Treatment for Pulmonary Arterial Hypertension ... - ATS Journals

FOCUSED REVIEW Treatment for Pulmonary Arterial Hypertension–Associated Right Ventricular Dysfunction Jose Gomez-Arroyo1,2, Julio Sandoval2, Marc A. Simon3, Erick Dominguez-Cano2, Norbert F. Voelkel4, and Harm J. Bogaard5 1

Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania; 2Departamento de Cardioneumologia, Instituto Nacional de Cardiologia “Ignacio Chavez,” Mexico City, Mexico; 3Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; 4Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia; and 5Department of Pulmonary Medicine, Vrije Universiteit Medical Center, Amsterdam, The Netherlands

Abstract Pulmonary arterial hypertension (PAH) includes a heterogeneous group of diseases characterized by pulmonary vasoconstriction and remodeling of the lung circulation. Although PAH is a disease of the lungs, patients with PAH frequently die of right heart failure. Indeed, survival of patients with PAH depends on the adaptive response of the right ventricle (RV) to the changes in the lung circulation. PAH-specific drugs affect the function of the RV through afterload reduction and perhaps also through direct effects on the myocardium. Prostacyclins, type 5 phosphodiesterase inhibitors, and guanylyl cyclase stimulators may directly enhance myocardial contractility through increased cyclic adenosine and guanosine monophosphate availability. Although this may initially improve cardiac performance, the long-term effects on myocardial oxygen consumption and function are unclear. Cardiac effects of endothelin receptor antagonists may be opposite, as

endothelin-1 is known to suppress cardiac contractility. Because PAH is increasingly considered as a disease with quasimalignant growth of cells in the pulmonary vascular wall, therapies are being developed that inhibit hypertrophy and angiogenesis, and promote apoptosis. The inherent danger of these therapies is a further compromise to the already ischemic, fibrotic, and dysfunctional RV. More recently, the right heart has been identified as a direct treatment target in PAH. The effects of well established therapies for left heart failure, such as b-adrenergic receptor blockers, inhibitors of the renin–angiotensin system, exercise training, and assist devices, are currently being investigated in PAH. Future treatment of patients with PAH will likely consist of a multifaceted approaches aiming to reduce the pressure in the lung circulation and improving right heart adaptation simultaneously. Keywords: heart failure; pharmacology; pulmonary heart disease; right ventricle

(Received in original form December 4, 2013; accepted in final form June 10, 2014 ) Correspondence and requests for reprints should be addressed to Harm Jan Bogaard, M.D., Ph.D., Department of Pulmonary Medicine, VU University Medical Center, PO Box 7057, Amsterdam 1007 MB, The Netherlands. E-mail: [email protected] Ann Am Thorac Soc Vol 11, No 7, pp 1101–1115, Sep 2014 Copyright © 2014 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201312-425FR Internet address: www.atsjournals.org

The primary determinant of survival in pulmonary arterial hypertension (PAH) is the response of the right ventricle (RV) to the functional and structural alterations of the pulmonary circulation (1–3). As reviewed recently (4), PAH-associated RV failure is thought to result from multiple interactions between an increased afterload and a derailed autocrine, paracrine, and neuroendocrine signaling, ultimately leading to RV–arterial uncoupling, a loss of cardiomyocytes, metabolic remodeling, mitochondrial dysfunction, maladaptive Focused Review

changes of the extracellular matrix, myocardial ischemia, and inflammation (5). The relative importance of these interacting pathological mechanisms is unclear, and the impact of current PAH treatments on the adapting RV are, likewise, obscure. In this Review, we sought to recapitulate some of the known effects of standard PAH treatments on the heart, as well as to explore potentially new additional therapies to directly treat RV failure. The pharmacological management of acute RV failure (with inotropes or vasopressors) is

not a topic included in this Review, and we refer the interested reader to existing reviews on this matter (6).

Current PAH-specific Pharmacotherapies and Their Effect on the RV Guidelines for the treatment of patients with PAH recommend oxygen and diuretics as needed, as well as anticoagulants in patients without contraindications (7, 8). Calcium 1101

FOCUSED REVIEW Table 1. Proposed direct cardiac effects of current pulmonary arterial hypertension therapies and their impact on the right ventricle Treatment

Prostacyclin analogs Endothelin receptor blockers PDE-5 inhibitors/sGC inducers Tyrosine kinase inhibitors Rho-kinase inhibitors

Statins

Proposed Direct Cardiac Effects

Impact on the Right Ventricle

↑Angiogenesis ↓Fibrosis Negative inotrope ↑Cardiomyocyte apoptosis ↓Cardiomyocyte apoptosis ↑Myocardial relaxation ↑Contractility ↓Angiogenesis ↑Mitochondrial Dysfunction ↑Cardiomyocyte apoptosis ↓Noncardiomyocyte apoptosis ↓Inflammation ↓Contractility Excessive reduction of hypertrophy ↓ROS production ↑Nitric oxide production ↓Inflammation

Positive effect Negative effect Positive effect Negative effect Positive effect Negative effect Positive effect

Definition of abbreviations: PDE-5 = phosphodiesterase-5; ROS = reactive oxygen species; sCG = soluble guanylate cyclase.

channel blockers are used in patients with significant pulmonary vascular reactivity, whereas other symptomatic patients are

treated with prostacyclin (PGI2) analogs, endothelin (ET)-1 receptor antagonists, and type 5 phosphodiesterase (PDE5)

inhibitors, alone or in combinations (7). It is clear that current pharmacotherapies improve pulmonary hemodynamics, cardiac performance, and functional class of patients with PAH; however, whether any of the clinical benefits from the above-mentioned groups of drugs can be explained by direct effects on the RV has not yet been fully investigated. When it comes to the evaluation of direct RV effects of vasodilator treatment in PAH, two pathophysiological concepts need to be considered. First, RV contractility is greater than normal in virtually all patients with PAH, and, therefore, RV dysfunction is best explained by an increase in afterload out of proportion to the increase in RV contractility (RV–arterial uncoupling, assessed using pressure–volume analysis) (9). RV–arterial coupling can be improved by either an increase in contractility or by a decrease in afterload. Even if a pulmonary vasodilator drug has negative inotropic effects, it could still improve RV–arterial coupling, as long as the decrease in afterload is larger than the decrease in contractility. Second, although a short-term increase in contractility may be beneficial, long-term effects of enhanced contractility

Table 2. Potential RV-targeted therapies and the direct or indirect effects on the right ventricle Drug

Proposed Effects on RV Function

Evidence for Use in PAH

Carvedilol, bisoprolol

↑Angiogenesis ↓Heart rate ↓Fibrosis Metabolic modulator

Only experimental evidence in animal models

Natriuretic peptides

↓Maladaptive hypertrophy ↓RV Volume-overload (by diuresis) ↓Apoptosis ↓Fibrosis Metabolic modulator Systemic vasodilators ↓Remodeling of extracellular matrix ↓Fibrosis ↑Fibrosis ↓Angiogenesis ↑Cardiomyocyte apoptosis

No evidence

Blockers of the renin–angiotensin–aldosterone Axis HDAC inhibitors (trichostatin-A and valproic acid)

Antioxidants (BH4, protandim)

Exercise

↓Fibrosis ↓Apoptosis ↓ROS-induced damage

No evidence Only experimental evidence in animal models Only experimental evidence in animal models One clinical trial: improved exercise capacity and increase 6-min walk distance

Definition of abbreviations: BH4 = tetrahydrobiopterin; HDAC = histone deacytelase; PAH = pulmonary arterial hypertension; ROS = reactive oxygen species; RV = right ventricle.

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FOCUSED REVIEW (and an accompanying increase in myocardial oxygen consumption) may be detrimental. In other words, increasing contractility might not be the ideal longterm goal of treatment if cardiac cellular homeostasis has not been similarly restored. Supportive Treatment and Calcium Channel Blockers

Oxygen is thought to lower pulmonary vascular resistance by releasing hypoxic pulmonary vasoconstriction and decelerating vascular remodeling; a target oxygen saturation of 90% has been recommended (10). There is no evidence for direct effects of supplemental oxygen on the RV in PAH, although either a protection against ischemia (11) or an increased production of reactive oxygen species (ROS) and suppression of hypoxiainducible factor-1a expression could be hypothesized. The consensus use of anticoagulant therapy is based on indirect evidence (12, 13); however, a recent analysis from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension reported that—at least in patients with idiopathic PAH— anticoagulant therapy was associated with a significantly better 3-year survival when compared with patients who never received anticoagulation (13). Although there are data to suggest that digoxin treatment results in an acute increase in cardiac output along with a reduction in serum norepinephrine levels (14), the long-term benefit of digoxin in PAH remains unclear. Diuretic treatment leads to symptomatic improvement in the fluid-overloaded patient. The beneficial effect of the aldosterone antagonist, spironolactone, in heart failure, however, is also associated with immune modulation, reversal of maladaptive remodeling, and prevention of hypokalemia and arrhythmia, which are all potentially important, but unexplored, mechanisms in RV dysfunction associated with PAH (15). Calcium channel blockers are used by a small group of patients with PAH with a positive vasoreactivity test in whom a survival benefit has been suggested (12). The consequences of potentially negative inotropic effects of calcium channel blockers on RV function in PAH are unknown, although dihydropyridine-type calcium channel blocker (nifedipine and Focused Review

amlodipine) are generally considered safe in PAH. Prostacyclin Analogs

For almost 20 years, intravenous administration of epoprostenol (synthetic PGI2) has been the cornerstone of PAH treatment (16). It is generally assumed that the therapeutic effect of PGI2 in PAH is explained by an induction of pulmonary vasodilatation and inhibition of vascular remodeling (17). However, no evidence exists that chronic prostacyclin treatment reverses lung vessel remodeling in PAH (18), and there are histological data to suggest that pulmonary vascular remodeling in PAH progresses despite long-term PGI2 treatment (19). Pogoriler and colleagues (20) reported that long-term prostacyclin treatment might have an antithrombotic effect, but does not prevent or reverse the formation of advanced vascular lesions. It has to be recognized, however, that PGI2 has important direct effects on the heart. In patients with severe heart failure, PGI2 treatment results in an immediate and substantial increase in cardiac output and a reduction in cardiac filling pressures (21). Recent work shows that, unlike other pulmonary vasodilators, PGI2 analogs improve RV stroke work in PAH (22), which is probably a better reflection of cardiac function than cardiac output. Although this improvement in cardiac function could be an adaptive response to systemic vasodilation or the result of pulmonary vasodilation with improved right ventriculo–arterial coupling (21,23), a direct effect on cardiac cells and cell signaling pathways is another possibility. In an animal model of flow-associated PAH, a PGI2 analog, iloprost, improved RV contractility and capillary-to-myocyte ratio, independently from a change in RV afterload (24). Syed and colleagues (25) recently reported that treatment with iloprost does not modify the pulmonary artery pressure (PAP), but does improve RV contractility and reduces fibrosis in the sugen (SU5416)/hypoxia rat model of RV failure and severe PAH. In addition, PGI2 has been reported to suppress pressure overload–induced left ventricular (LV) hypertrophy (26) and fibrosis (27). Both effects are considered to originate from the action of cells other than cardiomyocytes; however, the exact mechanism remains undetermined (26).

Potentially beneficial direct effects of PGI2 treatment on the heart were the main reason for initiating large clinical trials with epoprostenol treatment in patients with severe left heart failure. Unexpectedly, and despite previous positive results, 6 months of treatment with epoprostenol were associated with increased mortality (28, 29). A possible explanation for this adverse outcome was the increase in cardiac output upon initiation of epoprostenol therapy (21). As such, increases in myocardial contractility and cardiac output may initially improve exercise capacity, but the accompanying increase in myocardial oxygen consumption could be detrimental in the long term. Such a sequence of events could be related to the results from the Beraprost Study, which is the only randomized clinical trial with a follow-up time of 1 year with specific PAH therapy. It was reported that, although exercise capacity improved after 12 weeks of treatment with an oral PGI2 analog, this benefit disappeared after 1 year (30). Indeed, the effects of prostacyclin analogs on the function of the RV are still poorly understood. An increase in myocardial contractility may play a different role in PAH (where improved RV–arterial coupling is desired) when compared with end-stage left heart disease. In the future, it will be important to evaluate whether any potential direct cardiac effects of prostacyclin treatment depend on exposure time or are just an idiosyncratic response to therapy, specific for every patient. ET Receptor Blockers

In PAH and heart failure, ET-1 serum concentrations are elevated due to increased production by endothelial cells and cardiomyocytes in response to various stimuli (e.g., vasoactive hormones, growth factors, shear stress, hypoxia, and ROS) (31–34). ET-1 not only increases pulmonary vascular tone, but also regulates a variety of biological processes in nonvascular tissues. ET-1 augments cardiomyocyte contractility and plays a role in the development of pressure overload–induced cardiac hypertrophy (31, 35). In patients with PAH–associated heart failure, the direct effects of ET-1 signaling on the heart are mixed with indirect effects via stimulation of pulmonary vasoconstriction and vascular remodeling. ET-1 exerts its effects through two receptor subtypes, ETA and ETB, the former predominating in the rat 1103

FOCUSED REVIEW myocardium (36). Heart failure in rats leads to an increased ETA receptor density (33). ET-1 affects cardiomyocyte survival and pressure overload–induced hypertrophy by interacting with B-cell lymphoma 2 (37), the epidermal growth factor (EGF) receptor (EGF-R) (38), and mitogen-activated protein kinase (PK) cascades (35). Clinical trials in patients with left-sided heart failure with orally administered ET receptor antagonists (Research on Endothelin Antagonism in Chronic Heart Failure-1, Enrasentan Cooperative Randomized Evaluation, Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure, and Endothelin A Receptor Antagonist Trial in Heart Failure were the largest, although the results have never been fully published) suggest that direct effects of ET receptor antagonists on the heart are not favorable (39–41). It has been postulated that the inotropic actions of ET-1 are, in fact, beneficial in chronic heart failure, providing partial compensation for a decreased contractility. Detrimental actions of ET receptor blocker in the RV of patients with PAH have not (yet) been shown. Experimental studies, however, do suggest that ET receptor blockade worsens the contractility of the pressureoverloaded RV in rats (42). Whether this occurs in PAH and would translate into negative effects for individual patients would depend on the relative magnitudes of decreases in afterload and contractility and the resultant effect on RV–arterial coupling. PDE Inhibitors

Cyclic guanosine monophosphate (cGMP) is a ubiquitous intracellular secondary messenger. The natriuretic peptides generate cGMP via activation of the particulate guanyl cyclase, whereas nitric oxide (NO) induces the formation of cGMP through activation of soluble guanylate cyclase (sGC) (43). cGMP is degraded by the action of PDEs. Some PDE subtypes hydrolyze only cGMP (PDE5, PDE6, and PDE9), whereas others degrade cAMP (PDE3, PDE4, PDE7, and PDE8) or both cGMP and cAMP (PDE1 and PDE2) (44). cGMP lowers Ca21 sensitivity and intracellular Ca21 concentration in pulmonary vascular smooth muscle cells. The resulting vasodilating and antiproliferative properties of the molecule explain the therapeutic benefit of the PDE5 inhibitors, sildenafil and tadalafil, in PAH (45;46). More recently, the therapeutic benefit of increasing cGMP availability with the sGC stimulator, 1104

Riociguat, has been shown in a randomized clinical trial (47). cGMP/PKG signaling protects the heart from apoptosis (48, 49) and blunts the hypertrophic response to pressure overload and isoproterenol (an adrenergic agonist) (50–52). Multiple roles for cGMP in cardiac contractility, lusitropy, and ion channel responsivity have been well characterized; however, the extent to which natriuretic peptides predominate over NO to mediate these effects is less clear (53). The effect of cGMP on myocardial contractility depends on its interactions with PDEs and cAMP. Theoretically, cGMP can decrease contractility by decreasing cAMP concentrations through inhibition of adenylate cyclase and induction of PDE2 (54, 55). In addition, phosphorylation of troponin I by a cGMP-dependent PK can decrease the sensitivity of the contractile apparatus to Ca21 and accelerate myocardial relaxation (54). On the other hand, it was recently shown in patients with PAH and in rats with monocrotaline (MCT)-induced RV hypertrophy, that cGMP can, in fact, increase contractility by increasing cAMP concentrations (56). The authors explained this apparent paradox by cGMP-related inhibition of the cGMP-sensitive PDE3. They also showed that, compared with a normal RV, RV hypertrophy (both in humans and rats) is associated with a considerable decrease in PKG activity. At the same time, PDE5 was only expressed in the hypertrophic RV, and not in the normal RV (56). Once again, the long-term effects of PDE5 inhibition and sGC stimulation on RV adaptation in PAH are unknown. The initial preclinical evidence seemed to justify a provisional conclusion that these strategies could have positive direct effects on the heart. PDE5 inhibition prevents and reverses pressure overload–induced hypertrophy in mice, which was associated with enhanced systolic function (52). Sildenafil protects against cardiomyocyte apoptosis (48, 49), and may decrease myocardial oxygen consumption by inhibiting adenylate cyclase (55) and accelerating myocardial relaxation (54). Despite such positive experimental data, clinical studies of drugs that increase cGMP availability in patients with heart failure have yielded mixed results. After first positive results of PDE5 inhibition in patients with non-PAH heart failure with decreased (57, 58) and preserved ejection

fraction (59), recent randomized clinical trials using sildenafil and riociguat in these patient categories failed to meet their primary endpoints (60, 61). A single dose of sildenafil was shown to improve RV diastolic function in patients with PAH (62). It remains to be determined whether this is a direct cardiac effect, or whether it was mediated by a decrease in RV afterload.

New Treatment Strategies in PAH: Good for the Lung, Bad for the Heart? One hypothesis that has been advanced to explain the pathobiology of severe PAH is based on the concept of a quasimalignant nature of endothelial cells in the lung vasculature. This hypothesis postulates that, after an initial injury, pulmonary vascular endothelial cells undergo apoptosis, but a group of surviving cells switch their phenotype and become apoptosis resistant and hyperproliferative to the point of lumen occlusion. In other words, the hypothesis reflects a process of “wound healing gone awry” (5). There is now a search for molecular targets and mechanisms that could potentially drive this “quasimalignant” lung vessel remodeling. However, as the knowledge of the pathobiology of PAH evolves, future therapeutic strategies face one critical paradox: although the remodeled lung vasculature in PAH is characterized by angiogenesis, apoptosis resistance, and cell proliferation, the failing RV may suffer from ischemia, capillary rarefaction, and cardiomyocyte apoptosis (63). Thus, new treatments designed to tackle any quasimalignant feature in the sick-lung circulation could have detrimental effects in an ischemic, fibrotic, and dysfunctional RV. Experimental Models of RV Dysfunction

As is the case with many other diseases, potential new compounds for the treatment of PAH are generally tested first in animals. Several experimental models have been developed, and the interested reader is referred to a recent review on this topic providing a detailed overview (64). Rat models have generally provided superior insights into the mechanisms of severe pulmonary vascular disease and associated RV failure, as severe pulmonary hypertension is very difficult to induce

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FOCUSED REVIEW in mice (65). Pulmonary artery banding, which creates mechanical stress on the RV without pulmonary vascular disease, has been useful to explore side effects of drugs on RV adaptation without the interfering effects from changes in pulmonary vascular resistance (63, 66). Tyrosine Kinase Inhibitors

Platelet-derived growth factor (PDGF) has been implicated in the pathobiology of pulmonary vascular remodeling in PAH (67), and treatment with imatinib, an inhibitor of the tyrosine kinase domain of the PDGF receptor, has been beneficial in isolated cases (68–71). Nonetheless, a phase II trial with patients with PAH failed to meet its primary endpoint of improved exercise capacity after 4 months (72), and a randomized clinical trial in selected patients with PAH (pulmonary vascular resistance > 800 dyne$s$cm 25 ; Imatinib in Pulmonary Arterial Hypertension, a Randomized, Efficacy Study [IMPRES]) showed no improvements in functional class, time to clinical worsening, or mortality with imatinib, despite a small improvement in exercise capacity (73). The trial was discontinued because of severe side effects, in particular subdural hematoma. Another major concern with imatinib treatment in PAH is the fact that the drug may have detrimental effects on the heart (74, 75). After myocardial infarction, PDGF enhances cardiomyocyte survival, modulates inflammatory responses, and activates proangiogenic progenitor cells (76–78). Because RV capillary rarefaction and ischemia may play a role in the transition from adaptive hypertrophy to RV dilatation and failure (4, 63), imatinib could potentially worsen maladaptive cardiac remodeling in PAH. Negative direct cardiac effects were not seen in a post hoc analysis of echocardiographic parameters in patients treated with imatinib in the IMPRES trial, however (79). In contrast to PDGF receptor blockers, EGF-R blockers may have beneficial effects on both pulmonary vascular and RV remodeling. In maladaptive cardiac remodeling, activation of the type 1 angiotensin (AT) receptor (AT1R), the mineralocorticoid receptor, and the type A ET receptor (ETA) results in a transactivation of the EGF-R (38, 80, 81). Moreover, pulmonary hypertension in rats with MCT-induced PAH is ameliorated Focused Review

by EGF-R blockers (82). Interestingly, although not mechanistically tested, the reduced RV hypertrophy observed in this study might not have been necessarily the result of a reduced afterload, but could have resulted from decreased myocardial fibrosis and inflammation. Paradoxically, tyrosine kinase inhibitors are not only potential treatments for PAH, they have also been implicated in the development of the disease. First, the vascular endothelial growth factor receptor tyrosine kinase inhibitor, SU5416, in combination with a hypoxic or allergic challenge, has provided a useful tool to study PAH in rats (83). Second, Dasatinib, a dual c-src tyrosine kinase/Abelson kinase inhibitor used in the treatment of chronic myelogenous leukemia, was associated with cases of severe PAH, potentially reversible after dasatinib withdrawal (84). Possible dual effects of tyrosine kinase inhibitors need to be taken into account if this group of drugs is to be further developed for PAH treatment. Rho Kinase Inhibitors and 3-Hydroxy3-Methyl-Glutaryl-CoA Reductase Inhibitors (Statins)

Inhibition of Rho kinase (ROCK) has been suggested as a new target for PAH treatment. Acute administration of ROCK inhibitors has resulted in modest pulmonary vasodilation in patients with PAH (85, 86), and chronic administration prevented pulmonary vascular remodeling in experimental pulmonary hypertension (87–91). The effects of long-term ROCK inhibition on the RV in PAH are unknown and, based on the available literature, both beneficial (inhibition of apoptosis, reduction of inflammatory cell influx) and detrimental effects (contractile depression and excessive reduction of hypertrophy) can be postulated (4). Statins may interfere with ROCK activation through inhibition of isoprenoid synthesis and subsequent Rho geranylgeranylation, which is the proposed mechanism by which statins reduce cardiac ROS production and hypertrophy after ATII infusion and pressure overload (92). Additional beneficial effects of statins in heart failure consist of inhibition of ET-1 and renin–angiotensin signaling, stimulation of NO production, restoration of autonomic imbalance, and prevention of matrix metalloproteinase activation (93). Statins have been shown to be effective in reversing pulmonary vascular

remodeling and RV hypertrophy in the SU5416/hypoxia model (94), but the results from the clinical trial evaluating simvastatin in human PAH were disappointing (95). Control of Gene Expression by Histone Acetylation/Deacetylation

Histone-dependent packaging of genomic DNA is central mechanism for gene regulation in eukaryotes. When there is no transcription, DNA is wrapped around histone octameres in nucleosomes, which are the basic units of chromatin. The highly compact structure that is formed by interacting nucleosomes limits access of transcriptional enzymes to genomic DNA, thereby repressing gene expression (96). Acetylation of histones by histone acetylases relaxes the nucleosomal structures, thereby facilitating gene expression. The opposite effect is established by histone deacytelases (HDACs), which repress transcription. Inhibitors of HDACs have been shown to reverse pulmonary artery smooth muscle cell hypertrophy in experimental models of pulmonary hypertension (97). By repressing the transcription of genes encoding proteins involved in signaling that leads to cardiac hypertrophy (98, 99), HDAC inhibitors could be hypothesized to have positive direct effects on the RV. Surprisingly, RV adaptation to mechanical pressure overload in the pulmonary artery banding animal model is seriously hampered by the HDAC inhibitors, trichostatin A and valproic acid (66). The opposite effects of HDAC inhibitors in the two pressure-overloaded ventricles is a strong reminder of the fact that success of a drug in the treatment of left-sided heart failure does not guarantee beneficial effects in the context of PAHassociated RV failure.

RV-Targeted Therapies: a New Concept Indeed, patients with PAH die of RV failure, and the prognostic role of the RV has recently been revisited. van de Veerdonk and colleagues (3) demonstrated that, even after decreasing the pulmonary vascular resistance with PAH-specific therapy, those patients that remain with low RV ejection fraction continue to have a poor prognosis. However, despite its prognostic importance, the cellular and molecular 1105

FOCUSED REVIEW mechanisms that explain RV failure are limited and frequently extrapolated from studies of chronic left heart failure. Nonetheless, there is increasing evidence to support the hypothesis that mechanisms of RV failure may not be identical to those of the LV. Some therapeutic options to treat left heart failure have been successfully applied to treat the RV in experimental PAH, but others have demonstrated contradictory results (Table 1). b-Adrenoreceptor Blockers

Similar to patients with left heart failure, PAH is characterized by increased activity of the sympathetic nervous system (which finding has prognostic significance) (100) and down-regulation of the b-adrenergic receptor (AR) (101). Counteracting these mechanisms led to a firm central place of b-AR blocker treatment in patients with left heart failure (102). However, direct effects of b-AR blockade, such as systemic vasodilatation, reduction of myocardial contractility, and decreased heart rate, have prevented the use of this class of drugs in PAH. In portopulmonary hypertension, b-AR blockers have been associated with worsening hemodynamics and a decreased exercise capacity (103). There are, however, a number of reasons why the careful use of b-AR blockers in selected patients may be considered. The associated reduction of myocardial oxygen consumption is probably one of the explanations of the benefit of b-AR blockers in heart failure. In addition, leakiness of the Ryanodine receptor is reversed by b-AR blockers, thereby restoring Ca21 handling and preventing calcineurin/nuclear factor of activated T cells up-regulation (104). b-AR blockers are effective in preventing arrhythmias, which is a problem associated with a markedly increased mortality in PAH (105). Interestingly, in a recent prospective study, So and collaborators (106) reported that the use of b-AR blockers in PAH is not uncommon, and, most importantly, this study reported no statistical differences in PAH-related hospitalization or all-cause mortality between patients with or without b-AR blocker treatment. However, a properly designed clinical trial to assess the safety of this class of drugs is warranted. Experimentally, carvedilol treatment improves exercise tolerance, induces RV capillarization, and improves RV function 1106

(107, 108). In another study in rats with MCT-induced pulmonary hypertension, bisoprolol treatment resulted in an improved RV–arterial coupling and improved survival (109). In comparison to the more selective b1-AR blockers, carvedilol has a unique mechanism by which it suppresses ventricular arrhythmias through inhibition of the spontaneous release of calcium from the sarcoplasmic reticulum (110). In addition, carvedilol has intrinsic antioxidant properties (111, 112) by which the drug is capable of preventing ROS-induced cardiomyocyte apoptosis (113). Some of the cardioprotective effects of carvedilol seem to be independent of blockade of the a- or b-AR, such as direct transactivation of the EGF-R via b arrestin stimulation (114) and up-regulation of the expression of the peroxisome proliferator–activated receptor g coactivator 1-a (PGC-1a), a master regulator of mitochondrial biology and cardiac metabolism (115). Another strategy to restore b-AR function without the negative chronotropic effects of b-AR blockade would be to prevent G protein– coupled receptor kinase-2–mediated uncoupling of b-AR using the small molecule, Gallein (116). Angiotensin-Converting Enzyme Inhibitors and AT1R Antagonists

Although the renin angiotensin system is clearly involved in pressure overload related cardiac remodeling, the role of angiotensin-converting enzyme (ACE) inhibitors and AT1R antagonists in PAH has not been thoroughly evaluated, and its use as a treatment for PAH-associated RV failure remains controversial. In a small case series study, 4 days of treatment with captopril reduced mean PAP and increased RV ejection fraction in three out of four patients (117). In another study, however, 12 weeks of captopril did not modify pulmonary hemodynamics or exercise capacity (118). Experimentally, both the ACE inhibitor, Ramipril, and the AT1R blocker, losartan, improved RV systolic function in rabbits subjected to pulmonary artery banding. In contrast, no direct effects of ACE inhibitors or AT1R blockers on RV function or hypertrophy were seen in experimental models of pulmonary hypertension (94, 119, 120). The improved RV function after pulmonary artery banding with ACE inhibition seem to be related to a decreased rate of apoptosis, but

not as a consequence of reduced hypertrophy (121). Metabolic Modulators

Abnormal mitochondrial metabolism has long been implicated in the development of chronic heart failure, and it has been proposed that a switch from aerobic to anaerobic metabolism could contribute to the development of RV failure (122, 123). Whereas it has been demonstrated that RV failure is characterized by increased expression of glycolysis-related genes (107) and increased glycolysis enzymatic rates (124), it is unclear whether this “metabolic remodeling” is an adaptive or a maladaptive response. We have demonstrated that, along with increased glycolysis, RV failure is characterized by a down-regulated expression of multiple genes required for fatty acids metabolism, supporting a switch in substrate utilization (125). The mechanisms responsible for the down-regulation of fatty acid oxidation in the failing RV are not well defined, but reduced transcriptional activation of genes regulated by the coactivator PGC-1a and its corresponding nuclear receptor, peroxisome proliferator–activated receptor-a, appear to be involved (125). Multiple studies have shown that the rate of fatty acid oxidation is preserved or increased in physiological/adaptive LV hypertrophy, and that it decreases during the progression of heart failure (126). In a similar fashion, rats with adaptive RV hypertrophy after pulmonary artery banding have increased rates of fatty acid oxidation (127). However, whether or not decreased impaired fatty acid oxidation contributes to the development of RV failure has not been mechanistically evaluated. Metabolic modulators designed to block fatty acid oxidation, such as trimetazidine or ranolazine, have been used to prevent cardiac output reduction in rats with pulmonary artery banding; however, the effects of partial fatty acid oxidation inhibition is modest when treating established RV dysfunction (127). We have evaluated the effects of etomoxir, a potent fatty acid oxidation blocker in the SU5416/hypoxia PAH model, and report that etomoxir treatment neither worsens nor improves RV failure (Figure 1). Multiple clinical trials evaluating the role of fatty acid oxidation blockers in left heart failure have been designed; however, none of

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B p=NS

P=NS Vehicle

2.5

60

Etomoxir

2.0 TAPSE (mm)

40 20

1.5 1.0 P=0.013

0.5 0

P=0.013

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t en

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tm

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ea

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Etomoxir

t

0.0 Vehicle

tm

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Pr e

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Vehicle Treated

Etomoxir Treated

Figure 1. (A) Inhibition of fatty acid oxidation with etomoxir treatment had no impact in mean pulmonary artery pressure (MPAP) in comparison to vehicletreated rats. (B) Paired analysis demonstrated that 2-week treatment with etomoxir was insufficient to prevent deterioration in right ventricular (RV) function, as assessed by tricuspid annulus plane systolic excursion (TAPSE). (C–E) Echocardiographic analysis demonstrates no difference in RV diastolic area between controls and vehicle- and etomoxir-treated rats. Asterisks indicate right ventricles; right ventricular end-diastolic diameters were (A) 1.37 mm, (B) 5.17 mm, and (C) 6.15 mm. Red dotted lines indicate left ventricles.

these metabolic modulators has become a standard treatment of heart failure (128). It has also been proposed that not only fatty acid oxidation, but also glucose oxidation, is impaired, and that it could be restored using a pyruvate dehydrogenase kinase inhibitor: dichloroacetate (DCA) (124). In MCT-induced pulmonary hypertension, DCA decreased the severity of pulmonary hypertension and regressed RV hypertrophy, an effect that was perhaps partially related to a reduction in afterload. The effects of DCA therapy were only moderate in pulmonary artery banding– induced RV hypertrophy (124). A clinical trial studying DCA in PAH-associated RV failure is currently underway (NCT01083524; www.clinicaltrials.gov). Antioxidants and Tetrahydrobiopterin

ROS have long been implicated in the pathobiology of chronic left heart dysfunction (129), but their role in RV Focused Review

failure remains to be investigated in depth. ROS can reduce myocyte contractility by affecting calcium handling through suppression of L-type Ca21 channels and sarco/endoplasmic reticulum Ca21ATPase: the Ca21-ATPase of the sarcoplasmic reticulum (130, 131). ROS can be generated from many sources (such as reduced nicotinamide adenine dinucleotide phosphate [NADPH] oxidases). In the heart, mitochondria are an important source of ROS, as they are generated as by-products of an incomplete reduction of oxygen in the electron transport chain. ROS are very unstable, electrophilic, and react with macromolecules, such as proteins and nucleic acids, generating adducts and altering function (132). Interruption of the ATII-Rho-NAD(P)H-ROS pathway with the xanthine oxidase inhibitor, allopurinol, improves myocardial contractility (133) and ameliorates chronic hypoxic PAH in rats (134). Hydralazine inhibits NADPH oxidase,

but it is unclear whether its antioxidant effects can be achieved at concentrations that are employed clinically (53). Another source of ROS in chronic pressure overload comes from uncoupled NO synthase (NOS) 3, and is associated with reduced availability of tetrahydrobiopterin (BH4), an NOS3reducing cofactor. Supplementing BH4 in a pressure overload mouse model of NOS3 uncoupling has been shown to be sufficient to reduce ROS production and prevent maladaptive remodeling in experimental left heart failure (135). Probably the strongest evidence for the role of ROS in RV dysfunction comes from the study of hemeoxygenase-1 (HO-1) knockout mice. HO-1 plays a categorical role in the heart’s response to ROS by inducing the expression of genes that codify for antioxidant enzymes. However, Yet and collaborators (136) demonstrated that mice lacking HO-1 show severe RV dilatation and 1107

FOCUSED REVIEW infarction after hypoxia-induced pulmonary hypertension. On the other hand, we have shown that treatment with protrandim, up-regulates HO-1 expression and is associated with less RV dysfunction in experimental pulmonary hypertension (63). Importantly, ROS play a dual role in cells. Whereas ROS have a direct toxic effect, they also serve as signaling mediators to induce an antioxidant response (132). This dual role could potentially complicate the therapeutic potential of antioxidant treatment for RV failure.

Nonpharmacological RV-Targeted Therapies Exercise

It was previously believed that physical exercise had to be avoided by patients with PAH. After it was shown that exercise training corrected endothelial dysfunction and improved exercise capacity in chronic heart failure (137), a randomized controlled trial was designed to evaluate the effects of exercise rehabilitation in PAH (138). An exercise and respiratory training program of 4 months’ duration was well tolerated and improved scores of quality of life and exercise capacity (peak workload and oxygen uptake). The mean difference in the 6-minute walking distance between intervention and control groups (15 patients in both groups) was 111 m, which is a considerably larger improvement than observed in most PAH drug trials. Because systolic PAP at rest and exercise cardiac output did not change significantly after training, the authors attributed the positive outcome to adaptations in gas exchange and respiratory and peripheral muscle function (138). However, hemodynamic data were obtained noninvasively, and the increase in peak oxygen uptake could have been due to an improvement in RV performance. Experimental data have suggested that exercise could have direct positive effects in the heart. For instance, exercise induces the expression of PGC-1a, which is also associated with increased vascular endothelial growth factor expression and reduced capillary rarefaction (139). However, whether PGC-1a–induced angiogenesis could explain an improvement in RV function after exercise training has yet to be determined. 1108

Cardiac Resynchronization

Cardiac dyssynchrony is a common problem in left heart failure, and even patients with mild-to-moderate LV systolic dysfunction benefit from cardiacresynchronization therapy (140). Indeed, the Resynchronization–Defibrillation for Ambulatory Heart Failure Trial showed that, among patients with New York Heart Association class II or III heart failure, a wide QRS complex, and LV systolic dysfunction, the addition of cardiac resynchronization therapy to an implantable cardioverter–defibrillator reduced rates of death and hospitalization for heart failure (140). Recently, a post–follow-up analysis from the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy demonstrated that, in patients with mild heart failure, LV dysfunction, and left bundle-branch block, early intervention with cardiac resynchronization therapy with a defibrillator was associated with a significant long-term survival benefit. However resynchronization–defibrillation did not confer any clinical benefit in patients without left bundle-branch block (141). Ventricular dyssynchrony is also common in patients with PAH, and often easily recognized by echocardiogram (paradoxical septal movement); however, compared with the left heart failure, ventricular dyssynchrony in PAH is mostly caused by a difference in duration of RV contraction rather than a difference in the onset of contraction (142). There is significantly less evidence to support the use of cardiac resynchronization therapy in patients with severe RV failure, but experimental data have demonstrated that RV pacing improves RV systolic function, improves adverse diastolic interaction, and resynchronized RV and LV peak pressures (143). A small study evaluating RV pacing in patients with chronic thromboembolic pulmonary hypertension demonstrated an improvement in diastolic relaxation, LV stroke volume, and RV contractility (144), but larger studies evaluating safety and efficacy are warranted. Atrial Septostomy

It has been shown that some patients with PAH can benefit from “decompressing” therapeutic strategies, such as atrial septostomy (AS) or Pott’s shunt. AS is a procedure that creates a right-to-left

shunt at the interatrial septum level with the use of a balloon catheter in a step-bystep fashion (145). This results in an increase in LV preload and systemic cardiac output at the expense of a drop in systemic percent SaO2. Theoretically, the drop in SaO2% is compensated by the increase in cardiac output, and thus systemic oxygen transport is maintained. AS may also decompress the RV by reducing its preload (146, 147). The results of this intervention are sometimes spectacular, with disappearance of syncope and fluid retention within a matter of days; however, not all patients improve after septostomy, and the procedure is not risk free. In a recent review of almost 400 procedures performed worldwide (148), there was a 24-hour procedure-related mortality of about 7%, mainly resulting from refractory hypoxemia, and a 1-month mortality rate of 5% due to RV failure progression. It is fair to say, however, that, in most circumstances, this intervention has been performed in severely ill patients. There are no current guidelines for the optimal size of the shunt and, therefore, the appropriate size should be individualized. Massive right-to-left shunting as a result of an excessively large shunt may result in inadequate pulmonary blood flow and severe, refractory hypoxemia and death— the aim is to achieve a fall in SaO2% below 10%. No studies have evaluated the effect of shunting on the RV at the molecular level. It is important to underscore the fact that balloon dilation AS should only be performed in centers experienced in both interventional cardiology and pulmonary hypertension. The creation of a post-tricuspid shunt (“Potts’ anastomosis”) instead of an interatrial shunt might be another (surgical or transcatheter) approach to manage refractory RV dysfunction in the setting of PAH, particularly in children (149). Mechanical RV Support and Transplantation

Mechanical support of the failing RV has generally been thought of as a palliative, temporary approach, although, as newer technologies develop, there continues to be an interest in the potential for longer-term support. Extracorporeal membrane oxygenation has been reported as a method to support the RV in patients with pulmonary hypertension and massive pulmonary embolism (150, 151). It can be implanted quickly, making it advantageous

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FOCUSED REVIEW during emergent situations. Cannulae are implanted surgically, typically in a venoarterial arrangement, in which venous blood is withdrawn, pumped through an oxygenator, and then returned to the arterial system, bypassing the lungs. Risks include bleeding, thromboembolism, and vessel injury. Extracorporeal membrane oxygenation support is only temporary, and requires a plan for removal (i.e., there is a high likelihood of RV recovery, transplant within a short timeframe is likely and possible, or transition to a more permanent support [such as a RV assist device; to date, unlikely in PH] is an option). Mechanical circulatory assist devices, or ventricular assist devices (VADs), have been used in the setting of RV failure after cardiotomy, cardiac transplant, RV infarct,

or LV assist device (LVAD) implantation (152–155). They have not been used for the treatment of PAH-associated RV failure, largely owing to the concern of pulmonary hemorrhage due to input of high flows into a diseased vasculature, which is a result of the pumps being designed for support of the LV. This has raised interest in the concept of partial-assist pumps that could provide enough flow to assist circulation without the risk of pulmonary hemorrhage. Additional benefits of a partial-assist pump would be a smaller device size that could reduce surgical times and complications. These potential benefits must be weighed against the risk of thrombosis at lower flows, which has been another limiting factor in adapting LV pumps to the RV. In addition to thromboembolism, other risks of

mechanical blood pumps to bear in mind are bleeding and infection. For RV support, blood is typically withdrawn from a cannula surgically placed in the RV and returned from the pump via a cannula in the pulmonary artery. Although originally developed for support of the LV, there are two devices approved by the U.S. Food and Drug Administration for support of the RV, the Thoratec PVAD and CentriMag (both manufactured by Thoratec, Pleasanton, CA). The Thoratec PVAD is a pneumatically driven pulsatile pump that can be used for long-term support. The CentriMag is a continuous-flow pump used for short-term support (approved for up to 30 d) (156). The field of cardiac mechanical support has progressed to preferentially use continuous-flow (axial or

Decompensation

RV Failure

A. Insufficient hypertrophy/ growth arrest B. Capillary rarefaction/ decreased angiogenesis C. Metabolic remodelling/ Insufficient energy production D. Mitochondrial dysfunction E. RV-arterial uncoupling F. Increased ROS G. Extracellular matrix remodelling

Functional RV Hypertrophy

A. Sufficient hypertrophy B. Sufficient capillaries C. Sufficient energy D. Preserved mitochondrial function E. RV-A coupling

Treatment Goals

Maintenance of contractility at reduced energy consumption Reduction of fibrosis Improvement of capillary function Inhibition of inflammation and ROS stress Inhibition of apoptosis Maintenance of sufficient myocardial hypertrophy

Figure 2. Treatment goals for prevention of a deterioration of right ventricular (RV) function. After the initial hemodynamic changes in the lung circulation (reduced blood flow, increased resistance, and increased pulmonary artery pressure) the RV is capable of adaptation as long as there is sufficient hypertrophy, adequate capillary density, adequate substrate utilization and a controlled amount of reactive oxygen species (ROS). RV function decompensation may eventually occur, leading to severe RV dysfunction and failure. Treatment goals should be oriented toward maintenance of contractility with reduced energy consumption, prevention of metabolic remodeling, prevention of fibrosis, increased capillarization (induction of angiogenesis), control of ROS, adequate cell growth, and inhibition of cardiomyocyte apoptosis.

Focused Review

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FOCUSED REVIEW centrifugal in design) devices as they are smaller and have improved durability. Two continuous-flow devices have been developed that are placed percutaneously for temporary support: TandemHeart (CardiacAssist, Inc., Pittsburgh, PA) and Impella (Abiomed, Danvers, MA) (157– 159). The Impella has a unique design, with its small axial flow pump being located on the end of the catheter, where it sits in the ventricle, and its adaptation for RV support, the Impella RP, recently received approval in Europe with a trial in the United States to start soon (160, 161). Lung Transplantation

Lung transplantation should be considered for severe PAH if the RV is not severely dysfunctional (typically defined as the need for inotropic support), although such cases represent only 3% of all lung transplants (162). Combined heart–lung transplantation can occasionally be considering in cases of severe PAH with RV failure, although less than 100 cases are performed worldwide per year. Median survival after lung transplant is 5 years for PAH, which improves to 10 years for patients that survive the first year after

transplant; similar results are seen for heart–lung transplant (163). The limited number of organs available requires better treatment strategies for RV failure in PAH.

Conclusions The first decade of the 21st century finds the community of PAH trialists and researchers in a peculiar situation: the available drugs have some impact on patient survival, but do not alter the remodeled lung circulation. Conversely, effective treatments targeting the lung vessels could have detrimental effects on the failing RV. Thus, the development of PAH treatments that both reduce pulmonary vascular resistance and improve RV function is not straightforward. There are contrasting priorities within the different cell populations of heart and lungs. For example, we look for increased contractility in cardiomyocytes, but relaxation in pulmonary vascular smooth muscle cells. On the other hand, we look for apoptosis of the pulmonary endothelial cells in plexiform lesions, whereas we need to promote cardiomyocyte and cardiac

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endothelial cell survival. However, it is very possible to define common goals. Mitigating the inflammatory response, preventing ROS/ reactive nitrogen species disequilibrium, and reversing extracellular matrix remodeling are likely to be beneficial in both the heart and the pulmonary circulation. Aldosterone receptor blockers (and other inhibitors of the renin–angiotensin–aldosterone system), BH4, statins, and EGF-R blockers could fulfill the task. It may also be possible to specifically target the heart, without affecting pulmonary vasculature (Table 2). Specific support of RV function can perhaps be accomplished directly with carvedilol or metabolic modulators. Other important effects that ought to be considered for the treatment of RV failure are summarized in Figure 2. Finally, it is important to remember that PAH is a cardiopulmonary disease. Thus, as new treatments arise, trialists should not only focus on the lung circulation, but also consider every potential positive or negative effect that a drug may have on the RV. n Author disclosures are available with the text of this article at www.atsjournals.org.

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