Keywords

1 Introduction

The right ventricle (RV) is the anterior cardiac chamber located just behind the sternum. The RV receives systemic venous return and pumps it into the pulmonary arteries [1]. Under normal conditions, the RV requires little energy to pump venous blood to the pulmonary arteries since pulmonary circulation has a much lower vascular resistance than does systemic circulation [2]. The RV therefore usually has low oxygen consumption.

Until recently, most cardiology research was concerned with left ventricle (LV) physiologies and pathologies. In fact, in the early twentieth century, some groups hypothesized that human circulation could be maintained without RV function [3]. However, cardiovascular surgeons recognized the importance of RV function, and RV dysfunction appeared to be associated with major cardiovascular events in heart failure (HF) [4]. In addition, development of state-of-the-art cardiovascular imaging modalities such as echocardiography, cardiac magnetic resonance (CMR) imaging, and positron emission tomography (PET) have made it possible to noninvasively evaluate the functional and physiological characteristics of RV myocardium [5, 6]. Based on this background, research on the RV has progressed intensively in recent years.

One of the major causes of RV dysfunction is pulmonary hypertension (PH). PH is categorized into five groups as follows: Group 1, pulmonary artery hypertension (PAH); Group 2, PH with LV disease; Group 3, PH associated with lung disease and/or hypoxia; Group 4, PH due to chronic thrombosis and/or embolism; and Group 5, miscellaneous [7]. Elevated pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) may induce RV dysfunction in patients with PH [7]. However, the RV has a high capacity to adapt to pressure or volume overload before failing in its function [8]. Before myocardial fibrosis and RV heart failure develop, moderate to severe PH often leads to initial RV adaptation [9]. Given the increased arterial pressure in pulmonary circulation, the RV may require a significant power output in response to increased afterload, and this may increase the demand for oxygen in the RV [10]. In this circumstance, the RV may require improved mechanical efficiency in order to increase the power output. A study by Wong et al. showed that idiopathic PH with RV dysfunction was associated with increased RV myocardial oxygen consumption (MVO2) and reduced RV efficiency [11], a situation possibly mirroring the case of LV energetics in heart failure [12–14]. However, the study by Wong et al. lacked control subjects [11]. Yoshinaga et al. evaluated the RV oxidative metabolism in patients with PH and showed that patients with PH had increased oxidative metabolism in comparison with that of normal individuals [15]. Increasing RV oxidative metabolism was associated with several prognostic markers such as mean PAP (mPAP), PVR, and brain natriuretic peptide (BNP). These findings suggest that elevated RV oxidative metabolism may be a prognostic marker.

11C-acetate PET is a noninvasive technique for measuring regional and global myocardial oxidative metabolism [13, 16–19], which is correlated with tricarboxylic acid cycle flux and MVO2 [16]. RV myocardial oxidative metabolism can also be measured noninvasively using 11C-acetate PET [15, 17, 20–22]. HF therapies such as beta-blockers that reduce MVO2 are considered to improve the survival of patients with HF [23]. LV cardiac efficiency can be estimated noninvasively [12] by combining the mechanical work with the oxidative metabolism as measured by 11C-acetate PET. This form of LV efficiency measurement has been applied to evaluate several new HF treatments including beta-blockers, cardiac resynchronized therapy, surgical reconstruction therapy, and obstructive sleep apnea (OSA) syndrome treatments [13, 14, 24–26].

PH-specific vasodilators such as endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclin decrease pulmonary arterial pressure [7, 27]. These new vasodilators indeed improve survival in PH patients. Oikawa et al. reported that reducing mPAP through the use of epoprostenol was associated with reduced RV glucose metabolism observed by 18F-fluorodeoxyglucose (FDG) PET [28]. However, it is not clear whether such a treatment favorably affects RV myocardial oxidative metabolism.

The purpose of this study was to investigate the possible impacts of the intensified PH-specific vasodilator therapy on myocardial energetics using 11C-acetate PET.

2 Materials and Methods

2.1 Study Subjects

Study subjects were recruited from the first department of medicine at the Hokkaido University Hospital. The patient inclusion criteria were as follows: (1) a resting mPAP ≥ 25 mmHg and a pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg [7], (2) symptoms of PH in accordance with World Health Organization (WHO) functional class II or III, (3) PH subtypes chronic thromboembolic pulmonary hypertension (CTEPH) or PAH [29], and (4) stable condition (unchanged for > 4 weeks).

Exclusion criteria were secondary PH due to LV disease, unstable condition of patients, and permanent pacemaker implantation.

The study was approved by the Hokkaido University Graduate School of Medicine Human Research Ethics Board. Written informed consent was obtained from all patients.

2.2 Experimental Protocol

14 PH patients underwent right heart catheterization. Precapillary PH was diagnosed based on a mPAP ≥ 25 mmHg at rest and a PCWP ≤ 15 mmHg [7]. Among the 14 PH patients, nine patients started or added the PH-specific vasodilators based on the combined guidelines of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), and these nine patients were categorized as the intensified treatment group [30]. The remaining five patients did not change their treatments and served as a control group.

Within 7 days of right heart catheterization, all patients underwent blood sampling, CMR, and 11C-acetate PET at rest on the same day [15]. CMR and 11C-acetate PET were repeated after 10.7 ± 6.5 months for the intensified treatment group (Fig. 15.1). Patients with PH but without OSA served as the control group and underwent CMR and 11C-acetate PET at rest at baseline and after 10.6 ± 6.3 months (P = NS).

Fig. 15.1
figure 1

Study design of the current study. BNP brain natriuretic peptide, CMR cardiac magnetic resonance, RHC right heart catheterization, TX treatment

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WHO functional class evaluation and blood tests including BNP were measured at baseline and follow-up.

2.3 Right Heart Catheterization

A complete hemodynamic evaluation was performed in all PH patients using the standard technique for right heart catheterization. The hemodynamic measurements included mean right atrial pressure, mPAP, and mean PCWP. Cardiac output was determined through thermodilution. PVR was calculated as (mPAP – mean PCWP) divided by cardiac output.

2.4 Measurements of BNP

Blood samples were obtained for fasting conditions the morning before the PET studies. BNP data were obtained for all patients. Plasma BNP was measured using immunoradiometric assay [31].

2.5 Cardiac Magnetic Resonance Imaging

CMR imaging studies were performed using a 1.5-T Achieva magnetic resonance imaging system (Philips Medical Systems, Best, the Netherlands) equipped with master gradients (maximum gradient amplitude 33 mT/m and maximum slew rate 100 mT/m/msec). CMR data acquisition was performed on patients in the supine position with breath-holding in expiration. We used a five-element cardiac phased-array coil and a vector cardiographic method for electrocardiogram (ECG)-gating images. We performed localizing scans with breath-hold cine imaging and axial orientation. Coronal images were used for cardiac anatomy evaluation. CMR images spanned from bronchial bifurcation to diaphragm level thus allowing for whole-heart analysis. We obtained 12 short-axis cine slices during a steady-state free precession pulse sequence. The precession pulse sequence was as follows: repetition time = 2.8 msec, echo time = 1.4 msec, flip angle = 60, acquisition matrix = 192 × 256, field of view = 380 mm, slice thickness = 10 mm, inter-slice gap = 0 mm, and phases/cardiac cycle = 20 [32].

2.6 CMR Data Analysis

CMR images were analyzed using commercially available software (Extended MR Work Space: version 2.6.3, Philips Medical Systems, Amsterdam, the Netherlands). RV and LV volumes were measured using cine long-axis images. RV and LV endocardial borders were semiautomatically traced. We then calculated the RV ejection fraction (EF), LVEF, and RV volumes using this information [15]. RVEF was measured in transverse (axial) orientation. LVEF was measured in short-axial orientation [33]. All CMR images were analyzed by clinicians blinded to the clinical and imaging data.

2.7 Positron Emission Tomography

All patients were instructed to fast overnight. PH patients who had vasodilator treatments took their morning medications before the PET and CMR studies. Patients were positioned with the heart centered in the field of view in a whole-body PET scanner (ECAT HR+, Siemens/CTI Knoxville, TN) [34]. Dynamic PET acquisition was initiated (10 × 10 s (s); 2 × 30s; 5 × 100 s; 3 × 180 s; 2 × 300 s) [14] followed by intravenous administration of 20 mCi (mCi) [740 megabecquerel (MBq)] 11C-acetate.

2.8 11C-Acetate PET Data Analysis

The reconstructed dynamic PET images were analyzed by applying a region of interest over the whole LV and free wall of the RV myocardium in 3–5 midventricular transaxial planes [15, 20, 26]. A mono-exponential function was fit to the myocardial time-activity data. The clearance rate constant (kmono) was determined as described previously [13, 14, 34]. The mono-exponential fit began at the point when the blood pool was stable (usually 2–4 min after injection) (Fig. 15.2).

Fig. 15.2
figure 2

Example of left and right myocardial time-activity data from a 11C-acetate PET acquisition. A mono-exponential function fit to the myocardial clearance yields a clearance rate constant; kmono represents the rate of oxidative metabolism and reflects MVO2. Blue line represents left ventricular (LV) myocardium time-activity curve. Orange line represents right ventricular (RV) myocardium time-activity curve. Red line indicates blood time-activity curve

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All data were analyzed by clinicians blinded to the clinical and imaging data.

2.9 RV Work Per MVO2 Index Calculation

The 11C-acetate clearance data were combined with the stroke work data to derive myocardial efficiency using the LV work metabolic index (WMI) using the following equation [13, 14, 26].

WMI = SVI × SBP × HR/kmono; where SVI is the stroke volume index determined by CMR, SBP is systolic blood pressure, HR is heart rate, and kmono is the mono-exponential rate constant for 11C-acetate clearance from the myocardium.

As a modified LV work metabolic index equation, the RV work per MVO2 index was calculated as the ratio of RV SVI measured by CMR divided by RV MVO2. The equation was as follows [35]:

$$ \begin{array}{ll}\mathrm{R}\mathrm{V}\ \mathrm{work}\ \mathrm{per}\ {\mathrm{MVO}}_2\mathrm{index} = &\ \mathrm{R}\mathrm{V}\ \mathrm{S}\mathrm{V}\mathrm{I}\ /\ \mathrm{R}\mathrm{V}\ {\mathrm{k}}_{\mathrm{mono}}\times \mathrm{R}\mathrm{V}\ \mathrm{mass}\ \hfill \\ {}& \times 20\hfill \end{array} $$

2.10 Statistical Analysis

Continuous variables (using a logarithmic transformation on skewed distributions as appropriate) are presented as mean and standard deviations. Categorical variables are presented as frequencies with percentages. Differences in results for the PH group and the control group were examined for statistical significance with a two-sample t-test for continuous variables. A P value of less than 0.05 was considered indicative of a statistically significant difference. Statistical calculations were carried out using SAS software version 9.2 (SAS Institute, Inc., Cary, NC).

3 Results

3.1 Patient Characteristics

A total of 14 WHO functional class II or III PH patients were prospectively enrolled in the study between December 2009 and July 2011, and all PH patients completed the study protocol.

The baseline characteristics of the participants are shown in Table 15.1. There was no significant difference in mean age between members of the intensified PH treatment patient group and those of the control group.

Table 15.1 Patient characteristics
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3.2 Right Heart Catheterization

The baseline right heart catheterization data is shown in Table 15.1. There was no significant difference in the systolic PAP, diastolic PAP, mPAP, and PVR of the intensified PH treatment group and those of the control group.

3.3 LV and RV Systolic Function

The RVEF and LVEF were similar in both the intensified PH treatment group and the control group (Table 15.2).

Table 15.2 LV and RV functional measurements
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3.4 LV and RV Oxidative Metabolism

There was no statistically significant difference between the LV oxidative metabolism, kmono, of the intensified PH treatment group and that of the controls (P = 0.72). There was also no statistically significant difference between the RV oxidative metabolism, kmono, of the intensified PH treatment group and that of the controls (P = 0.18) (Table 15.2). In addition, the RV SVI per RV kmono was similar in both the intensified PH treatment group and the control group (P = 0.31).

3.5 Longer-Term Effects of Intensified PH-Specific Therapy on RV Metabolism and Work per Oxygen Consumption

The intensified PH therapy group tended to have reduced PVR compared with that of the control group (−20.6 ± 41.7 vs. −3.4 ± 33.2 %, P = 0.29). Intensified PH therapy tended to reduce BNP (377.2 ± 694.5 to 70.8 ± 132.6 mol/mL, P = 0.18).

Intensified PH therapy significantly reduced RV oxidative metabolism (0.044 ± 0.008 to 0.039 ± 0.007/min, P = 0.002) while increasing SVI (31.4 ± 10.1 to 39.3 ± 9.6 mL/m2, P = 0.017) (Fig. 15.3). As a result, the intensified PH-specific therapy significantly improved the RV work/oxygen consumption index (730.8 ± 253.6 to 1038.5 ± 262.7 mL/min + m2, P < 0.001) (Fig. 15.4). There was no significant change in LV kmono in this group (0.052 ± 0.008 to 0.050 ± 0.006/min, P = 0.35). The control group showed no changes in these parameters (RV kmono: 0.041 ± 0.006 to 0.049 ± 0.01/min, P = 0.15, RV work/oxygen consumption index: 829.1 ± 362.9 to 721.5 ± 241.2 mL/min + m2, P = 0.69).

Fig. 15.3
figure 3

Representative case of PAH patient who had intensified PH-specific vasodilator therapy. LV kmono did not change after the intensified PH-specific vasodilator treatment. In contrast, RV kmono was markedly reduced after the intensified PH-specific vasodilator therapy

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Fig. 15.4
figure 4

Effects of intensified PH-specific vasodilator therapy on RV work per oxygen consumption index. Patients who had intensified PH-specific vasodilator therapy had a significantly improved RV work per oxygen consumption index. In contrast, there was no significant difference in RV work per oxygen consumption index in control group. PH pulmonary hypertension, RV right ventricle, TX therapy

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4 Discussion

Intensified PH-specific vasodilator therapy tended to reduce PVR and BNP. The intensive PH-specific therapy led to reduction in right ventricular oxidative metabolism and a significant improvement in right ventricular work per oxygen consumption index in patients with pulmonary hypertension.

4.1 Increased RV Oxidative Metabolism in Patients with PH

The major determinants of myocardial metabolism are heart rate, contractility, and wall stress [36, 37]. Oxygen demand in the RV may also increase with elevated PAP [10].

In LV, heart failure is considered to be an energy-depleted state. Improved survival through the use of beta-blockers and vasodilator therapy is in part associated with the energy-sparing effects of these medications [38].

RV MVO2 was originally measured through right coronary venous blood sampling [10]. As noninvasive approaches, 11C-acetate and 15O-labeled tracers PET have also been applied for RV oxidative measurements in HF and PH [15, 17, 22, 26, 39, 40]. The current data revealed increased RV oxidative metabolism in patients with PH and reduced RV contraction. The current data agreed with findings of our previous study and the study by Wong et al. [15, 39].

4.2 Study Population and Effects of PH-Specific Vasodilator Therapy

In the current study, eight PH patients did not have PH-specific vasodilator therapy. One patient had a PH-specific vasodilator, but the PH control did not reach the standard control level. Therefore, these nine patients either started or added the PH-specific vasodilator. The remaining five patients already received PH-specific vasodilator treatments and they were stable. These five patients did not meet the criteria to add further vasodilators to control their PH based on ESC and ERS guidelines [30].

The intensified PH therapy group tended to have reduced mPAP. Although the mPAP did not reach statistically significant levels, this finding may be due to the small sample size, but it may still indicate that intensified PH-specific therapy had beneficial effects. In fact, BNP also tended to be reduced after the therapy, a finding that may indicate a secondary reduction in wall stress due to reduced mPAP. It may therefore be appropriate to evaluate the therapeutic effects on RV energetics in this study population.

4.3 Effects of PH-Specific Vasodilator Therapy on RV Oxidative Metabolism and Work per MVO2 Index

In the previous study, we evaluated RV power and RV efficiency using the following equation: RV efficiency = HR × mPAP × SV × 1.33 × 10−4/RV kmono × RV mass × 20 [35]. Using this equation, WHO functional classification II and III PH patients actually had increased RV power and RV efficiency compared to patients in the control group [15]. The increasing power and RV efficiency may be adaptive processes associated with increasing mPAP. In the LV, the LV efficiency is estimated using the WMI. The WMI was calculated as follows: WMI = SVI × SBP × HR/kmono [13]. LVHF treatments usually do not significantly change the HR and SBP [14]. In contrast, PH-specific vasodilators significantly reduce the mPAP [27]. Therefore, if the equation proposed by Sun et al. is simply applied to RV efficiency measurements [35], RV efficiency may be reduced after PH-specific vasodilator therapy since the reduction of mPAP would play a significant role over the increasing SVI. The afterload of pulmonary circulation is usually lower than that of systemic circulation [1, 41]. Therefore, the RV may have volume efficiency rather than pressure efficiency as would apply in the case of the LV. Therefore, we applied SVI per MVO2 index instead of Sun’s equation in the current study.

The SVI per MVO2 index shows that the intensified PH-specific vasodilator therapy significantly improved this parameter in comparison with that of controls. The trend of mPAP reduction may contribute to these improvements. Therefore, improving volume efficiency in the RV may be one of the therapeutic effects of PH-specific vasodilators, and doing so may contribute to the improvement of outcomes in patients with PH. This hypothesis should be tested in a larger study population in the future.

4.4 Limitations

The thickness of the RV free wall is usually 4–5 mm, which is thinner than the LV free wall. However, the current study population had thicker RV walls. When radiotracer uptake is measured, the partial volume effect may significantly attenuate the data. However, we analyzed the oxidative metabolism using mono-exponential fitting. This approach measures clearance of the radiotracer from the myocardium. Thus, the partial volume effect should be minimal.

5 Conclusion

Intensified PH-specific vasodilator therapy led to a reduction in right ventricular oxidative metabolism and a significant improvement in right ventricular work per oxygen consumption index in patients with pulmonary hypertension. These effects may contribute to the benefits of intensified PH-specific vasodilator therapy.