Pulmonary hypertension (PH) due to left heart disease (LHD) represents the most common cause of PH, and is associated with higher morbidity and mortality compared with LHD without PH.1 PH due to LHD is subcategorized into four distinct groups: 1) PH due to heart failure with reduced ejection fraction (HFrEF); 2) PH due to heart failure with preserved ejection fraction (HFpEF); 3) PH secondary to valvular heart disease; or 4) PH due to left heart inflow or outflow tract obstruction and congenital cardiomyopathies. The presence of PH secondary to LHD influences the medical and surgical management of advanced systolic heart failure, particularly in patients who develop refractory disease.2 Pulmonary hypertension is an important consideration when assessing candidacy for orthotopic heart transplantation (OHT). Severe PH (defined as pulmonary vascular resistance [PVR] > 5 wood units [WU] or transpulmonary pressure gradient [TPG] > 16–20 mm Hg) is considered a contraindication for transplantation.3,4 More recently, the increased use of mechanical circulatory support (MCS) has impacted clinical decision making with regard to the treatment of patients with refractory PH due to LHD. Many questions remain, including whether treatment of PH before MCS implantation is beneficial, when to reassess hemodynamics after implantation, and whether adjunctive therapy should be used in patients whose pulmonary pressures fail to normalize. Although patients with LHD may have other contributing factors such as chronic pulmonary embolism, hypoxia due to sleep apnea, chronic obstructive lung disease, or interstitial lung disease that could worsen PH, for the purposes of review, we focused solely on PH due to LHD. Furthermore, as advanced therapies for HF (i.e., MCS and OHT) are usually reserved for patients with HFrEF, our review highlights the characteristics of PH due to HFrEF, and addresses important clinical issues surrounding the treatment of these patients.1
Pulmonary Hypertension in Left Heart Disease
The hemodynamic parameters that define PH due to LHD are not uniform in practice or in the published literature.5 Generally, a resting mean pulmonary arterial pressure (mPAP) ≥ 25 mm Hg associated with left-ventricular dysfunction or other forms of LHD has been used to define PH due to LHD (Figure 1).6,7 Terms such as postcapillary PH (pulmonary venous hypertension, pulmonary capillary wedge pressure [PCWP] > 15 mm Hg), precapillary PH (pulmonary arterial hypertension, PCWP ≤ 15 mm Hg), or “out-of-proportion” PH have been used to better characterize and describe the pathophysiology of PH due to LHD.8 Historically, there were no clear hemodynamic parameters that defined out-of-proportion PH, although it is assumed that PH develops out-of-proportion to the elevated PCWP due to vascular remodeling.7,9,10
Vachiery et al.9 suggest a simple way to reconsider PH due to LHD: 1) an elevated PCWP, but no significant change in pulmonary circulation (i.e., no vascular remodeling); 2) an elevated PCWP with vascular remodeling; 3) a previously elevated but currently normal PCWP, with persistence of vascular remodeling. A key issue is, therefore, the degree of vascular remodeling that occurs due to this passive congestion, which secondarily results in a compensatory increase in right ventricular and systolic PA pressure. Thus, a challenge for Vachiery et al.’s9 approach to PH due to LHD is how to best describe pulmonary vascular remodeling without biopsy or imaging. They posited that an elevated diastolic pressure gradient (DPG)—diastolic PAP minus PCWP—may capture the passive nature of this remodeling process. Recent European Society of Cardiology/European Respiratory Society guidelines defined “out-of-proportion” PH as DPG > 7 mm Hg.8
Despite attempts to quantify the degree of remodeling using hemodynamic variables, the actual pathophysiologic processes leading to PH is not well-understood. The early stage of PH due to LHD is thought to be characterized by venous remodeling from pulmonary venous hypertension. An increase in pulmonary venous pressure results in reactive mechanical changes, which can trigger additional remodeling such as decreased nitric oxide availability, increased endothelin-1 expression, desensitization to natriuretic peptide-induced vasodilation, and arterial remodeling (Figure 2).11–13 Therefore, as the disease state progresses, pathophysiologic features of pulmonary arterial hypertension develop. Although data validating this process in humans is limited, preclinical models have demonstrated that such remodeling may be reversible.14,15
Medical Management of Left Heart Disease-Associated Pulmonary Hypertension
Although there are no Food and Drug Administration approved medications to treat PH due to LHD, pharmacotherapy for the treatment of PH has targeted two pathophysiologic mechanisms: 1) vasodilators for reversal of pulmonary arterial hypertension in the presence of a significant precapillary component; and 2) decongestion and left-ventricular unloading for reduction of pulmonary venous hypertension. One limitation of pulmonary artery vasodilation in patients with elevated left-sided filling pressures is the risk of increasing blood flow into a high-pressure vascular bed resulting in pulmonary edema and increased ventilation-perfusion mismatch.16 Vasodilators—nitroprusside and inhaled nitric oxide—may maintain benefit by reducing pulmonary pressures. However, other direct pulmonary vasodilators (e.g., prostaglandins and ET antagonists) have shown to be detrimental in patients with HF (Table 1).17–20 The Safety and Tolerability of Macitentan in Subjects with Combined Pre and Postcapillary Pulmonary Hypertension due to Left Ventricular Dysfunction (MELODY-1) trial aims to assess the effect of macitentan—an endothelin receptor antagonist (ERA) indicated for pulmonary arterial hypertension—on PH due to HFrEF and HFpEF; this Phase 2 trial will further elucidate the role of ERAs in PH due to LHD.21
Targeting the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate pathway is a potential therapeutic target for worsening HFrEF and PH. The left-ventricular systolic dysfunction associated with Pulmonary Hypertension Riociguat Trial (LEPHT) assessed the effect of riociguat on hemodynamics in patients with PH caused by systolic left-ventricular dysfunction (defined as ejection fraction ≤ 40%). Riociguat is a novel soluble guanylate cyclase stimulator with a dual mechanism of action: 1) it sensitizes guanylate cyclase to endogenous nitric oxide and 2) it directly stimulates guanylate cyclase independent of nitric oxide. In this randomized, double-blind, placebo-controlled study, mPAP did not significantly vary between the placebo and treatment arms; however, riociguat was well-tolerated, and improved cardiac index and pulmonary and systemic vascular resistance.24 Other soluble guanylate cyclase stimulators, such as vericuguat, are also being studied in patients with worsening HFrEF.25 Further clinical trials of novel soluble guanylate cycle stimulators are needed to determine the potential role of these drugs in patients with HFrEF.
Phosphodiesterase type 5 inhibitors that modulate endogenous nitric oxide production have shown promise in patients with HFrEF. An observational study of sildenafil in HFrEF patients with PH showed improvement in exercise capacity, quality of life, and rehospitalization. Clinical status and hemodynamic parameters, including PVR and cardiac output, improved as well.22 A long-term randomized placebo-controlled study of 46 patients supported these findings, showing an improvement in peak oxygen consumption from 14.8 ± 1.5 to 18.7 ± 1.7 ml/min/kg (p < 0.01) over 6 months in the treatment group, whereas the placebo group showed no improvement.23 Of note, sildenafil therapy in the HFpEF population did not result in significant improvement of exercise capacity or clinical status.26 The Food and Drug Administration has approved sildenafil for the treatment of pulmonary arterial hypertension, but not for the treatment of PH due to LHD; thus, larger, event-driven studies in a carefully selected patient population are needed to further understand the role of sildenafil in treating PH due to LHD.
Pulmonary Hypertension and Heart Transplantation
Pulmonary hypertension is a contraindication to OHT because of increased risk of early graft dysfunction from RV failure and all-cause mortality.4 An assessment of PH reversibility is an important component when evaluating the HFrEF patient who is being considered for OHT. A study from Stanford University demonstrated how two essential aspects of reversibility should be assessed. First, PVR must decrease to < 2.5 WU with the use of IV nitroprusside. Second, systolic blood pressure should remain > 85 mm Hg in response to nitroprusside therapy. This study showed that in 293 OHT candidates who were tolerant of nitroprusside, those with a PVR > 2.5 WU had a 3 month posttransplant mortality rate of 17.9% versus 6.9% (p < 0.02) in patients with a PVR ≤ 2.5 WU. The 3 month mortality after transplant in patients tolerant of nitroprusside was only 3.8%, compared with 40.6% in those who did not respond to nitroprusside, and 27.5% in those who responded, but experienced a drop in systolic blood pressure < 85 mm Hg.27 Of note, most studies consider nitroprusside to be the standard to test for PH reversibility in OHT candidates; however, vasodilators such as inhaled nitric oxide and inhaled prostacyclins have also been shown to be effective for demonstrating vascular reactivity in OHT candidates, but with minimal systemic hypotension given their selectivity for pulmonary vasculature.28–30
Inotropic therapy is an additional strategy to reducing pulmonary pressures before transplant or MCS. Pulmonary pressure monitoring and tailored medical therapy can be important for reducing PVR before transplant, particularly if pulmonary pressure monitoring allows for optimization of diuresis and inotropic therapy to meet hemodynamic goals.31–33 Short-term studies with milrinone have suggested that the decrease in PVR is primarily due to the acute increase in cardiac output.34 However, in patients with prohibitively high pulmonary pressures, long-term milrinone therapy may provide gradual normalization of PVR. Older studies that predate the use of modern heart failure therapies (such as implantable cardioverter defibrillator, cardiac resynchronization therapy, or aldosterone antagonist) suggest that this strategy is limited by the typically steep decline in survival among patients who are initiated on chronic inotropic support.35 A recent study evaluated outcomes of long-term inotropes in patients with HFrEF, and found that of the 60 patients who were placed on inotropes as a bridge to transplant or left-ventricular assist device (LVAD), 55 were successfully maintained on inotropes until transplant or LVAD. Survival on inotropes for patients who were not candidates for transplant or LVAD was found to be better than previously reported, but remained poor.36
Pulmonary Hypertension and Left Ventricular Assist Devices
If PH due to LHD is refractory to medical intervention, then treatment with LVAD therapy may provide an alternative strategy. For patients who meet LVAD implantation criteria, several studies have demonstrated that LVAD therapy can effectively reduce left-sided filling pressures and lead to PH improvement.37–41 The goals of lowering PA pressure with LVAD are twofold: 1) to prevent late RV dysfunction; and 2) to optimize PA pressures and permit successful OHT in patients who initially have preclusive PH. The reversal of PH with LVAD therapy was first demonstrated with pulsatile-flow LVADs.35,37,40 However, continuous-flow LVADs are now considered standard of care, and recent studies have demonstrated that continuous-flow LVADs are as effective as pulsatile devices for reversing PH (Table 2).37–39,41–45
More specifically, in a prospective 6 week study, 35 patients with severe HF and a PVR > 3.5 (despite pharmacotherapy challenge with inhaled nitric oxide, nitroglycerin, and prostaglandin I2) underwent support with Novacor, Micromed DeBakey, and DuraHeart LVADs. The average mPAP was 44 ± 6.2 mm Hg before LVAD implantation with a PVR of 5.1 ± 2.6 WU. Within 3 days of LVAD implantation, the PVR fell significantly to 2.9 ± 1.3 WU (p < 0.0001). After 6 weeks of support, the mPAP was reduced to 18.4 ± 4.3 mm Hg and PVR to 3.0 ± 0.8 WU.40 In a study of 43 patients who received the Heartmate XVE (pulsatile flow) and 34 patients who received the HeartMate II (continuous flow), there were significant reductions in mPAP as early as 1 month after implantation in the HeartMate II group.44
An observational study of 21 patients supported with HeartMate II LVAD therapy reviewed echocardiograms before LVAD implantation, as well as at 1 month and 6 months post-LVAD implantation.46 Here, PVR was derived from maximum tricuspid regurgitation velocity and right ventricular outflow tract velocity-time integral. At 1 month post-LVAD implantation, tricuspid regurgitation velocity decreased from 3.07 ± 0.44 m/s to 2.45 ± 0.34 m/s (p < 0.001) and PVR decreased from 3.51 ± 0.9 WU to 2.0 ± 0.5 WU (p < 0.001). Furthermore, a retrospective study identified 27 patients with fixed PH (defined as mPAP > 25 mm Hg, PVR > 2.5 WU, TPG > 12 mm Hg despite pharmacologic therapy) who received a continuous-flow LVAD. These 27 patients were divided into three groups on the basis of examination time during LVAD support. After LVAD implantation, mPAP fell from 37.26 ± 6.35 mm Hg to 21.00 ± 7.51 mm Hg (p = 0.007), PVR fell from 3.49 ± 1.47 WU to 1.53 ± 0.66 WU (p = 0.000), and TPG fell from 15.04 ± 5.22 mm Hg to 7.78 ± 3.21 mm Hg. This study also suggested that improvement in hemodynamic parameters occurred in the first 6 months post-LVAD implantation, with minimal improvement in pulmonary pressures after that time period.47 Similarly, a study of 29 patients with HFrEF and PH who were implanted with a continuous-flow LVAD observed significant reductions in mPAP, TPG, and PVR within 1 month post-LVAD implantation, reaching a nadir by 3 months.48
The ability of LVAD therapy to improve PH has proven useful in patients who are bridged to successful OHT. In a case series of six patients with end-stage heart failure and irreversible PH, all patients were successfully bridged to transplantation after LVAD implantation due to a reduction in pulmonary pressures. After LVAD implantation, PVR had fallen from 5.7 ± 0.7 WU to 2.0 ± 1.2 WU.49 In another study of 17 patients who received LVAD, six patients with PH were initially not considered suitable OHT candidates. With LVAD support, mPAP and PVR decreased, and four patients were successfully transplanted without major postoperative difficulties.43 A larger study of 54 patients who received an LVAD as bridge-to-transplant compared posttransplant outcomes between 22 patients with fixed PH before LVAD implantation (defined as PVR > 3 WU and resistant to vasodilators) and 32 patients who did not have fixed PH before LVAD implantation. Findings from this study demonstrated that pulmonary pressures were comparable between the two groups immediately pretransplant and during the first year posttransplant. The incidence of posttransplant RV failure and posttransplant survival was similar between groups.50
Although LVAD support is associated with a reduction in mPAP and PVR over weeks to months, and thus plays a crucial role as a bridge-to-transplant, a subset of patients may not respond to device therapy alone. In this patient population, additional pharmacotherapy may be needed for PH that persists after LVAD implantation. Tedford et al.51 studied 138 consecutive patients undergoing LVAD therapy with a PVR > 3 WU, and found that 58 patients had persistent elevation of PVR 1–2 weeks after LVAD implantation. Sixteen patients received sildenafil and 32 patients served as nonrandomized controls. At 12–15 weeks after LVAD placement, the sildenafil-treated patients exhibited a reduction in mPAP from 36.5 ± 8.6 mm Hg to 24.3 ± 3.6 mm Hg (p < 0.001) and experienced improvement in RV function. In contrast, the LVAD control patients did not have a statistically significant reduction in pulmonary pressures during the same time period, although there was a trend toward improvement. Thus, in patients who do not respond to LVAD therapy alone or do not respond rapidly, there could be benefit from adjuvant sildenafil therapy. The ability to lower pulmonary pressures in a shorter time frame allows for the potential of earlier transplantation.
The International Society of Heart and Lung Transplantation (ISHLT) guidelines for MCS recommend considering phosphodiesterase type 5 inhibitors for patients with persistent PH and RV dysfunction after LVAD implantation.52 ISHLT guidelines for heart transplant listing criteria suggest that adjuvant therapy post-LVAD implantation with phosphodiesterase type 5 inhibitors may be utilized.3 However, for the subset of patients that do not respond to LVAD therapy, there is no established hemodynamic definition or length of time after which one can describe persistent PH after LVAD implantation; therefore, each patient’s hemodynamic status post-LVAD implantation must be assessed on an individual basis. Concomitant use of phosphodiesterase type 5 inhibitors to help RV function in the setting of LVAD is increasingly being used in some centers. Further investigation of phosphodiesterase type 5 inhibitors for patients with persistent PH after LVAD implantation is necessary in the form of randomized controlled trials.
Risk Assessment and Re-Evaluation
Efforts to refine patient risk assessment and selection for LVAD therapy continue to be of interest. Preoperative hemodynamic variables, when combined with other variables into multivariable risk models can assess predictors of death after LVAD implantation. Preoperative risk stratification includes previously available scores, as well as novel scoring systems, to describe postoperative risk of RV failure, yet no model has specifically assessed the response of PH to chronic MCS or defined nonresponders. Such data would be informative with regard to decision making for transplantation or risk of late RV failure from elevated RV afterload.
Further investigation is also required to determine the frequency and best method for reassessing PH after MCS. Current ISHLT guidelines recommend revaluation of hemodynamics should be done 3–6 months after LVAD implantation to determine reversibility of PH.3 Furthermore, right heart catheterization is considered definitive for reassessment of PH; however, the Wireless Pulmonary Artery Hemodynamic Monitoring in Chronic Heart Failure (CHAMPION) trial demonstrated that in patients with HFrEF and HFpEF incorporating data from a wireless implantable hemodynamic monitor allowed for further optimization of patients’ medical management leading to fewer heart failure hospitalizations, decreased PAP, and improved quality of life.53 Thus, implantable hemodynamic monitoring may play a role in monitoring PH after LVAD implantation.
In addition, there may be an emerging role for noninvasive monitoring. The primary imaging modality to monitor patients with LVADs is echocardiography, which can determine ventricular size, function, and intracardiac hemodynamics.46 However, right ventricular assessment by echocardiography is subjective and can be limited by poor ultrasound windows in LVAD patients leading to inaccuracies and imprecision. As a result, additional studies will be required to determine the role of echocardiography in following PH and influencing clinical decisions after LVAD implantation.
Conclusions and Looking Forward
Pulmonary hypertension due to LHD is the most common form of PH. In many patients, the degree of PH is out of proportion to elevated left-sided filling pressures, as a result of both pulmonary venous hypertension and pulmonary arterial hypertension pathophysiology. An important step to the future study of this clinical problem will be to standardize definitions across disciplines to facilitate an evidence base that is interpretable across all clinical practice settings.
Pulmonary hypertension precludes heart transplantation in those with end-stage heart failure; thus LVADs will come to play a greater role as a strategy to improve pulmonary pressures before transplantation. Studies have demonstrated that LVADs can improve pulmonary pressures as early as 1 month. However, it may take up to 3–6 months to achieve maximum reversibility. Although recent guidelines suggest that re-evaluation of hemodynamics with right heart catheterization should be done 3–6 months after LVAD implantation, current indications for LVADs and the frequency and modality of monitoring PH after LVAD require ongoing investigation. Further discussion should also include utilizing pharmacologic therapy to target PH after LVAD implantation, as phosphodiesterase type 5 inhibitors may come to play an important role for expediting PH reversal for those who require transplantation sooner or for those who do not respond to device therapy alone. This will require a commitment to innovative clinical trial design incorporating active control subjects and registry data, as well as carefully selected outcomes that incorporate hemodynamics, functional status, and adverse events. Finally, improvements in device technology will certainly play an important role.
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