The evolving role of interventional cardiology in the treatment of pulmonary hypertension

Abstract

Pulmonary hypertension (PH) is a heterogeneous group of diseases defined by a mean pulmonary arterial pressure greater than 20 mmHg. Clinically, PH is classified into five groups and the group of PH generally defines the cause of PH and the therapeutic options. Currently, medical therapies that target the prostacyclin, endothelin, and nitric oxide pathways are used in pulmonary arterial hypertension and chronic thromboembolic PH (CTEPH) patients. Moreover, surgery can improve outcomes in PH as pulmonary thromboendarterectomy can be curative for CTEPH and lung transplantation is used for end-stage PH. Despite these diverse treatment options, PH patients continue to have high symptom burden and poor long-term outcomes. However, advances in percutaneous technology are opening new avenues for the management of PH. In this review, we discuss the available data supporting the use of four interventional procedures: balloon atrial septostomy, transcatheter Potts shunt, balloon pulmonary angioplasty, and pulmonary artery denervation for the treatment of PH. These procedures provide hemodynamic and functional improvements in PH patients, but they come with their own unique risk profiles. Hopefully, these procedures will continue to be refined and thereby provide a venue for interventional cardiology to safely and effectively improve outcomes for PH moving forward.

Pulmonary hypertension (PH) is defined as a mean pulmonary arterial pressure (mPAP) of >20 mmHg.¹ As a disease entity, PH is classified into five groups based on underlying pathophysiology as outlined by the sixth World Symposium on Pulmonary Hypertension (Table 1). Group 1 is pulmonary arterial hypertension (PAH), with the pathology localized in the precapillary vessels¹ and is characterized by mPAP >20 mmHg, pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) <15 mmHg, and pulmonary vascular resistance (PVR) >3 Wood units.¹ PAH is the best studied type of PH and has the most available treatment options.² Group 2 PH is due to left-sided heart disease, which includes both systolic and diastolic dysfunction and valvular disease,¹ and it is the most common type of PH encountered in the clinical arena³ and is distinguished from Group 1 PAH by PCWP or LVEDP >15 mmHg. Group 3 PH is due to chronic lung disease and/or hypoxia,¹ and these patients carry the worst prognosis of all PH types.⁴ Group 4 PH is due to chronic thromboembolic disease, and Group 5 PH is defined as multifactorial or unclear causes.¹ PH is a debilitating and lethal condition, and unfortunately the long-term prognosis remains quite poor. Registry data from expert centers show the median survival for PH is as low as 2.5 years in Group 3 PH⁵ and 5–7 years in PAH.^2,4

TABLE 1.

Classification of PH (Adopted from Simonneau et al¹)

1. PAH: mPAP >20 mmHg, PCWP <15 mmHg, PVR >3.0 wood units

1.1 Idiopathic PAH

1.2 Heritable PAH

1.3 Drug- and toxin-induced PAH

1.4 PAH associated with:

1.4.1 Connective tissue disease

1.4.2 HIV infection

1.4.3 Portal hypertension

1.4.4 Congenital heart disease

1.4.5 Schistosomiasis

1.5 PAH long-term responders to calcium channel blockers

1.6 PAH with overt features of venous/capillaries (PVOD/PCH) involvement

1.7 Persistent PH of the newborn syndrome

2. PH due to left heart disease: mPAP >20 mmHg, PCWP >15 mmHg

2.1 PH due to heart failure with preserved LVEF

2.2 PH due to heart failure with reduced LVEF

2.3 Valvular heart disease

2.4 Congenital/acquired cardiovascular conditions leading to post-capillary PH

3. PH due to lung diseases and/or hypoxia: mPAP >20 mmHg

3.1 Obstructive lung disease

3.2 Restrictive lung disease

3.3 Other lung disease with mixed restrictive/obstructive pattern

3.4 Hypoxia without lung disease

3.5 Developmental lung disorders

4. PH due to pulmonary artery obstructions: mPAP >20 mmHg

4.1 Chronic thromboembolic PH

4.2 Other pulmonary artery obstructions

5. PH with unclear and/or multifactorial mechanisms: mPAP >20 mmHg

5.1 Hematological disorders

5.2 Systemic and metabolic disorders

5.3 Others

5.4 Complex congenital heart disease

Abbreviations: LVEF, Left ventricular ejection fraction; mPAP, mean pulmonary arterial pressure; PAH, pulmonary arterial hypertension; PCH, pulmonary capillary hemangiomatosis; PCWP, pulmonary capillary wedge pressure; PH, pulmonary hypertension; PVOD, pulmonary veno-occlusive disease; PVR, pulmonary vascular resistance.

Currently, treatment in PH is dominated by either medical therapy or surgery (Figure 1). Pulmonary vasodilators that modulate the prostacyclin, endothelin, and nitric oxide pathways are the approved medical therapies² for PAH; meanwhile only medications targeting nitric oxide pathways, specifically riociguat,⁶ are approved for treatment of chronic thromboembolic PH (CTEPH). However, surveys of expert PH centers around the world show multiple pulmonary vasodilators are used in CTEPH patients.^7,8 Moreover, Phase II and III clinical trials demonstrate the endothelin receptor antagonist macitentan⁹ and treprostinil infusions¹⁰ augment exercise capacity and improve hemodynamics in CTEPH. Surgical approaches offer another invaluable tool for PH management as pulmonary thromboendarterectomy (PTE) can be curative in CTEPH,¹¹ and lung transplantation is used for end-stage PH patients.¹² However, medical therapy has not clearly improved survival in PAH and CTEPH,² and as many as 35–40% of CTEPH patients are deemed inoperable or have persistent PH after PTE.¹³ Furthermore, lung transplantation is limited by donor availability, and even after transplantation median survival ranges from 7 to 10 years.¹⁴ Thus, new treatment options are needed to improve quality of life and increase long-term survival in PH.

FIGURE 1.

Current treatment options for pulmonary hypertension. Medical therapy targeting the prostacyclin, endothelin, and nitric oxide pathways for Group 1 and 4 pulmonary hypertension (PH). Lung transplantation can be used in end-stage PH, and pulmonary thromboendarterectomy is the standard of care treatment for Group 4 PH

The vast advances in percutaneous technology used in interventional cardiology are now being harnessed to treat PH. Thus far the results are promising, albeit with limited numbers and the accompanied risks associated with invasive procedures. In this review, we highlight the evolving role of interventional cardiology in PH treatment by discussing the data supporting balloon atrial septostomy (BAS), transcatheter Potts shunt (TPS), balloon pulmonary angioplasty (BPA), and percutaneous pulmonary artery denervation (PADN) (Figure 2).

FIGURE 2.

Evolving percutaneous treatments for pulmonary hypertension (PH) include balloon atrial septostomy, transcatheter Potts shunt, balloon pulmonary angioplasty, and pulmonary artery denervation

1 |. BALLOON ATRIAL SEPTOSTOMY

BAS involves femoral venous vascular access followed by transcatheter delivery of a septal crossing apparatus. Transseptal puncture is performed under a mixed fluoroscopic and echocardiographic guidance (either transesophageal or intracardiac), and then a wire is advanced into the left superior pulmonary vein and a catheter is advanced into the left atrium. Graded balloon inflation is then performed until one of the following parameters is reached: LVEDP >18 mmHg, arterial oxygen saturation (SaO₂) <80% and/or a decrease of 10%, or the largest balloon (16 mm) is used.^15,16

BAS is the oldest interventional procedure for treatment of PH. BAS was first pioneered as a palliation procedure or procedure of last resort in rapidly decompensating patients. The first case of blade-BAS, a variant of BAS, was pioneered by Rich and Lam in 1983.¹⁷ They noted immediate hemodynamic improvements with a reduction in right atrial pressure (RAP) and improvement in cardiac index (CI). Unfortunately, due to unrecognized risk factors, the patient developed pulmonary edema and severe hypoxemia and quickly deteriorated. Future work identified these risk factors for mortality in BAS which included RAP >20 mmHg and SaO₂ <90%. Presence of baseline elevated RAP and hypoxemia carry a high probability of dramatic elevation of left atrial pressures leading to pulmonary edema and hypoxemia.¹⁸

Since that first case report by Rich and Lam, observational and retrospective studies have shown BAS enhances hemodynamics and functional status.¹⁹ There are clear physiologic mechanisms that underlie improved outcomes with BAS. Right ventricular failure due to PH reduces left ventricular preload and subsequent cardiac output, ultimately leading to cardiogenic shock and hemodynamic collapse.² BAS halts this vicious cycle by creating a right to left interatrial shunt, which increases left ventricular preload and cardiac output while simultaneously decreasing right ventricular preload, thereby reducing wall tension and stress. The immediate tradeoff is hypoxemia related to right to left interatrial shunting. However, this is largely negated by augmented cardiac output coupled with an elevation in hemoglobin leading to an overall improvement in end-organ oxygen delivery.²⁰

There have been no randomized controlled trials that demonstrated a benefit for BAS in PH patients. Nevertheless, a plethora of case reports, series, and observational cohorts demonstrated efficacy and safety. The graded BAS protocol described above showed immediate benefit in a series of 15 functional Class III or IV PAH patients as it reduced RV end diastolic pressure (15.5 ± 7–11 ± 7 mmHg, p < .05) and improved CI (2.2 ± 0.4 −3.0 ± 0.8 L min⁻¹ m⁻², p < .05) immediately and increased 6-minute walk distance (6MWD) (107 ± 127–217 ± 108 m, p < .001) within two-four weeks of the procedure.¹⁶ The favorable changes in exercise capacity and hemodynamics have been replicated in numerous studies.^21–25 A recent meta-analysis of 204 patients from 16 studies revealed BAS significantly reduced RAP (2.8 mmHg [95% confidence interval: 2.0–3.5 mmHg], p < .001) and increased CI (0.6 L/min/m² [95% confidence interval: 0.5–0.8 L min⁻¹ m⁻²], p < .001).¹⁹ Contemporary periprocedural complications were low, likely due to increased comfort with transseptal puncture and patient selection, but the most common procedural complication was hypoxemia, which occurred in 3% of the patients.¹⁹ The pooled incidence of mortality related to the procedure (within 48 hr) was 4.8% while short-term (≤30 days) and long-term (>30 days) mortality rates were 14.6 and 37.7%, respectively.¹⁹

Despite promising results in observation cohorts and case series, BAS has numerous obstacles to overcome. As described above, elevated RA pressure and hypoxemia are associated with periprocedural mortality. Aside from systemic hypoxemia, intracardiac shunting also increases the risk of systemic paradoxical thromboembolism.²⁶ Another obstacle is the high frequency of spontaneous closure, which occurs in as many as quarter of the BAS population¹⁹ and as high as 50% in other iatrogenic atrial septal defects.²⁷ The high closure rate implies effects of BAS could be attenuated over time and repeat intervention may be required. Therefore, the current indication for BAS is for bridge to transplant or palliative approaches for end-stage PAH patients. BAS has not been investigated in other PH subgroups.

2 |. TRANSCATHETER POTTS SHUNT

Both BAS and TPS were developed based on the observational data of improved outcomes in the Eisenmenger population, where the presence of either an atrial septal defect or persistent patent ductus arteriosus improves long-term survival.^28,29 The origin of the procedure dates back to 1946 when Dr. Potts performed a direct anastomosis between the left pulmonary artery (LPA) and the descending aorta (DA) in congenital cyanotic heart disease. More recently, Potts shunt physiology was pioneered as a transcatheter approach in both adult and pediatric PH patients with suprasystemic PH. This is likely a result of the expanding structural field in interventional cardiology in the last decade.

TPS is performed by obtaining both arterial and venous access using a transfemoral approach. A needle or radiofrequency puncture is performed in the DA at the level of the LPA under fluoroscopic guidance and then a 0.014 wire is snared into the LPA and externalized via the venous sheath. Then, with the use of either a dilator or balloon-assisted tracking, the DA sheath is advanced into the LPA and a covered stent is delivered and post dilated with angioplasty balloon as needed until the gradient across the shunt is <10 mmHg. Final imaging and repeat post procedure imaging is essential to evaluate for periprocedural thoracic bleeding.

There are theoretical advantages of TPS over BAS. Unlike intracardiac shunts, TPS avoids the risk of cerebrovascular and myocardial ischemia and dramatic systemic hypoxemia. Furthermore, placement of a covered stent minimizes the chance of spontaneous closure of the shunt. Despite no change in the preload on the RV, the afterload reduction associated with TPS effectively reduces the mean pulmonary pressure to that of the systemic pressure and thereby drops right ventricular wall stress. These theoretical advantages result in patient benefits as successful TPS resulted in minimal mediastinal hemorrhage, improved hemodynamics, no systemic hypoxemia, and augmented exercise capacity in three end-stage PAH patients.³⁰ A similar pattern was observed in four pediatric PH patients, and impressively there was discontinuation of intravenous vasodilators in three of the four patients.³¹

The rate of complications in TPS is high and frequently disastrous. In the Esch et al³⁰ case series, one of the procedures was complicated when the delivery sheath was pulled back into the DA and although access was re-established, the interim hematoma irreparably increased the DA-LPA distance beyond the size of the covered stent. This resulted in intrathoracic hemorrhage and death. In another series of six pediatric patients with severe PH, two patients developed cardiogenic shock with cardiac arrest within 30 min of the procedure.³¹ It was noted, however, that the two patients immediately decompensated upon induction of anesthesia, which complicated the course of the procedure; with one patient requiring CPR immediately upon induction.³¹ Therefore, patient selection and anatomy-focused pre-procedure planning with a minimalistic approach that avoids general sedation is crucial for procedural success. Hopefully, dedicated devices and greater comfort with alternative techniques, such as those used in transcaval approach to transcatheter aortic valve replacement,³² will increase future procedure success and reduce periprocedural complications.

TPS has not been widely implanted, likely due to the complication rates. However, it could provide hemodynamic benefit for PH patients that still have suprasystemic PA pressures after medical therapy. TPS would be limited to patients without transplant options.

3 |. BALLOON PULMONARY ANGIOPLASTY

BPA is a percutaneous treatment that targets obstructive lesions in CTEPH.³³ BPA requires either femoral or jugular venous access then directing catheters and undersized balloons guided over wires are used for angioplasty of the intra-arterial web and ring lesions in the pulmonary arteries to relieve obstruction and improve distal flow.³³ BPA generally requires multiple sessions and at each successive session balloon sizes and inflation pressures can be increased to achieve optimal results.³⁴ Balloon size ranges from 2.0 to 8.0 mm with inflation pressures ranging from 2 to 22 atm during angioplasty.^34,35

BPA may be the most established interventional procedure in PH treatment, but this procedure is still relatively young. The first report of BPA in CTEPH was published in 1988,³⁶ but it wasn’t until 2001 when the first series of BPA from a single center were described when Feinstein et al, analyzed the effects of BPA in 18 consecutive patients.³⁷ Although there were hemodynamic benefits, the complication rate was high as 11/18 patients had reperfusion edema and the mortality rate was 5.5% at 30 days.³⁷ More contemporary reports, which were predominately led by groups out of Japan, showed BPA is effective even in patients on pulmonary vasodilator therapy with more acceptable complication rates.^38–40 Advances in technology and approach including limits on the number of vessels angioplastied per procedure,⁴¹ size of balloons,³³ lesion characterization (subtotal lesions: 15.5%, ring-like: <3%, web lesions<3%, and torutous 43.2% complication rates),³⁵ and use of pressure wires to guide therapy³⁴ have made BPA an effective and safe option for CTEPH. However, BPA still has important complications including hemoptysis, reperfusion edema, wire injury, vessel rupture, and even death.³³ A multicenter registry from Japan revealed the rates of mechanical ventilation of 5.5% and a 30-day mortality of 2.6% in BPA patients.⁴²

Studies in BPA have largely been single-centered in nature, but they have demonstrated positive functional and hemodynamic effects.³³ Importantly, the hemodynamic effects of BPA are long-lived as follow-up of >3.5 years showed the benefits were maintained.⁴³ Moreover, there are suggestions that BPA can improve survival as Aoki et al, showed a 98% survival at 5 years in 77 BPA patients, which was significantly (p < .01) better than a historical control group treated with only medical therapy, who had a 77.5% survival over the same time frame.⁴⁴ Consistent with this finding, the hemodynamic effects of BPA seem to be greater than that of medical therapy, and most of the BPA studies were conducted with patients already receiving medical therapy.^33,44 We recently performed a meta-analysis that compared the effects of BPA in 755 patients and medical therapy in 849 patients. BPA was superior to medical therapy as the reduction in mPAP (BPA: 14.8 mmHg [95% confidence interval: 11.5–18.2 mmHg] vs. medical therapy: 4.9 mmHg [95% confidence interval: 2.8–6.9 mmHg]) and PVR (BPA: 3.1 Wood units [95% confidence interval: 1.4–4.9 Wood units] vs. medical therapy: 1.6 Wood units [95% confidence interval: 0.8–2.4 Wood units]) and improvements in 6MWD were greater (BPA: 71.0 m [95% confidence interval: 47.4–94.5 m] vs. medical therapy: 47.8 m [95% confidence interval: 34.5–61.2 m]).⁴⁵ However, it is important to note that this was not a direct head-to-head comparison in matched patients. That question was answered by the Riociguat versus BPA in non-operable CTEPH (RACE) trial. RACE directly compared the efficacy of BPA to the soluble guanylate cyclase activator riociguat in 105 patients. Although the full manuscript has not been published, the results of the study were presented at the European Respiratory Society meeting.⁴⁶ BPA was superior to riociguat medical therapy with regards to the primary end point, which was change in PVR (60 vs. 32% reduction in PVR, p < .0001). However, it was at the expense of increased adverse effects (50% of BPA patients had ≥1 serious adverse events while 26% of riociguat patients had ≥1 serious adverse events).⁴⁶

In the current treatment algorithm, BPA is second-line to PTE and is used when the lesions are located in the segmental to subsegmental arteries of the pulmonary vasculature.⁴⁷ However, the decision of BPA versus PTE requires a multidisciplinary team that uses advanced imaging including digital subtraction angiography and CT angiography.⁴⁷ While BPA has beneficial effects in CTEPH with a now acceptable risk profile, more studies are needed to define the optimal role of BPA and how it may be used in hybrid approaches that implement the combination of medical therapy and PTE in various iterations.

4 |. PULMONARY ARTERY DENERVATION

The most recent addition to percutaneous PH treatment is PADN. PADN is performed using femoral venous access and then an 8-french long sheath is placed into the pulmonary artery. Pulmonary angiography is used to define the main, right, and left pulmonary arteries for guidance of ablation catheter placement.⁴⁸ Ablations are then performed with the LPA receiving the least number of ablations due to the proximity of the left recurrent laryngeal nerve and concern for nerve damage.⁴⁹ The rationale for PADN is based on the consistent observation that excess sympathetic activation occurs in PH, but beta-adrenergic blocker treatment in small clinical trials does not significantly alter disease course in PH.⁵⁰ Moreover, there are preclinical studies that demonstrated efficacy of PADN in animal models.^51,52 Therefore, the jump from animals to human was initiated, and thus far early studies are promising.

In PAH, there is evidence of efficacy of PADN. The first trial was the pulmonary artery denervation (PADN-1) for treatment of pulmonary artery hypertension (TROPHY1) study. PADN-1 was a single-center, prospective trial that compared eight patients who refused PADN to 13 patients who received PADN. All patients were on at least two therapies for PAH (consisting of: diuretics, beraprost, bosentan, or sildenafil) prior to enrolling in the trial. PADN immediately improved hemodynamics with a reduction in mPAP (55 ± 5–39 ± 7 mmHg, p < .01) and PVR (1883 ± 281–1,150 ± 208 dyne*s/cm⁵, p < .001) with an increase in pulmonary arterial compliance (PAC) (0.2 ± 0.1–0.4 ± 0.1 mL/mmHg, p < .001) and CI (2.0 ± 0.2–2.6 ± 0.1 L min⁻¹ m⁻², p < .001). Importantly, these beneficial hemodynamic effects were maintained or even heightened for at least 3 months (mPAP: 36 ± 5 mmHg, PVR: 763 ± 162 dyne*s/cm⁵, PAC: 0.4 ± 0.1 mL/mmHg, and CI: 2.8 ± 0.3 L min⁻¹ m⁻², p < .001). There were no significant changes in these hemodynamic parameters in the patients who refused PADN. Finally, PADN improved 6MWD by over 150 m (324 ± 21–491 ± 38 m, p < .006).⁴⁸

While the results of PADN-1 were promising, criticism related to nonrandomized design, immediacy of results, and quality of the PAH population due to male predominance and high proportion on supplemental oxygen emerged.⁵³ As a result, a second trial followed PADN-1 and involved a total of 66 PH patients (39 Group 1 PAH and 27 patients with either Group 2 or Group 4 PH).⁵⁴ Again they showed a reduction in mPAP with both immediate drop at the time of procedure as well as continued improvement over 6 months (53.1 ± 19.1–44.8 ± 16.4 mmHg, p < .001). A significant reduction in PVR was also observed (13.2 ± 6.9–8.4 ± 5.8 Wood units, p < .001) along with increased in cardiac output (3.3 ± 1.2–4.0 ± 1.1 L/min, p < .001) and 6MWD (increase by a mean of 94 ± 73 m, p = .041). These effects were sustained at 1 year. This trial was then followed by a subgroup analysis of the same data in patients with and without pericardial effusion. Those without pericardial effusion showed a greater effect across hemodynamic parameters, including mPAP, PVR, CI, and 6MWD.⁵⁵ However, controversy again rose as the two manuscripts reported differences in baseline variables and responses.

More recently, the single-arm, multicenter TROPHY1 trial was conducted. TROPHY1 examined the utility of ultrasound mediated PADN in 23 PAH patients with advanced disease as all patients were already on dual or triple therapy.⁴⁹ This differed from the earlier PADN trials which primarily enrolled a lower risk population. PADN significantly reduced mPAP (5.1 ± 7.4 mmHg, p < .01) and PVR (94 ± 151 dyne*s/cm⁵, p < .001) and increased PAC (0.39 ± 0.83 mL/mmHg, p < .01) and 6MWD (42 ± 63 m, p < .02) 4–6 months post procedure.⁴⁹ PADN was well tolerated as there were no procedure-related serious adverse events. There are some important differences between the two studies as PADN-1 showed immediate hemodynamic changes and increased CI while TROPHY1 had delayed beneficial effects and no significant change in cardiac output. However, the fact that TROPHY1 showed important hemodynamic benefits may have alleviated some of the concerns from PADN-1, and thus these two trials provide proof-of-principle that PADN is efficacious in PAH.

There is also a positive and randomized controlled trial using PADN in Group 2 PH. PADN in Patients with PH associated with left heart failure (PADN-5) was a multicenter trial that compared the effects of PADN (n = 48) versus sildenafil (up to 40 mg three times/day) plus sham PADN (n = 50 patients) in Group 2 PH patients (mPAP≥25 mmHg, PCWP >15 mmHg, and PVR >3 Wood units).⁵⁶ 6 months post-procedure, PADN significantly reduced mPAP (38.8 ± 10.6–28.6 ± 6.5 mmHg, p < .001) and PVR (6.4 ± 3.2–4.2 ± 1.5 Wood units, p < .001). There was a significant increase in PAC (1.9 ± 0.9–3.9 ± 1.0 mL/mmHg, p < .001), CI (1.7 ± 0.8–2.5 ± 0.7 mL min⁻¹ m⁻², p = .038) and 6MWD (351 ± 106–435 ± 108 m, p < .001).⁵⁶ There were no significant changes in any of these variables in the sildenafil arm. Collectively, these results suggest PADN could be a treatment option for Group 2 PH. This is exciting because current medical therapy does not consistently improve outcomes in this patient population, and there may be increased risk of adverse events.⁵⁷

While there are data suggesting PADN is safe and effective in Groups 1, 2, and even 4 PH, the utility of PADN in other types of PH has not been fully explored. This may be an important area for further investigation to help determine the widespread utility of this procedure. Moreover, the timing of PADN and how to combine it with currently approved therapies remains an open area for investigation.

5 |. CONCLUSION

In summary, we highlighted the data revealing the utility of BAS, TPS, BPA, and PADN in PH. While each treatment modality has inherent risks and will require continued optimization, they do provide distinct hemodynamic and functional benefits for PH patients. As a result, careful patient selection by a multidisciplinary team at centers of excellence is needed to optimize outcomes and reduce adverse events. Future randomized controlled studies are needed to determine how to optimally implement these procedures in the current treatment algorithms, how they can be integrated with medical and surgical treatments, and whether these therapies are effective across PH subtypes. However, these procedures provide new approaches that will hopefully improve outcomes for PH patients in the future.