Despite the increasing number of patients with heart failure with preserved ejection fraction (HFpEF), currently there is no proven therapy for HFpEF [
Based on transpulmonary pressure gradient (TPG = mPAP − PAWP), pulmonary hypertension due to left heart disease (PH-LHD) could be classified into two groups: passive PH (PPH; TPG < 12 mmHg) and reactive PH (RPH, also known as the out of proportion PH; TPG ≥ 12 mmHg). The 2015 European Society of Cardiology (ESC) guidelines for the diagnosis and treatment of PH further separated PH-LHD into isolated postcapillary PH and mixed pre- and postcapillary PH. This classification was based on whether the diastolic pressure gradient (DPG = DPAP − PAWP) is lower or higher than 7 [
Fasudil is a Rho-kinase inhibitor that blocks the activity of Rho kinase by competing the ATP binding site of the Rho-kinase catalytic domain with ATP and thus plays an important role in relaxing pulmonary vasculature. A variety of clinical studies suggested that the Rho-kinase pathway is involved in many cellular functions including proliferation, migration, and contraction of the vascular smooth muscle cell [
To date, few clinical trials of Rho kinase inhibitors have been reported in PH associated with left ventricular HFpEF. The goal of this study is to investigate the effects of fasudil on PH-HFpEF and determine the response differences to treatment between RPH and PPH.
The study population was prospectively recruited from patients with heart failure (HF) symptoms from August 2014 to February 2017 in Zhoupu Hospital and Shanghai Renji Hospital. According to the 2016 ESC guidelines for heart failure, all symptomatic HF patients who underwent echocardiography with left ventricular ejection fraction (LVEF) ≥50% [
As proposed by the ASE [
Mitral valve peak E-wave velocity (
According to ASE guidelines for the assessment of right heart [
All HFpEF patients suspected with PH by echocardiography had received optimal treatment for HFpEF and other primary diseases for 2–4 weeks, including adequate drug therapies (i.e., diuretics, nitrates, ACEI/ARB, and beta blockers) and/or interventional therapies (i.e., coronary artery stenting or pacemaker implantation). Following the above initial treatment of primary cardiac diseases, right heart catheterization (RHC) was performed, and the patients with mPAP ≥25 mmHg and PAWP >15 mmHg were confirmed as PH-HFpEF [
Right atrial pressure, right ventricular pressure, pulmonary artery pressure including PASP, mean pulmonary artery pressure (mPAP), diastolic pulmonary arterial pressure (DPAP), and pulmonary artery wedge pressure (PAWP) were measured by RHC using a 6-lumen Edward catheter. We replaced PAWP by LVEDP when there was PAWP measurement error caused by incomplete balloon incarceration. Cardiac output (CO) was measured in triplicate by the thermodilution technique. TPG was calculated as mPAP minus PAWP, and PVR was calculated using the following formula: (mPAP − PAWP)/CO. Among these PH-HFpEF patients, those TPG ≤12 mmHg were considered as PPH, whereas TPG >12 mmHg were classified as RPH.
The PH-HFpEF patients aged 60–80 years with HFpEF secondary to coronary disease, hypertension, degenerative valvular heart disease (except for patients with severe mitral or aortic valvular organic disease), cardiomyopathy, and New York Heart Association (NYHA) functional class II–IV were enrolled.
The exclusion criteria include the following: Severe liver or kidney diseases, malignant tumor, and cerebrovascular disease Restrictive cardiomyopathy, hypertrophic obstructive cardiomyopathy, constrictive pericarditis, moderate-to-severe mitral stenosis, or aortic stenosis PH caused by congenital heart disease, rheumatic heart disease, autoimmune disease, chronic obstructive pulmonary disease, chronic thromboembolism, pulmonary vascular abnormalities, and idiopathic PAH (IPAH) Patients who are treated with calcium blockers, prostacyclin, or endothelin receptor antagonists Patients with incomplete data
A total of 58 PH-HFpEF patients were enrolled, of which 35 were diagnosed with RPH while 23 patients were confirmed as PPH.
These enrolled patients were treated with fasudil (fasudil injection solution from the Tianjin Hongri Pharmaceutical Ltd by Share Ltd), 30 mg intravenous drip twice a day for 2 weeks. During the treatment, the heart rate, blood pressure, liver function, renal function, and electrolytes were closely monitored in case adverse events or background therapy remained unchanged.
Data collection was undertaken and compared pre- and posttreatment results in all patients, including Doppler echocardiography, measurement of 6MWD, NYHA heart failure functional classification, and laboratory tests results, such as NT-pro-BNP and SvO2.
We evaluated the cardiac function of patients based on NYHA classification and 6-minute walking distance (6MWD). The efficacy of fasudil was determined according to the changes of NYHA classification: (1) markedly effective: heart failure is basically controlled or cardiac functional classification increased by 2 and above; (2) effective: cardiac functional classification increases by 1, but less than 2; (3) ineffective: cardiac function is better than before, but its classification did not change; and (4) deterioration: cardiac functional classification decreases by 1 or more.
Continuous variables are expressed as mean ± SEM unless otherwise stated. The differences of baseline and baseline changes between RPH and PPH were compared using Student’s
Two-sided
The patients’ demographic and etiological data and pulmonary hemodynamic measurements, as well as the medication used for basic diseases and heart failure treatment, are summarized in Table
Baseline characteristics and pulmonary hemodynamics by RHC.
Variable | PPH group ( |
RPH group ( |
|
---|---|---|---|
|
|||
Male, |
16 (69.57) | 23 (65.71) | 0.783 |
Female, |
7 (30.43) | 12 (34.29) | 0.684 |
Age (years) | 69.78 ± 10.22 | 70.60 ± 11.14 | 0.891 |
|
|||
|
|||
Coronary artery disease (%) | 9 (39.13) | 13 (37.14) | 0.965 |
Hypertensive heart disease (%) | 2 (8.70) | 3 (8.57) | 0.974 |
Coronary heart disease with hypertension (%) | 7 (30.43) | 10 (28.57) | 0.862 |
Dilated cardiomyopathy (%) | 2 (8.69) | 3 (8.57) | 0.975 |
Degenerative valvular heart disease (%) | 3 (13.04) | 6 (17.14) | 0.763 |
Course of disease (years) | 3.09 ± 2.22 | 3.69 ± 2.64 |
0.012 |
|
|||
|
|||
Diuretics | 22 (95.65) | 33 (94.29) | 0.912 |
Hydrochlorothiazide 25 mg qd | 15 | 24 | |
Torasemide 20 mg qd | 7 | 9 | |
Antisterone | 22 | 31 | |
Nitrates | 17 (73.91) | 26 (74.29) | 0.893 |
ACEI/ARB | 19 (82.61) | 29 (82.86) | 0.981 |
|
20 (86.96) | 28 (80.00) | 0.261 |
|
|||
|
|||
PASP (mmHg) | 47.17 ± 8.47 | 62.9 ± 17.47 | 0.003 |
mPAP (mmHg) | 33.82 ± 7.26 | 45.26 ± 14.96 | 0.007 |
PAWP (mmHg) | 23.26 ± 5.26 | 23.14 ± 5.26 | 0.947 |
TPG (mmHg) | 10.08 ± 1.88 | 22.11 ± 2.25 | 0.000 |
PVR (WU) | 2.15 ± 0.88 | 5.24 ± 2.55 | 0.003 |
CO (L/min) | 4.84 ± 1.56 | 4.19 ± 1.26 | 0.000 |
|
|||
|
|||
NYHA I-II/III-IV | 5/18 | 8/27 | 0.9426 |
Data are presented as number and rate or mean ± standard deviation; Student’s
The disease course in the RPH group was longer than that in the PPH group (3.69 ± 2.64 years versus 3.09 ± 2.22 years,
As shown in Table
Cardiac effect of fasudil treatment determined by echocardiography.
Variable | PPH ( |
RPH ( | ||||
---|---|---|---|---|---|---|
Pretreatment | Posttreatment |
|
Pretreatment | Posttreatment |
|
|
LAD (mm) | 46.50 ± 4.75 | 45.50 ± 4.51 | 0.987 | 47.00 ± 6.25 | 46.63 ± 5.50 | 0.379 |
LVEDD (mm) | 45.10 ± 6.14 | 46.07 ± 8.12 | 0.697 | 47.14 ± 8.40 | 47.63 ± 7.73 | 0.497 |
LVESD (mm) | 27.91 ± 3.16 | 28.21 ± 2.88 | 0.378 | 29.02 ± 3.64 | 29.91 ± 4.06 | 0.788 |
IVST | 11.01 ± 1.56 | 10.98 ± 1.96 | 0.916 | 11.85 ± 2.03 | 11.35 ± 1.96 | 0.895 |
LVPW | 10.82 ± 1.16 | 10.01 ± 0.96 | 0.816 | 11.01 ± 1.76 | 10.87 ± 1.86 | 0.941 |
|
49.97 ± 6.85 | 52.59 ± 8.37 | 0.062 | 50.35 ± 8.22 | 53.43 ± 9.22 | 0.059 |
|
62.03 ± 10.31 | 63.36 ± 9.37 | 0.096 | 64.5 ± 11.80 | 54.52 ± 12.65 |
0.016 |
|
2.89 ± 1.03 | 3.03 ± 1.11 | 0.074 | 2.98 ± 1.16 | 4.05 ± 1.02 | 0.071 |
|
0.80 ± 0.11 | 0.83 ± 0.14 | 0.069 | 0.78 ± 0.19 | 0.98 ± 0.12 |
0.011 |
|
17.29 ± 2.21 | 17.36 ± 1.89 | 0.098 | 16.89 ± 1.11 | 13.19 ± 1.79 |
0.011 |
EF (%) | 61.64 ± 10.31 | 64.83 ± 12.37 | 0.069 | 62.43 ± 11.80 | 64.24 ± 9.65 | 0.485 |
PASP (mmHg) | 49.87 ± 8.50 | 49.48 ± 8.64 | 0.444 | 64.37 ± 13.82† | 63.51 ± 13.79 |
0.017 |
Data are presented as mean ± standard deviation; differences in change from baseline between groups were evaluated using Student’s
After 2 weeks of therapy with fasudil, the left ventricular diastolic function in RPH group, as indicated by decreased
At baseline, there were no statistical differences between the study groups in SvO2, NT-pro-BNP, 6MWD, and NYHA classification.
In both groups, NT-pro-BNP and 6MWD were improved after treatment as summarized in Table
Effect of fasudil on SpO2, NT-pro-BNP, and 6MWD.
Variable | PPH ( |
RPH ( | ||||
---|---|---|---|---|---|---|
Pretreatment | Posttreatment |
|
Pretreatment | Posttreatment |
|
|
SpO2 (%) | 92.89 ± 3.97 | 93.15 ± 5.13 | 0.071 | 91.30 ± 4.68 | 93.07 ± 4.80 | 0.052 |
NT-pro-BNP (ng/ml) (min, max) | 3664 (789, 21150) | 1149 (750, 4651) |
0.031 | 3980 (1312, 24000) | 1287 (155, 8210) |
0.004 |
6MWD (m) | 361.75 ± 50.24 | 401.34 ± 59.56 |
0.042 | 345.60 ± 44.55 | 400.7 ± 59.41 |
0.001 |
Normally distributed data are presented as mean ± standard deviation; nonnormally distributed data are presented as minimum and maximum; normally distributed variables were evaluated using Student’s
The number of cases of NYHA classification change.
Efficacy | PPH ( |
RPH ( |
|
---|---|---|---|
Markedly effective (%) | 2 (8.70) | 8 (22.86) | |
Effective (%) | 9 (39.13) | 18 (51.43) | |
Ineffective or deterioration (%) | 12 (52.17) | 9 (25.17) | |
Total effective (%) | 11 (47.83) | 26 (74.29) | 0.040 |
Data are presented as patient number and %; enumeration data are tested by
Fasudil treatment-induced changes of patient’s NYHA classification in the RPH and PPH groups.
During the 2-week treatment, no adverse event was observed in either group; patient’s liver function, renal function, electrolyte, blood, urine, and stool routine tests were all normal. Two patients in the PPH group and 3 patients in the RPH group reported some mild side effects including slightly decreased heart rate and blood pressure, dizziness, and fatigue, which were all reported tolerable to the patients and thus fasudil treatment was not discontinued.
Heart failure with preserved ejection fraction originates from left ventricular diastolic dysfunction secondary to impaired relaxation and stiffened myocardium. The increased load of left ventricle exposes the lung vasculature to pressure-induced challenges. In the long term, the sustained pulmonary hemodynamic change not only leads to pulmonary hypertension but also increases the pulsatile loading on the right ventricle [
The management of pulmonary hypertension due to left heart disease (PH-LHD) focuses on treating the primary left heart disease and improves left ventricular function, thereby alleviating PH. However, even with optimal treatment, the clinical symptoms and mortality of this disease cannot be improved. Aronson et al. [
Recently, whether PH caused by pulmonary vascular remodeling in late PH-LHD can be treated with targeted drugs has drawn much attention. FIRST [
The results of our current prospective controlled trial show that fasudil can reduce pulmonary artery pressure and improve cardiac function more significantly in RPH-HFpEF than in PPH-HFpEF patients. We found that RPH patients had a longer course of heart failure, higher levels of PASP, mPAP, TPG, and PVR than those of PPH patients. These findings may be explained by the hypothesis that RPH and PPH have different pathophysiology, and PPH and RPH may be two different stages of PH-HFpEF. PPH is the early stage due to passive transduction of the increased pulmonary venous pressure, whereas RPH is the advanced stage characterized by vascular constriction and proliferation caused by chronic progressive increase of pulmonary artery wedged pressure and pulmonary artery pressure, which leads to the elevation of TPG and PVR, as well as pulmonary vasculopathy. In contrast, there was no significant difference between RPH and PPH in NT-pro-BNP, 6MWD, NYHA, and other cardiac functional indexes suggesting that the cardiac functional impairment of RPH might not be proportional to the increase of pulmonary artery pressure.
Fasudil is a potent selective inhibitor of Rho kinase. Several trials studying the acute- or long-term effects of fasudil on PAH have demonstrated that fasudil improves pulmonary hemodynamics [
In animal studies, fasudil was reported to decrease the mean pulmonary arterial pressure, right ventricular hypertrophy, and pulmonary arteriolar medial thickness and augment pulmonary expression of endothelial nitric oxide synthase (eNOS) in rats with PH secondary to left ventricular dysfunction [
With regard to the left heart, Guo et al. [
In terms of study limitations, the main limitations of the current study include the relatively small number of trial size, the lack of RHC reexamination, and the data of RV function improvement, which limit the precision for estimation of the magnitude of effects. In addition, there is no placebo control group in this study which restricts the accuracy of the efficacy estimation of fasudil. Lastly, the long-term effect of fasudil on RPH or PPH-HFpEF is still unknown.
In summary, Newman et al. had proposed that redefining pulmonary hypertension through pulmonary vascular disease phenomics and resolving the heterogeneity of the PH syndrome will allow for more targeted therapeutics [
The authors declare that they have no conflicts of interest.
Xiang Zhang and Xueming Zhang contributed equally to this work.
This study was supported by grants from National Natural Science Foundation of China (no. 81570040) and Health and Family Planning Commission of Pudong New Area (PW2014A-45).