Effects of Nitric Oxide on Hemodynamics After Transcatheter Mitral Valve Repair Complicated by Pulmonary Hypertension　― A Study Protocol ―

Abstract

Background: Elevated pulmonary arterial pressure (PAP) is associated with poor prognosis in patients with functional mitral regurgitation (MR) undergoing transcatheter mitral valve repair (TMVr). Nitric oxide (NO) inhalation therapy reduces PAP and pulmonary vascular resistance (PVR) after open-heart surgery, but its efficacy in patients with pulmonary hypertension (PH) undergoing catheter intervention remains unclear.

Methods and Results: This open-label, interventional, randomized controlled trial will investigate the efficacy of NO inhalation therapy after TMVr for MR complicated by PH. A total of 40 patients aged ≥18 years diagnosed with PH (mean PAP >20 mmHg) during preoperative right heart catheterization and scheduled for TMVr for MR are included in this study. Patients receiving pulmonary vasodilators, with NO contraindications, and with unstable conditions requiring intravenous catecholamines or mechanical circulatory support devices are excluded. Eligible patients are randomly allocated to the NO inhalation or control group in a 1 : 1 ratio. NO (20 ppm) is administered post-TMVr (D0) until the day after TMVr (D1). The control group is administered oxygen as necessary. The primary endpoint is the change in PVR (baseline to D1). The secondary endpoints include changes in cardiac index and mean PAP (baseline to D1), changes in PVR immediately before NO administration post-TMVr to D1, and postoperative complication rates.

Conclusions: This study will assess the efficacy of NO inhalation in patients with PH undergoing TMVr for MR.

The prevalence of heart failure (HF) continues to increase with the aging of national populations worldwide, referred to as the “heart failure pandemic”.¹ Pulmonary hypertension (PH) is a common complication of HF and is diagnosed in 26–80% of patients with left ventricular dysfunction.^2,3 HF complicated by PH has a poor prognosis,⁴ and PH is an independent prognostic factor in patients with HF; however, few effective treatments exist for PH associated with left-sided heart disease (PH-LHD). Guidelines for managing PH-LHD recommend reducing the left ventricular filling pressure or left atrial pressure with appropriate treatment for the causative left heart disease.⁵ Pulmonary vasodilators such as phosphodiesterase-5 inhibitors and endothelin receptor antagonists have not demonstrated efficacy against PH-LHD,⁶ so their use is not recommended.⁵ Nitric oxide (NO), an inhaled pulmonary vasodilator, increases cardiac output and reduces pulmonary vascular resistance (PVR) in postoperative patients with mitral stenosis and PH.⁷ NO inhalation reduces PAP, PVR, and the required catecholamine dose in patients after open-heart surgery.⁸

Recently, various heart surgeries have been performed using transcatheter interventions. Transcatheter mitral valve repair (TMVr) is used for mitral regurgitation (MR),⁹ and an elevated preoperative PAP is associated with poor prognosis in patients undergoing TMVr for functional MR complicated by HF.¹⁰ Although preoperative PH complications are poor prognostic factors in patients undergoing TMVr, few studies have evaluated the impact of postoperative PH. Additionally, the efficacy of NO inhalation therapy has mostly been investigated after open-heart surgery, and its usefulness after catheter treatment, which is less invasive than open-heart surgery, remains unclear.

Although an effective treatment for PH-LHD in patients with HF is needed, no therapeutic evidence exists regarding hemodynamic improvements after TMVr in patients with severe MR complicated by PH. NO inhalation therapy can dilate the pulmonary artery and help improve PH post-TMVr. This randomized controlled trial (RCT) aims to investigate the efficacy of NO inhalation after TMVr in patients with MR complicated by PH.

Methods

Study Design

This is an open-label, interventional, non-blinded RCT. Figure 1 presents the study flow chart.

Figure 1.

Flow chart of the randomized controlled trial. mPAP, mean pulmonary arterial pressure; NO, nitric oxide; TMVr, transcatheter mitral valve repair.

Eligibility Criteria

The inclusion criteria are as follows.

1. Scheduled for TMVr because of MR.

2. Preoperative right heart catheterization showing PH (mean PAP [mPAP] >20 mmHg).

3. Age ≥18 years (as of the date of written informed consent).

4. Written informed consent before trial enrolment.

The exclusion criteria are as follows.

1. NO contraindications (complete dependence on a right-to-left shunt for life support).

2. Treatment planned for valvular diseases other than MR.

3. Pulmonary vasodilators (phosphodiesterase 5 inhibitors, guanylate cyclase stimulants, endothelin receptor antagonists, prostacyclin, and prostacyclin receptor agonists) have been administered to treat target diseases.

4. Requires continuous administration of the following concomitant drugs: sodium nitroprusside, nitroglycerin, and sulfonamides.

5. Current use of mechanical circulatory support devices such as aortic balloon pumps, Impella circulatory support pump catheters, and percutaneous cardiopulmonary support devices for severe HF.

6. Current catecholamine use.

7. Pregnancy or breastfeeding.

8. Refusal to use contraception during trial participation.

9. The principal investigator or sub-investigator determines that participation in this trial is inappropriate for other safety reasons.

Randomization

Eligible patients will be randomly allocated to the NO inhalation or control group in a 1 : 1 ratio using stratified permuted block randomization. The stratification factor will be the origin of MR (primary vs. secondary).

Treatment Protocol

The treatment protocol is initiated after the patient returns to the cardiovascular care unit after TMVr (D0). A Swan-Ganz catheter is inserted during TMVr, and hemodynamic data from the right heart catheterization are obtained immediately before starting the treatment protocol. Hemodynamics are monitored until the next day. For the treatment protocol, NO (INOflo^® for inhalation 800 ppm) inhalation therapy is administered (concentration: 20 ppm) using INOflo DS (Mallinckrodt Pharmaceuticals) until the day after TMVr (D1) (Figure 2). Oxygen is administered as needed to control blood oxygen saturation in both groups. NO is gradually weaned after completion of the treatment protocol to prevent potential rebound PH.

Figure 2.

Treatment protocol of the randomized controlled trial. mPAP, mean pulmonary arterial pressure; MR, mitral regurgitation; NO, nitric oxide; R, randomization; RHC, right heart catheterization; TMVr, transcatheter mitral valve repair.

Data Collection

Patient background, medications taken, laboratory findings, ECGs, echocardiographic data, and catheterization data are collected at the time of registration. After TMVr (D0), data are obtained from right heart catheterization. On the day after the treatment protocol was initiated (D1), laboratory findings, ECGs, echocardiographic data, and right heart catheterization data are collected. During right heart catheterization, the pressure in the right atrium (RAP), right ventricle, pulmonary artery (PAP), pulmonary artery wedge (PAWP), and systemic arterial pressure (AP) are recorded. Cardiac output (CO) is measured using the thermodilution and Fick methods. PVR is calculated as PVR = 80 × (mPAP − PAWP) / CO, and systemic vascular resistance (SVR) is calculated as SVR = 80 × (mean AP − RAP) / CO. The cardiac index (CI) is calculated as the CO divided by the body surface area. Postoperative complications are also recorded.

Endpoints

The primary endpoint is the change in PVR from baseline to D1. Intergroup differences in the change in PVR from baseline to D1 are computed. Secondary endpoints include changes in the CI and mPAP from baseline to D1. We also assess the change in PVR after TMVr using the intergroup difference for changes in PVR immediately before NO administration post-TMVr (D0) to D1. Postoperative complications are defined as follows: acute renal failure (increase in serum creatinine by ≥0.3 mg/dL within 48 h, an increase in serum creatinine levels to ≥1.5-fold that of baseline or urine volume <0.5 mL/kg/h for 6 h), re-intubation, sepsis (serious organ damage caused by infectious disease), cardiogenic shock, and subsequent emergency surgery.

Ethics and Dissemination

This study is being conducted in compliance with the ethical principles of the Declaration of Helsinki and its revisions, the Clinical Trials Act, the Personal Information Protection Act, and related laws and regulations. This study has been reviewed and approved by the Certified Review Board of Kyoto Prefectural University of Medicine from ethical, scientific, and medical/pharmaceutical perspectives before implementation. After confirming that the patient fully understands the content, voluntary written consent for participation will be obtained. This trial has been registered (registration number: jRCTs051230200) in the Japan Registry of Clinical Trials (jRCT), a clinical research database established by the Ministry of Health, Labour and Welfare, Government of Japan, based on the Clinical Research Act. The results will then be published in a peer-reviewed journal.

Statistical Analysis

Previous research⁷ investigating the effect of NO inhalation on hemodynamics in patients with mitral stenosis and severe PH after mitral valve surgery showed that the change in PVR from baseline to 48 h post-surgery was −117 dynes · s · cm⁻⁵ in the NO inhalation group (95% confidence interval: −34 to −200 dynes · s · cm⁻⁵), and the intergroup difference for the change in PVR was approximately 152 dynes · s · cm⁻⁵, with a standard deviation of 138 dynes · s · cm⁻⁵. We assume that the PVR of the target population in the present RCT will be lower than that in the aforementioned study. Therefore, the intergroup difference for the change in PVR is conservatively assumed to be 110 dynes · s · cm⁻⁵, with a standard deviation of 130 dynes · s · cm⁻⁵. Using an unpaired t-test and assuming equal variance with a one-sided significance level of 0.05, the required sample size has been calculated as 18 patients per group to achieve 80% statistical power. Assuming some exclusions from the analysis, we have set the target sample size to 20 patients in each group, for a total of 40 patients.

The full analysis set (FAS) is defined as the target population analyzed for efficacy, and the safety analysis set (SAF) is defined as the target population analyzed for adverse events. The FAS includes all enrolled patients, excluding those who are found to be ineligible after enrolment, those not undergoing TMVr, and those with clinical information lost or removed after enrolment. SAF includes all patients who have received the protocol treatment at least once.

Primary analysis is to compare the change in PVR from baseline to D1 between groups using an unpaired t-test with a one-sided significance level of 0.05. If the null hypothesis is rejected, NO inhalation treatment is concluded superior to the control treatment. The secondary endpoints, the changes in CI and mPAP from baseline to D1 and the change in PVR from D0 to D1, are tested using an unpaired t-test at a one-sided significance level of 0.05, without adjusting for multiplicity. The proportions of all postoperative complications are compared using the chi-squared test. The proportions of all adverse events are also calculated. An interim analysis has not been planned for this study. We plan to complete patient registration by June 30, 2026.

Discussion

This ongoing RCT focuses on patients undergoing TMVr for MR complicated by PH. The efficacy of postoperative NO inhalation therapy will be examined by randomized comparison with a control group to verify its superiority. The primary endpoint is the change in PVR from baseline to D1. The secondary endpoints are changes in CI and mPAP from baseline to D1, changes in PVR post-TMVr, and postoperative complication rates.

In the COAPT trial, TMVr demonstrated a lower rate of post-TMVr hospitalization for HF, lower all-cause mortality rate, and greater improvement in the quality of life than guideline-directed medical therapy alone in patients with HF and severe functional MR.¹¹ Guidelines suggest that TMVr should be considered when selecting symptomatic patients with severe functional MR who meet the COAPT criteria.¹² In a subanalysis of the COAPT trial,¹³ patients with severe functional MR complicated by PH demonstrated worse prognoses. Although preoperative PH is a poor prognostic factor in patients undergoing TMVr, few studies have addressed the impact of postoperative PH.¹³

Although several studies have investigated the usefulness of PH-specific treatments for PH-LHD, evidence of their benefits is limited. According to guidelines, drugs approved for PAH are not recommended for PH-LHD.⁶ In contrast, NO inhalation therapy is a pulmonary vasodilator therapy in which NO is administered directly to the alveoli via the airways.¹⁴ NO decreases PAP and PVR, reducing afterload on the right ventricle and improving oxygenation by promoting gas exchange. However, the efficacy of NO inhalation therapy has only been evaluated in patients undergoing open-heart surgery. Few studies have examined the efficacy of NO inhalation therapy after less-invasive catheter treatment, particularly in patients with PH-LHD.

Study Limitations

First, an open-label design was adopted because the intervention involves inhalation therapy, for which blinding is inherently difficult owing to the challenge of creating a credible placebo. Although this design may introduce potential bias, the observation period after randomization is short, and the impact of such bias is considered limited, as the outcomes are based on objective physiological parameters. Second, we could not evaluate right ventricular function.¹⁵ Additionally, the primary endpoint is assessed 1 day after TMVr, which may not be sufficient to evaluate the long-term effects of inhaled NO. Nevertheless, this study primarily aims to evaluate whether inhaled NO contributes to early postoperative stability, including improved hemodynamics, following TMVr in patients with MR complicated by PH, rather than assess long-term outcomes. Further long-term studies or larger RCTs are needed to investigate the potential long-term effects of inhaled NO on outcomes.

Conclusions

In this ongoing RCT, we are investigating the efficacy of postoperative NO inhalation therapy after TMVr for MR complicated by PH. We will directly evaluate hemodynamics using right heart catheterization and assess the changes in PVR, mPAP, and CI. The results of this RCT may clarify the post-procedural efficacy and hemodynamic improvement effect of NO inhalation in patients with PH-LHD who undergo TMVr for MR and may contribute significantly to ameliorating PH post-TMVr.

Disclosures

This RCT is conducted by the principal investigator (Satoaki Matoba) with funding support from INO Therapeutic LLC under a contract for investigator-initiated research. INO Therapeutic, LLC, is a subsidiary of Mallinckrodt Pharmaceuticals. Mallinckrodt Pharmaceuticals has special approval for foreign-manufactured trial drugs and devices. Air Water Inc. is an exclusively foreign-manufactured marketing authorization holder. INO Therapeutic LLC and Air Water Inc. are not involved in the planning, implementation, tabulation, storage, statistical analysis, or interpretation of this RCT.

Acknowledgments

We thank Editage (www.editage.jp) for English language editing.

IRB Information

The present study was approved by Certified Review Board of Kyoto Prefectural University of Medicine (Reference number: 2023002-3).

Author Contributions

N.N. wrote the manuscript. R.T., N.N., A.Y., K.Z., M.N., S.T. and S.M. planned and organized the study. R.T., N.N., H.T., and K.Z. conducted the study. K.Y. performed monitoring. S.M. designed and directed the study. All authors have read and approved the manuscript.

Data Availability

This manuscript describes the protocol for this ongoing RCT. Therefore, we cannot elaborate on unpublished data.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circrep.CR-25-0137

References

• 1.   Kanaoka K, Iwanaga Y, Sumita Y, Nakai M, Miyamoto Y. Management and outcomes of acute heart failure hospitalizations in Japan. Circ J 2024; 88: 1265–1273, doi:10.1253/circj.CJ-23-0350.
• 2.   Ghio S, Gavazzi A, Campana C, Inserra C, Klersy C, Sebastiani R, et al. Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure. J Am Coll Cardiol 2001; 37: 183–188, doi:10.1016/s0735-1097(00)01102-5.
• 3.   Lam CSP, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT, Redfield MM. Pulmonary hypertension in heart failure with preserved ejection fraction: A community-based study. J Am Coll Cardiol 2009; 53: 1119–1126, doi:10.1016/j.jacc.2008.11.051.
• 4.   Kjaergaard J, Akkan D, Iversen KK, Kjoller E, Køber L, Torp-Pedersen C, et al. Prognostic importance of pulmonary hypertension in patients with heart failure. Am J Cardiol 2007; 99: 1146–1150, doi:10.1016/j.amjcard.2006.11.052.
• 5.   Kitai T, Kohsaka S, Kato T, Kato E, Sato K, Teramoto K, et al. JCS/JHFS 2025 Guideline on diagnosis and treatment of heart failure. Circ J 2025; 89: 1278–1444, doi:10.1253/circj.CJ-25-0002.
• 6.   Vachiéry JL, Delcroix M, Al-Hiti H, Efficace M, Hutyra M, Lack G, et al. Macitentan in pulmonary hypertension due to left ventricular dysfunction. Eur Respir J 2018; 51: 1701886, doi:10.1183/13993003.01886-2017.
• 7.   Fernandes JL, Sampaio RO, Brandão CM, Accorsi TA, Cardoso LF, Spina GS, et al. Comparison of inhaled nitric oxide versus oxygen on hemodynamics in patients with mitral stenosis and severe pulmonary hypertension after mitral valve surgery. Am J Cardiol 2011; 107: 1040–1045, doi:10.1016/j.amjcard.2010.11.030.
• 8.   Nakane T, Esaki J, Ueda R, Honda M, Okabayashi H. Inhaled nitric oxide improves pulmonary hypertension and organ functions after adult heart valve surgeries. Gen Thorac Cardiovasc Surg 2021; 69: 1519–1526, doi:10.1007/s11748-021-01651-z.
• 9.   Imamura T, Nakai M, Iwanaga Y, Sumita Y, Tao M, Ohno Y, et al. Two-year clinical outcome of MitraClip transcatheter edge-to-edge repair from the J-MITRA registry data. Circ J 2024; 88: 539–548, doi:10.1253/circj.CJ-23-0924.
• 10.   Ben-Yehuda O, Shahim B, Chen S, Liu M, Redfors B, Hahn RT, et al. Pulmonary hypertension in transcatheter mitral valve repair for secondary mitral regurgitation: The COAPT trial. J Am Coll Cardiol 2020; 76: 2595–2606, doi:10.1016/j.jacc.2020.09.609.
• 11.   Stone GW, Abraham WT, Lindenfeld J, Kar S, Grayburn PA, Lim DS, et al. Five-year follow-up after transcatheter repair of secondary mitral regurgitation. N Engl J Med 2023; 388: 2037–2048, doi:10.1056/NEJMoa2300213.
• 12.   Vahanian A, Beyersdorf F, Praz F, Milojevic M, Baldus S, Bauersachs J, et al. 2021 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J 2022; 43: 561–632, doi:10.1093/eurheartj/ehab395.
• 13.   Kuwata S, Izumo M, Okuno T, Shiokawa N, Sato Y, Koga M, et al. Impact of renal congestion in patients with secondary mitral regurgitation after mitral transcatheter edge-to-edge repair. Circ J 2024; 88: 510–516, doi:10.1253/circj.CJ-23-0240.
• 14.   Ueda J, Tsuji A, Aoki T, Asano R, Kiko T, Hayashi H, et al. Phase 2 study to evaluate the efficacy and safety of inhaled nitric oxide therapy in patients with severe right heart failure associated with pulmonary hypertension: Protocol for the PHiNO study. Circ Rep 2025; 7: 308–312, doi:10.1253/circrep.CR-24-0125.
• 15.   Amaki M, Kurashima S, Irie Y, Okada A, Ogata S, Ito S, et al. Reduced pulmonary artery compliance in a conscious state predicts cardiac event after transcatheter edge-to-edge repair in patients with ventricular secondary mitral regurgitation. Circ J 2025; 89: 1480–1487, doi:10.1253/circj.CJ-24-0541.