricular infarction is typically associated with inferior MI involving the interventricular septum and with occlusion of a dominant proximal right coronary artery. Because the RV is thin walled and functions at low oxygen demands and low pressure with coronary perfusion throughout systole and diastole, extensive irreversible RV damage is unusual.²⁷ The prognosis of RV infarction is largely determined by the degree of associated LV infarction.²⁸ Volume therapy (200–1000 mL over the first several hours following the acute infarction) that has become standard on the basis of animal and human data²⁹ is only of benefit in the presence of low right atrial pressures. Echocardiography and haemodynamic monitoring with a Swan–Ganz catheter are required to estimate the dissociation between pulmonary wedge pressure (PWP) and LV filling disturbance.

	Correction of RV pressure overload – decreasing afterload

Top Abstract Definition Spectrum of disorders causing... Correction of RV volume... Correction of RV pressure... Treatment of RV contractility Ventilation and correction of... Physical and respiratory... Acknowledgements References

 
Acute RV pressure overload is mostly because of acute PE. Although available data are flawed by the lack of an impact of thrombolysis on mortality after acute PE, thrombolysis can prevent clinical deterioration and an escalation of treatment during the hospital stay, suggesting an acute effect on RV function after thrombolysis.³⁰ Another contemporary study employing the recombinant fibrin-specific agent tenecteplase is under way (PEITHO) to test the hypothesis that thrombolysis is superior to standard heparin in a cohort of about 1000 patients with submassive, biomarker-positive PE. Alternatively, in selected cases, interventional³¹ or surgical thrombectomy are indicated.³²

The most elegant way of relieving chronic RV dysfunction/failure is to correct increased afterload as the underlying cause. This concept has been the strategy of choice for chronic ‘major-vessel’ thrombo-embolic PH (CTEPH). This disorder results from obstruction of the pulmonary vascular bed by non-resolving thrombo-embolic. One subset of CTEPH represents the complication of acute pulmonary embolism, which has been estimated to lead into CTEPH in 0.5–3.8% of cases within two years.^33,34 In contrast to PAH which manifests in pulmonary vessels of <300 µm diameter, CTEPH has been initially discriminated from PAH by its major vessel involvement of the vascular remodelling process,³⁵ rendering it accessible to surgical intervention with removal of the obstructing lesions,^36,37 and near-complete normalization of RV function within 6 months.³⁸ Accordingly, pulmonary endarterectomy (PEA) is the treatment of choice for CTEPH.³⁹ Untreated patients with CTEPH progress to right heart failure and death,⁴⁰ albeit, generally slower than patients with PAH.⁴¹

The ultimate way of relieving increased RV afterload in severe PH is lung transplantation,⁴² with contemporary 5 year survival rates approximating 48–58% (Meyers et al.⁴³ and unpublished Viennese PH lung transplant database, courtesy of Walter Klepetko). Unilateral or bilateral lung transplantations are practiced. As soon as RV afterload is relieved, the right ventricle enters a dramatic remodelling process, leading to near-normalization of volume indices and function.⁴⁴

	Treatment of RV contractility

Top Abstract Definition Spectrum of disorders causing... Correction of RV volume... Correction of RV pressure... Treatment of RV contractility Ventilation and correction of... Physical and respiratory... Acknowledgements References

 
In PH, RV dysfunction and failure are mainly the results of increased, longstanding, pressure overload of the RV. Specific PH therapies are directed at reducing PVR and pressure by alleviating microvascular obstructions. Prostacyclins,^8,45,46 endothelin receptor antagonists, phosphodiesterase (PDE) inhibitors, and calcium-channel blockers are treatments efficiently targeting increased RV afterload. However, the long-term benefits of these treatments are currently estimated to pertain in <25% of patients, and are sought to be combined with additional strategies, i.e. balloon atrial septostomy or PEA.

Vasodilators
The most common circumstance requiring treatment to improve RV contractility is in the context of acute (e.g. PE) and chronic PH (e.g. PAH). Vasodilators are employed to reduce RV afterload, thus impacting on contractility. The ideal agent in this category of drugs is highly selective for the pulmonary vasculature, causing neglectable ventilation/perfusion mismatches, and permits to maintain systemic arterial pressure. Because flow of the right coronary artery is dependent on the pressure gradient between the aorta and the RV, sufficient systemic arterial pressure is a prerequisite for sufficient coronary arterial supply to the RV.

Prostacyclin (PgI₂) and prostaglandin E₁
Prostacyclins are very potent pulmonary vasodilators that are metabolized within the lungs and harbour a significant degree of pulmonary vascular selectivity.⁶ In addition to an acute effect, a chronic effect on PVR has been well documented in clinical studies of PH.⁸

PGE1 has been evaluated in conjunction with norepinephrin after major cardiac surgery,⁴⁷ to reduce RV afterload while maintaining RV perfusion. It has been recommended for these conditions to administer PGE1 intravenously, while giving the vasopressor via a left atrial catheter for higher selectivity. A similar beneficial effect has been demonstrated for inhaled prostacyclins and prostacyclin analogues in RV failure.^48,49 Chronic intravenous epoprostenol infusion therapy in patients with PAH has been shown to improve RV function.⁵⁰

Calcium antagonists
Calcium antagonists are not suited for the treatment of RV failure because of their reduction in systemic arterial pressure and negative inotropic effects. Furthermore, they negatively impact gas exchange.

Hydralazine
A dose of 12.5–50 mg of hydralazine, four to six times a day, significantly increases CO by releasing norepinephrine from terminal nerves without causing significant ventilation perfusion mismatch through a compensatory increase in Sv_O2.

Angiotensin-converting enzyme inhibitors
Angiotensin-converting enzyme inhibitors have been shown to be inefficient for the treatment of RV hypertrophy and cor pulmonale.⁵¹ In addition, intravenous enalapril causes significant systemic hypotension.

Adenosine
Adenosine is a short-acting (half-life, <10 s) vasoactive drug employed in diagnostic testing of pulmonary vasoreactivity. Adenosine lacks significant systemic effects and decreases pulmonary artery pressure and PVR without impacting Pa_O2 in PH after cardiac surgery.⁵²

Nitrates
Nitroglycerine, isosorbid-dinitrate, and sodium-nitroprusside are non-selective vasodilators and of little use for the treatment of RV failure/dysfunction.⁵³

Other agents
The general concept based on pathophysiological differences between these disorders that PH and RV failure are treated like systemic hypertension and LV failure is invalid.⁵⁴ The future roles of endothelin receptor blockers,⁵⁵ potassium channel openers,⁵⁶ Rho-kinase inhibitors,⁵⁶ and Tyrosine-kinase inhibitors⁵⁷ in the treatment of RV dysfunction by directly affecting and alleviating pulmonary vascular remodelling remain to be established. A measurable improvement in echocardiographic RV parameters has been shown within 16 weeks of treatment with the endothelin receptor antagonist bosentan.⁵⁸

Inotropes
To combat the threat of a fall in systemic arterial pressures in the context of severe RV dysfunction, vasopressors are to be used in parallel to specific vasodilators and diuretics.

Isoproterenol and dobutamine
Beta-adrenergic compounds exert pulmonary vasodilation and may impair gas exchange; yet, their positive inotropic effects with subsequent increase in Sv_O2 may counterbalance ventilation/perfusion mismatching. Dobutamine causes less arrhythmia, increases in heart rate, and myocardial ischemia than isoproterenol, and exerts a beneficial effect on RV volume overload with PH during liver transplantation.⁵⁹ Dobutamine is also useful in the treatment of right heart failure after cardiac transplantation, when cardiac denervation triggers relative bradycardia.

Phosphodiesterase inhibitors
Milrinone and enoximone have been labelled ‘inodilators’ because of their positive inotropic and vasodilatory effects. Their drawback is a prolonged half-life that has made their use for the indication of RV failure after cardiac surgery in children difficult.^60–62

Levosimendan
Levosimendan is a myocardial calcium sensitizer⁶³ and vasodilator.⁶⁴ It acts without illiciting an increase in cAMP, an increase in intracellular calcium, or increase in energy consumption. There is no increase in arryhthmogenicity, worsening in relaxation, or an anti-stunning effect. Beta-blockers do not antagonize its effects. The intravenous formulation of levosimendan has been studied in several randomized comparative studies in patients with decompensated heart failure and it has produced significant, dose-dependent increases in CO and stroke volume, and decreases in PWP and other pulmonary haemodynamic variables.^65–68 Preliminary data also exist on similar beneficial haemodynamic effects in patients with PH.⁶⁹ These uncontrolled data demonstrated a reduction in PVR and transpulmonary gradient with levosimendan in six patients with end-stage heart failure and severe PH. Levosimendan exerts positive inotropic effects in the myocardium in contrast to calcium-channel blockers, and decreases PAP through a mechanism not addressed with current therapies.⁶⁴

A recent, controlled unpublished study has shown that levosimendan is efficacious in various forms of PH, lowering mPAP and PVR, and increasing CO and mixed venous oxygen saturation. Repeated dosing seems to be effective without development of tolerance. However, the values of haemodynamic parameters before a repeated study drug infusion at 8 weeks were unchanged compared with those before the initial 24 h study-drug infusion. One may speculate that higher doses or shorter dosing intervals should be tested in larger patient populations with overt right heart failure and low blood pressure.

	Ventilation and correction of hypoxia

Top Abstract Definition Spectrum of disorders causing... Correction of RV volume... Correction of RV pressure... Treatment of RV contractility Ventilation and correction of... Physical and respiratory... Acknowledgements References

 
Exercise haemodynamics in RV failure correlate with resting haemodynamics, rise of CO correlates with rise of PVR and mPAP, and the rise of CO is dependent on RV contractile reserve. There is usually no change of V/Q mismatches under exercise. CO limits aerobic capacity, and ventilatory work is increased under exercise. Ventilatory efficiency is limited by hyperventilation and an increased alveolar dead-space.⁷⁰ Acute improvement of haemodynamics immediately increases aerobic capacity.

Oxygen is a selective pulmonary vasodilator. Oxygen therapy improves cardiac index and PVR in patients with PH, without reducing systemic arterial saturation.⁷¹

	Physical and respiratory training

Top Abstract Definition Spectrum of disorders causing... Correction of RV volume... Correction of RV pressure... Treatment of RV contractility Ventilation and correction of... Physical and respiratory... Acknowledgements References

 
The breathlessness of PH patients during exercise can be related to the relative hypoperfusion of their well-ventilated alveoli (increased ‘dead space’). Ventilation/perfusion mismatching, hypoxia, and an increased hydrogen ion stimulus to ventilation resulting from a low work rate lactic acidosis⁷⁰ are the underlying mechanisms of breathlessness. A recent randomized study has demonstrated a beneficial effect of standardized exercise and respiratory training in patients with severe PH.⁷² Exercise training was well tolerated and improved scores of quality of life, WHO functional class, peak oxygen consumption, oxygen consumption at the anaerobic threshold, and achieved workload.

	Acknowledgements

Top Abstract Definition Spectrum of disorders causing... Correction of RV volume... Correction of RV pressure... Treatment of RV contractility Ventilation and correction of... Physical and respiratory... Acknowledgements References

 
This research was supported by the Österreichischer Selbsthilfeverein Lungenhochdruck, Proposal reference number FP6-018725 and FWFS9406-B11 (to I.M.L.).

Conflict of interest: none declared.

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Top Abstract Definition Spectrum of disorders causing... Correction of RV volume... Correction of RV pressure... Treatment of RV contractility Ventilation and correction of... Physical and respiratory... Acknowledgements References

 

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