Pulmonary hypertension can be caused by various underlying conditions, most commonly left heart disease (LHD). PH-LHD is highly variable in prevalence, given its dependence on severity and duration of LHD and the degree of hemodynamic decompensation . Presence of pulmonary hypertension in patients with LHD is invariably linked to greater disability and decreased survival [2,3]. In fact, several studies have confirmed that elevated pulmonary vascular resistance (PVR) is associated with a proportionately higher risk of post-transplant right heart failure [4,5]. Therefore, significant precapillary pulmonary hypertension is considered a relative contraindication for potential heart-transplant candidates .
The degree of pulmonary hypertension which would pose an absolute contraindication to heart transplant is debatable and has been defined in terms of PVR, transpulmonary gradient (TPG), and, more recently, diastolic pulmonary gradient [6–8]. The cornerstone of therapy continues to be correction of the underlying LHD. Several pharmacological agents have been used in the assessment of reversibility of pulmonary hypertension in an attempt to lower PVR and associated passive congestion, and to improve the patient's candidacy for successful heart transplant. When these therapies fail to lower the left ventricular filling pressures, mechanical unloading of the left ventricle (LV) may be used to reverse both the passive and reactive components of PH-LHD .
PATHOPHYSIOLOGY OF PULMONARY HYPERTENSION-ASSOCIATED WITH LEFT HEART DISEASE
Classically, PH-LHD has been explained by an elevation of the pulmonary venous pressure, which usually is elevated concordantly with left atrial pressures. In these patients, the mean pulmonary artery pressure (PAP) will increase in response to the increase in the left ventricular pressures in a passive fashion. However, some patients with heart failure present with elevated pulmonary pressures that are ‘out of proportion’ to the expected by mere backward pressure transmission from the left-sided chambers. In this context, there is a ‘reactive’ elevation in pulmonary pressure incremental to the pre-existing passive pressure.
Reactive pulmonary hypertension, defined as TPG above 12 mmHg, is associated with an elevated pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure (LVEDP) . It likely reflects the additive effects of a dynamic component (associated with a protective or exaggerated pulmonary circulation vasoconstriction) on to a ‘fixed’ component that includes pulmonary circulation remodeling. This remodeling of the pulmonary circulation includes arteriolar wall thickening, fibrosis, increase in muscular layer of pulmonary arteries and veins, alveolar capillary thickening, and diminished lymphatic drainage . This late-stage anatomic remodeling likely is the result of prolonged elevations and changes in the genetic ‘cassette’ in response to endothelial-transduced alterations in nitric oxide, endothelin, and vasoactive moieties . Thus, endothelial dysfunction, characterized by an imbalance between vasoconstrictor, vasodilator, and growth factor-related mediators, is one of the most important physiological determinants in the development of reactive pulmonary hypertension.
Patients with LHD also have a dysregulation in arginine metabolism, which is associated with higher PAP . There is abnormal nitric oxide metabolism, with the accumulation of methylated arginine metabolites, which are independent predictors of disease progression and adverse long-term prognosis [14,15]. In addition, these patients have enhanced production and dysregulation of free oxygen radicals . This increase in free oxygen radicals leads to a reduction in nitric oxide levels, increase in protein oxidation, and reduction of both synthesis and bioactivity of the nitric oxide. Such changes could account for the abnormal small pulmonary vessel vaso-reactivity and smooth muscle hypertrophy and growth.
Patients with pulmonary hypertension also manifest increased levels of vasoconstrictor substances, like endothelin 1 . Endothelin activates the ETA and ETB receptors of the vascular smooth cells of the pulmonary arteries, causing vasoconstriction. Both receptors also mediate smooth muscle cell proliferation in the pulmonary arteries leading to an increase in vascular resistance frequently seen in patients with pulmonary hypertension [17,18]. Animal studies have demonstrated that in patients with LHD, there is a functional shift of the endothelin receptors, and endothelin becomes more active on the ETA receptor, which is associated with decreases in cardiac output, increase in PVR, and vasoconstriction of the pulmonary veins that also contribute to increase in total PVR [19,20].
Finally, patients with heart failure may have additional comorbidities like sleep apnea that is associated with an increase in sympathetic nervous system activation, which it can lead to myocyte hypertrophy, vascular smooth muscle hypertrophy, and changes in vascular wall thickness seen in patients with PH-LHD .
DIAGNOSIS OF PULMONARY HYPERTENSION-LEFT HEART DISEASE
Echocardiography provides valuable data in diagnosis of both cause and severity of pulmonary hypertension. However, right heart catheterization remains the gold standard for confirming the presence of and further defining the hemodynamic effects of pulmonary hypertension. Generally, a mean PAP greater than 25 mmHg in the presence of elevated PCWP (>15 mmHg) or LVEDP (>18 mmHg) is required to define pulmonary hypertension secondary to LHD. Both TPG and PVR are commonly used to determine the degree of precapillary pulmonary hypertension and suitability for heart transplant. A PVR greater than 1.5 Wood Unit and/or TPG above 12 mmHg in the setting of elevated PCWP or LVEDP suggest a ‘mixed’ picture, with hemodynamic features of both pulmonary venous/postcapillary pulmonary hypertension and precapillary pulmonary hypertension. However, TPG is sensitive to changes in cardiac output as well as left atrial pressures, making it a relatively insensitive marker for differentiating the reversibility in pulmonary vascular tone [7,22]. More recently, it has been suggested that an elevated diastolic PAP to mean PCWP ratio (DPG) may be a better measure of advanced pulmonary vascular remodeling, and thereby a prognosticator of death in patients with pulmonary hypertension out-of-proportion to left-sided filling pressures . However, it was not shown to predict survival after heart transplant in patients with pulmonary hypertension, and an elevated TPG and PVR in a large United Network for Organ Sharing (UNOS) cohort analysis [23▪▪].
Of note, these definitions and thresholds are not uniform in practice and are extrapolated from clinical experience rather than large, prospective studies. Their values vary based on the degree of hemodynamic compromise, making them less-than-perfect surrogates for pulmonary vascular remodeling and therefore postheart transplant outcomes.
MANAGEMENT OF PULMONARY HYPERTENSION IN POTENTIAL HEART-TRANSPLANT RECIPIENTS: CURRENT GUIDELINES
It is recommended to obtain right heart catheterization in patients undergoing evaluation for heart transplant, with vasodilator challenge for those with elevated PVR. For patients with reversible pulmonary hypertension, and marginal response to maximal medical therapy, or mechanical support, it is recommended to perform hemodynamic assessment on patients listed for heart transplant every 3–6 months .
As far as therapies for patients with PH-LHD are concerned, there are no class I recommendations in terms of pulmonary vascular remodeling. The consensus is that for these patients, the best treatment is optimization of the underlying disease including neuro-hormonal modulators for patients with systolic heart failure, optimal medical treatment of systemic hypertension, and normalization of volume status, with appropriate management of any valvular heart disease . Concomitant conditions that can exacerbate pulmonary hypertension such as chronic obstructive pulmonary disease, sleep apnea, and pulmonary emboli should be identified and aggressively treated.
The traditional therapeutic strategy in PH-LHD is to lower the left-sided filing pressures, thereby relieving the ‘backward’ hydrostatic pressure causing right heart congestion . As long as the PVR is relatively low, this can be achieved by diuresis and vasodilators [26–28]. In patients with elevated PVR, the role of selective pulmonary vasodilators is the subject of multiple, largely unfavorable clinical trials (Table 1). Although the rationale behind using therapies specifically targeting pulmonary vasculature has a sound pathobiological basis, their routine use outside of the realm of clinical trials should generally be avoided.
Systemic vasodilators, including nitroprusside and nesiritide, are commonly used in patients with PH-LHD, although there is no clinical benefit of routine use of nesiritide in acutely decompensated patients with heart failure . These agents lower PAP by increasing both venous and arterial capacitance, thereby lowering the hydrostatic component of LHD [26,30]. In patients with acute heart failure exacerbation, these exogenous nitric oxide donors may be used to help lower the vascular resistance, thereby promoting ventricular unloading. Nitroprusside is the preferred agent for assessing reversibility of PH-LHD. For those patients who respond to this strategy, the intravenous agents are then transitioned to oral agents such as nitrates, hydralazine, or angiotensin-converting enzyme inhibitors . In patients with decompensated end-stage heart failure, these agents are used in conjunction with inotropes as a bridge to more definitive/ surgical procedures. Unfortunately, their use in these patients may be limited by systemic hypotension. In such cases, careful use of inhaled nitric oxide in the setting of hemodynamic monitoring in the ICU may be a suitable alternative . In fact, inhaled nitric oxide is being increasingly used in the perioperative period after a left ventricular assist device (LVAD) implant to manage acute right heart failure and pulmonary hypertension . Long-term use of inhaled nitric oxide is limited by short half-life, cost, and risk of rebound pulmonary hypertension upon discontinuation [25,33].
Phosphodiesterase type 3 inhibitors
Milrinone enhances cardiac contractility and causes direct vasodilation in both pulmonary and systemic vasculature by inhibiting phosphodiesterase (PDE) type 3, thereby enhancing intracellular cyclic adenosine monophosphate levels . The predominant effect is increased cardiac output with fall in filling pressures, although the impact on TPG is less impressive. It is commonly used in its intravenous form to support patients with end-stage heart failure in both acute and chronic settings . Oral forms of this therapy have shown disappointing results in terms of clinical efficacy and adverse events [36,37].
Phosphodiesterase type 5 inhibitors
In patients with pulmonary arterial hypertension (PAH), phosphodiesterase type 5 inhibitors (PDE5i) affect pulmonary vascular remodeling, reduce PVR, and improve functional capacity [38,39]. PDE-5 inhibitors may also decrease left ventricular afterload and can improve left ventricular diastolic function . As a result, from a physiological perspective, PDE5i have been an appealing therapy for patients with left-sided heart failure/PH-LHD, elevated PVR, or right ventricular dysfunction.
Sildenafil is perhaps the best studied PDE5i in PH-LHD, and a variety of single-center studies have shown hemodynamic and symptomatic benefits with sildenafil therapy in these patients. Guazzi et al. demonstrated that sildenafil was well tolerated in a cohort of stable chronic heart failure patients and was associated with decrease in pulmonary artery (PA) pressures and increase in peak VO2. These findings were supported by two studies by Lewis et al.[42,43], which demonstrated that sildenafil treatment resulted in significant improvements in exercise hemodynamics and gas exchange, and was also associated with improved quality of life and functional capacity in patients with systolic heart failure and pulmonary hypertension/right ventricular dysfunction. In patients with diastolic heart failure and severe secondary pulmonary hypertension, Guazzi et al. also demonstrated that long-term sildenafil therapy decreased wedge pressure, right atrial pressure, and PVR, and was associated with improved right ventricular function. However, in contrast to these results, the RELAX trial of sildenafil in patients with diastolic heart failure showed no benefit of sildenafil vs. placebo in improving peak VO2, though it should be noted that pulmonary hypertension/right ventricular dysfunction was not required for entry into RELAX trial .
With regards to the use of sildenafil specifically to lower TPG and PVR in chronic heart failure patients to facilitate their candidacy for transplant, a variety of small single-center studies have demonstrated that this is a feasible strategy in selected patients. The largest such study by De Santo et al. treated 31 patients with left ventricular systolic dysfunction and fixed pulmonary hypertension with sildenafil for 12 weeks, with decrease in TPG and PVR, such that all patients could be transplanted. These findings were replicated in other centers using treatment with sildenafil alone or in combination with other pulmonary vasodilators [47–50].
Endothelin receptor antagonists and prostanoids
Although earlier trials and anecdotal experience targeting PAH-approved therapies in PH-LHD showed promise, multiple randomized controlled trials have resulted in disappointing results with potentially serious drug-related adverse events (Table 1). The hemodynamic alterations caused by these agents did not effectively translate into clinical benefit [51,52]. Both selective (darusentan and sitaxentan) and nonselective (tezosentan and bosentan) agents showed similarly disappointing results [52–55]. Clinicians have also used low-dose prostanoids in patients with advanced heart failure as a bridge to transplant, but it should be done in selected patients under careful hemodynamic monitoring. It is to be noted that most of these studies did not stratify patients with LHD for the presence of pulmonary hypertension or have a predefined strategy for volume control. Therefore, like PDE-5 inhibitors, these agents should not be totally eliminated as potential agents till they have been studied in appropriate clinical trials in PH-LHD.
Riociguat is a novel soluble guanylate cyclase stimulator that sensitizes the receptors to endogenous nitric oxide and directly stimulates soluble guanylate cyclase independently of nitric oxide. In addition to its vasodilatory effects, it has additional antifibrotic, antiproliferative, and anti-inflammatory properties. In a multicenter, randomized, placebo-controlled trial in patients with pulmonary hypertension due to systolic heart failure, no effect on the primary endpoint (a change in mean PAP after 16 weeks) was observed at any dose of riociguat compared with placebo [56▪]. In patients with heart failure with preserved ejection fraction and pulmonary hypertension, it was well tolerated and improved hemodynamic parameters, but showed no significant effect on mean PAP . Another oral soluble guanylate cyclase inhibitor, Vericiguat, is undergoing a phase II clinical trial in patients with systolic and diastolic heart failure (ClinicalTrials.gov Identifier: NCT01951625)
In a subset of patients with advanced heart failure, PA pressures, and more importantly PVR and TPG, remain elevated despite intensive medical therapy with diuretics, vasodilators, and inotropic therapy. In addition, some of these patients will be intolerant to the pulmonary vasodilation therapies described above due to worsening left-heart congestion and pulmonary edema, especially those with significantly elevated left ventricular filling pressures at baseline. Alternatively, the reduction in PVR and TPG seen with pulmonary vasodilators may be insufficient to facilitate a patient's candidacy for heart transplant.
In these patients with fixed pulmonary hypertension, there is an increased risk of post-transplant mortality and right ventricular failure  such that consideration should instead be given to a trial of temporary or durable mechanical circulatory support to maximize left ventricular unloading, lower left atrial pressure, and in some cases allow time for pulmonary vascular remodeling.
The most commonly employed short-term mechanical circulatory support (MCS) device is an intra-aortic balloon pump (IABP). The IABP can improve coronary perfusion, lower left ventricular afterload, decrease mitral regurgitation, and provide a modest increase in cardiac output, all of which may impact PA pressures and PVR. However, in patients with nonischemic cardiomyopathy and minimal mitral regurgitation, the hemodynamics effects of the IABP are less pronounced. More substantial improvements in cardiac output and left ventricular filling pressures can be obtained by using temporary percutaneous MCS devices such as the Impella and Tandem Heart. These devices provide greater increases in cardiac output and lowering of left ventricular filling pressures vs. IABP [59,60]. Although there have been a variety of anecdotes regarding their use to effect lowering of PVR and TPG in patients with fixed pulmonary hypertension, they have not been well studied in this population. Moreover, these devices are typically employed for short-term MCS, and in many patients with fixed pulmonary hypertension, reduction of PVR and TPG requires a longer period of sustained left ventricular unloading.
Durable implantable LVAD therapies allow long-term sustained reductions in left heart filling pressures and increases in cardiac output. In the era of pulsatile LVADs, patients with fixed left heart-related pulmonary hypertension typically had normalization of PA pressures/PVR within 6 months of LVAD implant [9,61]. This has also been documented in patients treated with the newer generation of continuous-flow LVADs [62▪]. In patients with residual pulmonary hypertension early post-LVAD implantation, a single-center study with sildenafil revealed significant reduction in PA pressure and PVR, allowing eligibility for heart transplant. In addition, in some patients, LVAD implantation will allow adequate left ventricular unloading to allow treatment with pulmonary vasodilation therapy, which might not have been tolerated pre-LVAD .
The importance of a failing right ventricle (RV) in the setting of PH-LHD should be the subject of future studies. Correctly defining and refining how clinicians determine the relative proportions of pre and postcapillary pulmonary hypertension will be paramount in deciding whether downstream treatments, drug, or device, are appropriate for individual patients. It is critically important for clinical trialists to redesign existing protocols profiling PAH-specific therapies in LHD to include patients with pulmonary hypertension and make use of suitable algorithms to maintain euvolemia. Not till then can we effectively judge whether these potentially useful medications are appropriate for use in WHO group 2 pulmonary hypertension patients waiting for transplant. Until then, clinicians should exercise utmost caution before using these medications in clinical practice. The incorporation of durable LVAD use in the context of treating PH-LHD with or without combined use of PAH-specific therapies should be further explored and studied as a viable option to maximize listing potential for selected candidates.
Pulmonary hypertension-left heart disease is the most common form of pulmonary hypertension encountered in clinical practice, especially given the rising epidemic of left heart failure. It is challenging to determine the reversibility of pulmonary hypertension in these patients, especially in those who have pulmonary hypertension out of proportion to their left-sided filling pressures. Given its association with worse prognosis, it affects the eligibility for heart transplant in patients with end-stage heart failure. The optimal therapeutic options, both medical and device-based, remain a subject of ongoing quest for future studies.
Disclosure: No funding relevant to this manuscript.
Financial support and sponsorship
Not relevant to this article.
Conflicts of interest
All authors receive institutional research grants from Thoratec Inc, Pleasanton, CA, Bayer Pharmaceuticals, United Therapeutics, Gilead Sciences and Actelion Pharmaceuticals.
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