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doi:10.1378/chest.06-1263
(Chest. 2007; 132:11-17)
© 2007 American College of Chest Physicians
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Right Ventricular Diastolic Dysfunction and the Acute Effects of Sildenafil in Pulmonary Hypertension Patients*

C. Tji-Joong Gan, MSc; Sebastiaan Holverda, MSc; J. Tim Marcus, PhD; Walter J. Paulus, MD, PhD; Koen M. Marques, MD; Jean G.F. Bronzwaer, MD, PhD; Jos W. Twisk, PhD; Anco Boonstra, MD, PhD; Pieter E. Postmus, MD, PhD, FCCP and Anton Vonk-Noordegraaf, MD, PhD

* From the Departments of Pulmonary Diseases (Mr. Gan, Mr. Holverda, and Drs. Boonstra, Postmus, and Vonk-Noordegraaf), Physics and Medical Technology (Dr. Marcus), Physiology (Dr. Paulus), Cardiology (Drs. Marques and Bronzwaer), and Clinical Epidemiology and Biostatistics (Dr. Twisk), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands.

Correspondence to: Anton Vonk-Noordegraaf, MD, PhD, VU University Medical Center, De Boelelaan 1117 PO Box 7057, 1007 MB Amsterdam, the Netherlands; e-mail: a.vonk{at}vumc.nl

Abstract

Aims: This study investigated whether right ventricular (RV) diastolic function is impaired in pulmonary hypertension (PH) patients, and whether it is related to RV mass and afterload. In addition, the effects of an acute reduction of RV afterload by the oral intake of sildenafil were studied. Finally, we assessed whether diastolic function is related to cardiac parameters of disease severity.

Methods and results: Twenty-five PH patients and 11 control subjects were studied. Right-heart catheterization and N-terminal pro-brain natriuretic peptide (NT-proBNP) sampling were performed in patients. MRI measured RV ejection fraction, mass, and diastolic function. Isovolumic relaxation time (IVRT), normalized early peak filling rate (E), atrium-induced peak filling rate (A), and E/A ratio described diastolic function. Compared to control subjects, patients had prolonged mean (± SD) IVRT (133.5 ± 53.2 vs 29.3 ± 20.8 ms, respectively; p < 0.001), decreased E (3.0 ± 1.6 vs 6.4 ± 2.5 s–1, respectively; p < 0.001) and E/A ratio (1.1 ± 0.7 vs 5.3 ± 4.9, respectively; p < 0.001), and increased A (3.0 ± 1.4 vs 1.5 ± 0.9 s–1, respectively; p = 0.001). IVRT was related to RV mass (r25 = 0.56; p = 0.005) and pulmonary vascular resistance (r25 = 0.74; p < 0.0001). Sildenafil therapy reduced RV afterload and improved RV diastolic and systolic function. IVRT was correlated with NT-proBNP level (r = 0.70; p < 0.001), and was inversely related to cardiac index (r = –0.70; p < 0.001) and RV ejection fraction (r = –0.69; p < 0.001).

Conclusion: In PH patients, RV diastolic dysfunction is related to RV mass and afterload. RV diastolic function improves by reducing afterload. The correlations between diastolic function and prognostic parameters showed that diastolic function is most impaired in patients with severe disease.

Key Words: diastole • pulmonary hypertension • right ventricular function

Pulmonary hypertension (PH) is a disease that affects the right ventricle (RV) by an increased afterload. Eventually, patients die due to right-heart failure. Although research has mainly focused on the influence of PH on RV systolic function and the prognostic significance of this parameter, insight into the role of diastolic function in PH patients is scarce. Research performed on the left ventricle has shown that diastolic dysfunction plays a significant role in patients with left ventricular pressure overload and heart failure,1 and is influenced by left ventricular afterload2 and wall thickness.3 Thus, there are arguments that RV diastolic function may be impaired in PH patients, as follows: first, due to increased RV afterload, myocardial relaxation, and filling may be impaired; and, second, RV compensatory hypertrophy to increased afterload reduces ventricular compliance and may impair diastolic function.

In this study, we investigated whether RV diastolic function is impaired in PH patients, and whether this impairment is related to RV mass and afterload. Sildenafil was used to investigate whether a short-term reduction of RV afterload improves RV diastolic function. Finally, we assessed the relation between RV diastolic function and cardiac parameters, which reflects disease severity in PH patients.

Materials and Methods

Patients
Twenty-five PH patients with normal renal function and 11 nonsmoking, healthy control subjects were studied. Eighteen patients were referred to our center for the initial evaluation of PH, and seven patients were referred for the evaluation of treatment effects (three patients were receiving epoprostenol, and four patients were receiving bosentan). The different etiologies of PH were distributed as follows: idiopathic pulmonary arterial hypertension (PAH) [n = 18]; PAH related to the limited type of systemic sclerosis (n = 5); and PH due to chronic thrombotic disease (n = 2). PH due to left-sided heart disease, interstitial lung disease, or hypoxemia were excluded by further diagnostic workup according to the guidelines on the diagnosis of PAH.4 The study was approved by the Institutional Review Board on Research Involving Human Subjects of the VU University Medical Center. Written informed consent was obtained from all subjects.

Study Design
All patients underwent an MRI scan and right-heart catheterization on 2 consecutive days. There was no significant difference in heart rate during cardiac catheterization and MRI (mean heart rate: catheterization, 80.3 ± 12.0 beats/min; MRI, 83.1 ± 13.6 beats/min; t22 = 1.1 [paired t test]; p =0.27), and all patients were in sinus rhythm. Blood was sampled from a peripheral vein with the patient at rest within 24 h of MRI measurements. Plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) were analyzed (ELECSYS 1010 bench top analyzer; Roche Diagnostics; Amsterdam, the Netherlands). The 6-min walk test was performed a day before right-heart catheterization.

To study the effects of RV afterload reduction on diastolic function, 10 patients (idiopathic PAH, n = 7; PAH related to the limited type of systemic sclerosis, n = 1; and PH due to chronic thrombotic disease, n = 2) were admitted to the ICU for pulmonary vasoreactivity testing with inhaled NO (iNO) and oral sildenafil. ECG, and arterial and pulmonary artery pressures were monitored continuously during the test. Each patient inhaled 20 to 30 ppm NO for 5 min. After hemodynamics returned to baseline values, the patient received 50 mg of sildenafil. Measurements were performed at baseline, after receiving iNO, and 50 min after receiving sildenafil.

In these 10 patients, the effect of sildenafil on MRI-measured RV function was studied 1 day prior to vasoreactivity testing in the ICU. For technical reasons, iNO was not possible in the MRI. Baseline MRI measurements were performed at rest and were repeated 50 min after sildenafil administration with a fasting period between the measurements. In this study, we chose a dosage of 50 mg of sildenafil. This dosage has been shown to be safe and pulmonary specific, and the maximum effect has been shown after 45 min.56

Cardiac Catheterization
Right-heart catheterization was performed with a 7F Swan-Ganz catheter (131HF7; Baxter Healthcare Corp; Irvine, CA). Right atrial, RV, and pulmonary artery pressures were measured. Blood was sampled to assess mixed venous oxygen saturation. Arterial oxygen saturation was measured from blood sampled from the radial or femoral artery. Cardiac output was assessed by the Fick method, and pulmonary vascular resistance (PVR) was calculated using the standard formula.

MRI Measurements
MRI was performed (1.5T Sonata scanner; Siemens Medical Solutions; Erlangen, Germany) according to the protocol described earlier.7 Four-chamber cine images were acquired by steady-state free-precession imaging, with 11 phase-encoding lines per heartbeat in a 14-heartbeat breathhold. With 30 reconstructed phases, the effective temporal resolution was in the range between 25 and 34 ms. Perpendicular to the four-chambered end-diastolic image, a stack of consecutive short-axis breathhold cine images were acquired with the same sequence parameters as those used for the four-chambered cine image and with slice distance of 10 mm. From this stack of parallel short-axis cine images, quantitative analysis of RV volumes and mass was performed (MR Analytical Software System; Medis; Leiden, the Netherlands). An RV two-chambered cine series was localized as the image plane orthogonal to the most basal cardiac short-axis plane that intersected both the pulmonary and the tricuspid valve. This cine series displayed the onset of pulmonary valve closing and tricuspid valve opening.

Finally, stroke volume was measured using magnetic resonance phase-contrast flow quantification in an image plane orthogonal to the main pulmonary artery, at 1 cm distance downstream from the pulmonary valves. Velocity sensitivity was 150 cm/s, and temporal resolution was 22 ms. The RV ejection fraction was obtained by the ratio of RV stroke volume and RV end-diastolic volume.

Quantification of RV Diastolic Function
Isovolumic relaxation time (IVRT) was the time interval between pulmonary valve closing and tricuspid valve opening8 and was normalized for the R-R interval because of differences in heart rate. RV filling was quantified from the RV volumetric filling curves as assessed from the stack of short-axis cine images.9 RV early peak filling rate (E), atrium-induced peak filling rate (A) [both measures were normalized for RV end-diastolic volume], and E/A ratio-quantified RV diastolic filling pattern.

Statistical Analysis
A statistical software package (SPSS, version 12.0; SPSS; Chicago, IL) was used for statistical analyses, and p < 0.05 was considered to be statistically significant. Results are reported as the mean ± SD for descriptive statistics. Results after iNO and sildenafil administration are reported as the median (interquartile range [IQR]).

The Mann-Whitney test was performed to compare RV parameters between PH patients and control subjects, and the Wilcoxon matched paired rank test was performed to compare hemodynamics after iNO and sildenafil administration, and to compare RV diastolic and systolic function before and after sildenafil administration. Pearson correlation analyses were performed to investigate significant correlations. Because of multiple testing, the threshold for significance was adjusted using the Bonferroni correction for families of tests, where 0.05 divided by the number of tests assessed the adjusted significance level.

Results

There was no difference between the PH patients and control subjects with respect to mean age (PH patients, 49.1 ± 15.3 years; control subjects, 46.5 ± 11.4 years; t34 = 0.59 [t test]; p = 0.56) and the proportion of men/women (PH patients, 5/20; control subjects, 3/8; p = 0.41 [Fisher exact test]). Patient characteristics and hemodynamics are summarized in Table 1 . The majority of patients were female and in New York Heart Association functional class III. Hemodynamics yielded the characteristics of RV pressure overload. PH patients had a hypertrophied RV with impaired systolic function (Table 2 ).


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  		Table 1. Characteristics and Hemodynamic Variables*

 

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  		Table 2. MRI Measurements in Control Subjects and PH Patients

 
Figure 1 shows magnetic resonance RV, two-chambered, cine images of a PH patient. The ECG below the images marks the time point within the cardiac cycle when the MRI pictures were obtained.


Figure 1
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  		Figure 1. MRI RV, two-chambered cine images of a PH patient. The ECG marks the time points within the cardiac cycle where the MRI images were obtained. The images were acquired at end-diastole (left), the onset of pulmonary valve closing (middle), and tricuspid valve opening (right). The white arrows depict pulmonary valve closing (middle) and tricuspid valve opening (right). The images were acquired 0 ms (left), 311 ms (middle), and 457 ms (right) from the ECG R wave, with an R-R interval of 622 ms. The IVRT in this patient is 146 ms, which is 23% of a heart beat. RA = right atrium; PA = pulmonary artery.

 
The first cine image marks the start of RV contraction. The onset of pulmonary valve closing and tricuspid valve opening was assessed from cine images shown in Fig 1, middle and right, respectively. IVRT was calculated accordingly. In PH patients, IVRT was prolonged compared to that in control subjects, as shown in Table 2.

Figure 2 , left, A, illustrates the average change in RV volume over time in control subjects and PH patients obtained from magnetic resonance short-axis cine images. In control subjects, RV filling is characterized by E, a plateau phase, and A. In contrast, E is absent in PH patients while A is more pronounced. The difference in RV filling is more explicitly shown in Figure 2, right, B, which shows the average RV filling rate in control subjects and patients. In PH patients, E is reduced when compared to control subjects, and toward end-diastole A is higher and shows a significant atrial contribution (data shown in Table 2). The Bonferroni correction-adjusted significance level was p < 0.005.


Figure 2
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  		Figure 2. Left, A: average RV volume graph of control subjects ({blacksquare}) [n = 11] and PH patients ({blacktriangleup}) [n = 25]. Time is normalized for the individual R-R interval, and RV volume is normalized for end-diastolic volume. The graph starts at end-diastole, maximum RV volume. Compared to control subjects, the fast volume increase is absent and atrial contribution is more important in PH patients. Right, B: average RV volume rate graph of control subjects ({blacksquare}) [n = 11] and PH patients ({blacktriangleup}) [n = 25], which illustrates that the RV filling pattern in PH patients has changed significantly compared to that in control subjects. The data on RV filling are shown in Table 2.

 
To assess the effects of RV hypertrophy and afterload on diastolic function, the different diastolic parameters were correlated to RV mass and PVR. Since we performed six Pearson correlation analyses, the Bonferroni correction-adjusted significance level was p < 0.008. IRVT was related to RV mass and PVR, as illustrated in Figure 3 , left, A, and right, B, respectively, whereas E and E/A ratio did not reach significance (p > 0.1).


Figure 3
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  		Figure 3. Relation of normalized IVRT with RV mass index (r25 = 0.56; p = 0.005) and PVR (r25 = 0.76; p < 0.0001). The Bonferroni correction-adjusted significance level for the correlations was p < 0.008.

 
Acute Effects of iNO and Sildenafil
Three patients were receiving monotherapy (epoprostenol or bosentan) at the time of pulmonary vasoreactivity testing. Compared to baseline levels (median, 54.0 mm Hg; IQR, 44.5 to 61.5), levels of iNO (median, 43.0 mm Hg; IQR, 37.5 to 53.0) and sildenafil (median, 44.0 mm Hg; IQR, 35.5 to 54.0) decreased mean pulmonary artery pressure (p = 0.004 [Wilcoxon signed matched rank test]). Changes in PVR and stroke volume during vasoreactivity testing are shown in Figure 4 . Compared to baseline levels (median, 643.5 dyne · s · cm–5; IQR, 414.8 to 1070.5), levels of iNO (median, 500.0 dyne · s · cm–5; IQR, 309.5 to 728.8) and sildenafil (median, 511.5 dyne · s · cm–5; IQR, 320.0 to 789.8) decreased PVR (iNO, p = 0.002 [Wilcoxon signed matched rank test]; sildenafil, p = 0.004 [Wilcoxon signed matched rank test]). The decrease after iNO administration was no different than after sildenafil administration (p = 0.432 [Wilcoxon signed matched rank test]). Compared to baseline levels (median, 60.5 mL; IQR, 49.3 to 76.3), iNO (median, 62.5 mL; IQR, 57.8 to 87.8) did not change stroke volume (p = 0.084), while sildenafil (median, 69.5 mL; IQR, 55.8 to 85.3) increased stroke volume (p = 0.002) [Fig 4, right, B] (Bonferroni correction-adjusted significance level, p < 0.006 [Wilcoxon signed matched rank test]).


Figure 4
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  		Figure 4. Individual changes in (left, A) PVR and (right, B) stroke volume (SV) in response to 20 to 30 ppm iNO and 50 min after the administration of 50 mg of sildenafil. Bonferroni correction-adjusted significance level, p < 0.005 (Wilcoxon signed matched rank test).

 
Sildenafil was used to study the effect of afterload reduction on RV diastolic function in the MRI. The individual response in diastolic and systolic function to a reduction in RV afterload is shown in Figure 5 . The normalized IVRT decreased after sildenafil administration (median, 0.12; IQR, 0.08 to 0.22) when compared to baseline (median, 0.19; IQR, 0.14 to 0.28; p < 0.0001 [Wilcoxon signed matched rank test]). RV ejection fraction improved with sildenafil administration (median, 34.5%; IQR, 28.3 to 40.3) when compared to baseline (median, 41%; IQR, 32.5 to 46.3; p = 0.008 [Wilcoxon signed matched rank test]). There was no significant change in RV peak filling (p = 0.077) or heart rate (p = 0.373) after sildenafil administration (Bonferroni correction-adjusted significance level, p < 0.01 [Wilcoxon signed matched rank test]).


Figure 5
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  		Figure 5. The changes in normalized IVRT (left, A) and RV ejection fraction (right, B) to a reduction in RV afterload with sildenafil in PH patients (n = 10). Wilcoxon signed matched rank test, with Bonferroni correction-adjusted significance level of p < 0.01.

 
Correlations of RV Diastolic Function With Cardiac Parameters of Disease Severity
IVRT was not significantly related to right atrial pressure (r25 = 0.47; p = 0.018) but was related to NT-proBNP (r25 = 0.70; p < 0.001), and was inversely related to cardiac index (r25 = –0.70; p < 0.001) and RV ejection fraction (r25 = –0.69; p < 0.001). The Bonferroni correction-adjusted significance level was p < 0.01.

Discussion

This study showed the following: (1) in PH patients, RV diastolic function, quantified by RV IVRT, peak filling rate, and filling pattern, was significantly impaired compared to control subjects; (2) diastolic function was related to RV mass and afterload, and improved by reducing RV afterload; and (3) RV diastolic dysfunction was related to parameters of disease severity.

Diastolic Function in PH
Diastole is characterized by ventricular relaxation and filling. Therefore, not one single parameter can describe diastolic function.10 In this study, we used time and volume. Earlier research1112 focused on estimating pulmonary artery pressure by IVRT. Our findings of prolonged IVRT in chronic RV pressure overload are in agreement with those of experimental and clinical studies.13141516 Stojnic et al15 showed that IVRT was prolonged in PH patients. This finding was confirmed by Tei et al14 in primary PH patients. Although diastolic function was not the primary focus in these studies, the data revealed the presence of diastolic dysfunction in PH patients. It has been shown that chronic RV pressure overload increased IVRT.1316 Our data showed that, compared to control subjects, there was a redistribution of RV filling in PH patients that was characterized by a reduced E, an increased A, and a decreased E/A ratio. From these data, it might be concluded that in PH patients RV filling is largely dependent on atrial contraction.

Mechanism of RV Diastolic Dysfunction in PH
The mechanism of diastolic dysfunction could be intramyocardial or extramyocardial. Chronic RV pressure overload results in compensatory hypertrophy to decrease wall stress. However, ventricular compliance decreases concomitantly. Therefore, ventricular hypertrophy has been suggested to cause diastolic dysfunction.3 Our data are in agreement with the latter, since IVRT was related to RV mass. Furthermore, IVRT was related to RV afterload, and an acute decrease in RV afterload improved diastolic function, which indicates that in PH patients the cause of diastolic dysfunction is in part extramyocardial. Since the reduction of PVR by iNO and sildenafil was not different, which is in agreement with the findings of earlier studies,1718 improvement of stroke volume and RV systolic function with sildenafil therapy might be attributed to the decreased afterload. However, stroke volume was greater with sildenafil therapy when compared to that with iNO therapy, while the decrease in PVR was not different. This suggests a direct effect of sildenafil on the cardiomyocyte, which has been shown in experimental research.1920 In contrast to sildenafil, iNO solely affects the pulmonary vessels because of its short half-life. Thus, improvement of RV diastolic function with sildenafil therapy might be due to decreased afterload and a concomitant direct effect on the myocardium. There was no effect of afterload reduction on RV filling. This is in agreement with the results of research21 that has been performed on the left ventricle, which showed that the effect of myocardial relaxation on left ventricular filling pressures is heart rate-dependent. Since heart rate remained unchanged after sildenafil, this mechanism may also account for the situation in the RV.

Relation of Diastolic Function and Disease Severity
Correlations of IVRT with cardiac parameters (ie, right atrial pressure, NT-proBNP level, cardiac index, and RV ejection fraction), reflecting disease severity in PH patients, were assessed.222324 Right atrial pressure was not significantly related to IVRT, but there was a trend in which elevated right atrial pressure was associated with prolonged IVRT. This relation is not surprising, since right atrial pressure is considered to be a reflection of RV diastolic function. IVRT was related to NT-proBNP, and was inversely related to cardiac index and RV systolic function, which emphasizes the importance of global RV dysfunction in PH patients. Based on the relations, we speculate that diastolic dysfunction is not only a reflection of disease severity, but might also be an independent factor contributing to right heart failure and death in PH patients.

Study Limitations
To characterize diastolic function, RV pressure decline should be assessed next to IVRT and ventricular filling. However, pressure measurements were recorded with a fluid-filled catheter. It has been generally assumed that the frequency response of fluid-filled catheters is insufficient for instantaneous pressure measurements, which is essential to measurements of pressure decline. Since one of our aims was to relate diastolic function to RV mass and ejection fraction, we chose MRI to measure RV diastolic function. The experience in measuring diastolic function by MRI is limited, when compared to that with echocardiography. However, the feasibility has been recognized.925 Furthermore, our measurements of IVRT are comparable to the results obtained in echocardiographic studies.2627 The study group was too small to draw any firm conclusions on the clinical value of diastolic dysfunction in PH patients. Larger studies and temporal assessment are warranted to assess the clinical value of RV diastolic function in PH patients.

Conclusion

RV diastolic function is impaired in PH patients, which is related to RV mass and the extent of RV afterload, and improves by reducing RV afterload. The correlations that were found between diastolic function and well-known prognostic parameters in PH patients showed that diastolic function is most impaired in patients with severe disease.

Footnotes

Abbreviations: A = atrium-induced peak filling rate; E = early peak filling rate; iNO = inhaled nitric oxide; IQR = interquartile range; IVRT = isovolumic relaxation time; NT-proBNP = N-terminal pro-brain natriuretic peptide; PAH = pulmonary arterial hypertension; PH = pulmonary hypertension; PVR = pulmonary vascular resistance; RV = right ventricle ventricular

Mr. Gan was financially supported by the Netherlands Organisation for Scientific Research (NWO), Mozaiek grant, project No. 017.001.154.

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Received for publication May 17, 2006. Accepted for publication December 30, 2006.

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