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* From the 2nd Medical Clinic, Department of Cardiology (Drs. Menzel, Wagner, Mohr-Kahaly, Braeuninger, and Meyer), and Clinic for Cardiothoracic and Vascular Surgery (Drs. Kramm and Mayer), Johannes Gutenberg University, Langenbeckstrasse 1, D-55101 Mainz, Germany.
Correspondence to: Thomas Menzel, MD, Richard Wagner Strasse 17A, D-65193 Wiesbaden, Germany; e-mail: menzel{at}mail.uni-mainz.de
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Abstract |
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Design: Thirty-nine patients (16 women and 23 men; mean ± SD age, 55 ± 12 years) with severe CTEPH were examined before and 13 ± 8 days after PTE by way of transthoracic echocardiography and right heart catheterization.
Measurements and results: Examination results confirmed in all cases that before surgery the right ventricles were enlarged and systolic function was impaired. Moderate to severe tricuspid valve regurgitation was observed. Left ventricular eccentricity indexes reflected a leftward displacement of the interventricular septum. End-diastolic left ventricular size and systolic function had decreased, and the left ventricular filling pattern showed impaired diastolic function. After surgery, mean pulmonary artery pressure was significantly lower (48 ± 10 mm Hg vs 25 ± 7 mm Hg; p < 0.05). The calculated end-diastolic and end-systolic right ventricular areas had decreased: 30 ± 7 cm2 vs 21 ± 5 cm2 (p < 0.05) and 24 ± 6 cm2 vs 14 ± 4 cm2 (p < 0.05), respectively. Right ventricular fractional area change had increased (20 ± 7% vs 33 ± 8%; p < 0.05). Most of the patients exhibited a marked decrease in the severity of tricuspid regurgitation. Septal motion, left ventricular systolic function, and diastolic filling pattern returned to normal values (early to late diastolic left ventricular inflow ratio, 0.70 ± 0.33 vs 1.35 ± 0.51; p < 0.05). The mean cardiac index also improved (2.7 ± 0.6 L/min/m2 vs 3.7 ± 0.8 L/min/m2).
Conclusions: In CTEPH, functions are impaired in the right as well as the left ventricles of the heart. Improved lung perfusion and the reduction of right ventricular pressure overload are direct results of PTE, which in turn bring a profound reduction of right ventricular size and a recovery of systolic function. Normalization of interventricular septal motion as well as improved venous return to the left atrium lead to a normalization of left ventricular diastolic and systolic function, and the cardiac index improves.
Key Words: chronic thromboembolic pulmonary hypertension • echocardiography • pulmonary thromboendarterectomy
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Chronic thromboembolic pulmonary hypertension (CTEPH) constitutes a rare disease that is estimated to follow after < 1% of all cases of acute pulmonary embolism. Several mechanisms are pos-tulated to be responsible for the development of chronic pulmonary hypertension after the acute embolic event. A recurrence of embolism has been reported subsequent to 2.5 to 7% of adequately treated pulmonary embolic events.1 2 Failure to resolve the embolus causes hypertensive lesions in the open vascular bed and further increases pulmonary vascular resistance. An in situ thrombus growth has also been reported.3
CTEPH causes right ventricular (RV) pressure overload, which leads to functional and morphologic alterations of both right and left ventricles. These changes result in a decreased cardiac index (CI). As has been shown for lung transplantation, repair of congenital heart disease, and pulmonary thromboendarterectomy (PTE), the hemodynamic and cardiac changes remain partially reversible, even after years of illness.4 5 6 7 8 9 10 11 12 13 14 15 16 17
Long-term outcome after PTE has been reported to be very satisfactory.5 7 8 A recent investigation of 22 patients, 48 to 72 months after they underwent PTE, showed a marked improvement of clinical condition as well as New York Heart Association (NYHA) functional class and a significantly reduced pulmonary vascular resistance in comparison with presurgical data.18 A 6-year survival rate of 75% has been reported by Archibald et al,19 and the perioperative mortality risk of PTE is < 10%.1 6 20 In comparison, the 5-year survival rate without surgery is around 35% for severe CTEPH.21
We examined RV and left ventricular (LV) function and geometry in patients with CTEPH before and after PTE. The preexistent changes that had led to a diminished cardiac output and their alteration after reduction of the RV afterload were investigated, as well as the underlying pathophysiologic mechanisms. New insights into LV filling properties derived by Doppler echocardiography and new insights into the mechanisms of systolic LV function were taken into consideration.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Patients were investigated 12 ± 8 days before and 13 ± 8 days after surgery. Four patients had coronary artery disease, two of which underwent additional coronary bypass surgery. None of the patients experienced previous or perioperative myocardial infarction. In one patient, a mitral valve replacement was necessary, due to mitral valve prolapse with severe mitral regurgitation.
PTE
The endarterectomy of pulmonary arteries was performed with a
standardized technique, using extracorporeal circulation, deep
hypothermia, and periods of circulatory arrest.21
22
23
Transthoracic Echocardiography
Two-dimensional and Doppler echocardiography were performed,
using standard techniques on commercially available equipment (Sonos
2500 [2.0/2.5 MHz] or Sonos 5500 [S4 Ultraband transducer 2–4
MHz]; Hewlett-Packard; Andover, MA). Images were obtained with
patients lying in the left lateral position. Measurements were
performed in end-expiration during examination. The results of three
heart cycles were averaged for each variable. In case of atrial
fibrillation, five heart cycles were averaged.
The RV end-diastolic cavity area (EDA) and RV end-systolic cavity area (ESA) were determined planimetrically in the apical four-chamber view. Fractional area change (FAC) was calculated as follows24 : RV-FAC = (RV-EDA - RV-ESA)/RV-EDA x 100
The severity of tricuspid regurgitation (TR) was assessed by
way of color Doppler echocardiography. In accordance with Miyatake et
al,25
the area of the regurgitant jet was planimetrically
determined in the apical four-chamber view: 4 + TR, jet area > 10
cm2; 3 + TR, jet area > 4 and 
10
cm2; 2 + TR, jet area > 2 and 4
cm2; and 1 + TR, jet area > 0 and 2
cm2.
In pulmonary hypertension, a dorsal and left-lateral displacement of the left ventricle occurs, rendering the echocardiographic determination of LV size and systolic function inaccurate from the apical position. Thus, LV-EDA and LV-ESA cross-sectional areas were determined in the parasternal short-axis view (at the level of the mitral valve-chordae tendinae transition) to measure systolic function. LV-FAC was used instead of the ejection fraction. End-diastole was defined as peak of the R wave of the QRS complex; for end-systole, the point of maximum LV posterior wall thickening was taken.26 LV-FAC was calculated as follows: (LV-EDA - LV-ESA)/LV-EDA x 100
End-diastolic eccentricity index of the left ventricle was measured according to Ryan et al.27 In order to prove early diastolic leftward septal motion, we took an early-diastolic index (measured at two stop-frames after maximal posterior wall thickening was observed), instead of the end-systolic eccentricity index (at the point of maximum LV posterior wall thickening).
LV diastolic function was evaluated by Doppler echocardiographic assessment of the transmitral flow pattern, in accordance with Oh et al28 and Appelton et al.29 Variables determined were peak flow velocity in early diastole and at atrial contraction (E- and A-wave velocities), early to late diastolic left ventricular inflow ratio (E/A), E-wave deceleration velocity, and isovolumic relaxation time. In each patient case, a Valsalva maneuver was performed before and after surgery to distinguish a "true-normal" from a pseudonormal diastolic filling pattern.
A Doppler echocardiography-derived index of overall LV function30 was calculated on the measurements of two intervals, expressing the LV performance index: (A - B)/B
where A = the interval between cessation and onset of mitral inflow, and B = the ejection time of LV outflow.
Using Doppler echocardiography, the CI was determined according to
Marshall and Weymann,31
with the following formula:
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Cardiac Catheterization
In all patient-cases included in this study, a hemodynamic
examination was performed with a Swan-Ganz catheter to attain
preoperative and postoperative determinations of the mean pulmonary
artery pressure, mean pulmonary capillary pressure, pulmonary vascular
resistance, and CI (thermodilution method). In 28 cases, coronary
arteriography was also performed.
Statistical Methods
Statistical Analysis System version 6.12 (SAS Institute; Cary,
NC) was employed to process the study results. Continuous variables
were expressed as mean ± SD. Preoperative and postoperative
continuous variables were compared by the Wilcoxon signed-rank test.
The two-sided Cochran-Armitage trend test (exact p values) was used to
determine the dependence of the E/A of LV filling on preoperative and
postoperative NYHA functional class ratings. An E/A > 1 was
considered a positive test result. All p values 
0.05 were
considered to be not statistically significant (NS) in both tests.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Echocardiographic Variables
There were certain few patients for which not all parameters in
question could be determined with satisfactory accuracy (shown in
detail in Tables 1
2
3
). Before surgery, the area of the right ventricle was enlarged in all
patients (both end-diastolic and end-systolic). Systolic function was
impaired. On examination after surgery, both RV area measurements were
smaller in all patients, and systolic function had improved (Table 1)
.
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Before surgery, end-diastolic and early diastolic LV eccentricity indexes were both elevated. After surgery, both parameters returned to near-normal values (Table 2) . After surgery, the mean cross-sectional area of the left ventricle increased significantly in the end-diastolic phase, whereby the end-systolic area remained unchanged. Thus, LV-FAC represented a significant increase (Table 2) .
Preoperative LV diastolic function was, in general, abnormal: the maximal early diastolic filling velocity was lower and the maximal filling velocity at atrial contraction was slightly higher than the normal, age-adjusted range. After surgery, both parameters returned to normal values. The mean E/A was low before surgery, but lay within normal range afterwards. The lowered velocity of deceleration in early diastolic filling increased significantly. Neither before nor after surgery could a pseudonormalization or restrictive filling pattern be observed in any of the patients. Prolonged isovolumic relaxation time returned to normal (Table 2) .
The E/A could be determined in 36 patient-cases. The patients with an E/A < 1 were classified with statistical significance in higher NYHA stages before and also after surgery. For patients in NYHA class IV before surgery, an E/A < 1 was found in 10 cases and an E/A > 1 was found in none. For patients in NYHA class III before surgery, an E/A < 1 was found in 19 cases and an E/A > 1 was found in 2 cases. For patients in NYHA class II before surgery, an E/A < 1 was found in three cases and an E/A > 1 was found in two cases.
After surgery, none of the patients could be classified as NYHA class IV. For patients in NYHA class III after surgery, an E/A < 1 was observed in four cases and an E/A > 1 was found in one of the cases. For patients in NYHA class II after surgery, an E/A < 1 could be observed in five cases and an E/A > 1 was found in eight cases. For patients in NYHA class I after surgery, an E/A < 1 could be observed in 2 cases and an E/A > 1 was found in 16 cases.
The LV performance index declined substantially after surgery, indicating an improvement of diastolic as well as systolic LV function. The mean CI was below normal before surgery and increased significantly after PTE (Table 2) .
Hemodynamic Variables
Pulmonary vascular resistance and mean pulmonary artery pressure
were elevated in preoperative measurements. After PTE, a marked
decrease could be shown for both parameters. Mean capillary wedge
pressure lay within normal range in preoperative and postoperative
measurements. Heart rate did not change after PTE (Table 3)
. Invasively
determined CI was below normal before surgery, and it increased
significantly after surgery.
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TR
The dilatation and alteration of RV geometry lead to annular
dilatation of the tricuspid valve, which causes functional
TR.33
The results of this are increased RV preload,
decreased efficiency of RV stroke work, and decreased RV output, which
further increase tricuspid valve incompetence. Although several studies
on PTE have been published, no investigators have systematically
compared the preoperative and postoperative severity of TR. Only
Jamieson and coworkers6
point out that in the setting of
pulmonary hypertension, even severe cases of TR do not require valve
surgery, as PTE induces substantial improvement of valvular function.
In this study, moderate to severe functional TR could be detected in
most of the patients. The severity of TR was found to be significantly
reduced after surgery, however, which proves that PTE interrupts the
pathophysiologic cycle described above.
LV Geometry
Due to ventricular interdependence within the restricted
intrapericardial space, marked RV dilatation causes a significant
alteration in LV geometry, which is characterized by a leftward
displacement of the interventricular septum. This can be demonstrated
during the whole heart cycle,27
but is most marked at
early diastole, decreasing substantially by
end-diastole.34
The elevated preoperative LV eccentricity
indexes shown in our investigation confirm the previous findings. In
our investigation, the same indexes returned to near normal values
after PTE.
LV Diastolic Function
A number of investigators have emphasized that impaired LV
diastolic filling is the most important cause of left heart failure in
patients with pulmonary hypertension.26
34
35
A
normalization of the previously altered diastolic filling pattern was
shown in examination results after PTE.32
The prompt
reversibility of impaired LV compliance confirms the assumption of a
functional rather than a structural change of the LV
myocardium.36
The preoperative finding of prolonged isovolumic relaxation time as well as the lowered E wave and E-wave deceleration velocities also indicate that changes of diastolic filling are most severe in the early diastole, which corresponds to the disproportional septal displacement during this phase of the heart cycle, as has been described elsewhere.34 The isovolumic relaxation time reflects the interval from aortic valve closure to the onset of mitral flow, and is determined primarily by the rate of LV relaxation and left atrial pressure. Its prolongation in pulmonary hypertension can be explained by a reduced LV preload due to right heart failure and, more importantly, the leftward shift of the interventricular septum during diastole, which decreases LV pressure decline velocity. This also results in the decreased E wave and E-wave deceleration velocities of presurgery measurements.
Our perception that lower cardiac output in pulmonary hypertension may be due to impaired LV diastolic function is supported by findings in the case of patients undergoing atrial septostomy. In this case, cardiac output improves after the intervention because of a decrease in RV preload and increase of LV preload due to the shunt flow.37
In this study, the significantly higher NYHA classification of the patients with an E/A < 1 (impaired diastolic LV filling), both before and after PTE, also supports the concept that impaired LV filling is a major pathophysiologic factor in patients with CTEPH. With PTE, LV geometry is restored and RV function improves, so that LV diastolic function returns to normal.
LV Systolic Function
Prior to surgery, impaired diastolic filling led to a decreased LV
end-diastolic cross-sectional area (ie, reduced
end-diastolic volume). Our measurements show a postoperative
normalization of end-diastolic LV area (equal volume). Because
end-systolic chamber sizes remain unchanged, the determinations that
indicated impaired systolic LV function, as measured by FAC before
surgery, also returned to normal range after PTE.
Overall LV Function
The Doppler echocardiography-derived LV performance index
published by Tei and coworkers30
was demonstrated to be
highly correlated with both peak diastolic LV pressure drop and peak
systolic LV pressure rise, as well as the time constant of relaxation
(
). In our study, the mean LV performance index was 0.62 ± 0.26
before PTE, and it decreased to 0.38 ± 0.15 after surgery. This
result indicates an increase of peak diastolic LV pressure drop and an
improvement of systolic LV function after surgery. It confirms the
findings discussed above. In addition, the lower index indicates a rise
of peak systolic LV pressure rise, which could also confirm our above
described finding of improvement in LV diastolic filling.
CI
The presurgery chain of causalities diminishing CI can be
summarized as follows. Obliteration of the pulmonary vascular bed leads
to a RV pressure overload as well as a reduced LV preload. RV
enlargement causes a leftward shift of the interventricular septum.
This alters LV geometry and results in a diastolic and systolic
functional impairment. Thus, the CI returns to almost normal values
after thromboendarterectomy of the pulmonary arteries (Fig 1)
.
Limitations
In this study, invasive and echocardiographic examinations were
not performed simultaneously. However, heart rate and mean arterial BP
did not differ significantly in these examinations. It is difficult to
assess the size and systolic function of the right ventricle with great
accuracy because of its shape and the difficulties in tracing
endocardial borders. RV size may also appear different if the
transducer is placed over the RV or the LV apex, or if it is slightly
rotated. A reasonable image quality had to be achieved for the
examination results to be included in this study.
Determining the severity of TR by way of color Doppler echocardiography technique has several limitations. Thus, care was taken to use the optimal gain setting for each study examination. In pulmonary hypertension, a dorsal and left-lateral displacement of the left ventricle occurs. Thus, in some cases, the optimal transducer position could not be achieved for alignment with mitral inflow, which is directed to the lateral wall of the left ventricle. The same occurred in some of the examinations in which aortic outflow was determined. In these cases, a correction was made for the angle between the Doppler echocardiographic beam and flow direction.
Clinical Implications
The pathophysiologic mechanisms delineated in this study show that
clinical symptoms of patients with CTEPH are due to both RV and LV
functional impairment. PTE interrupts the underlying cycle and results
in an improvement of cardiac function and clinical symptoms as well.
Thus, patients with severe CTEPH benefit from PTE.
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Acknowledgements |
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Footnotes |
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Received for publication October 14, 1999. Accepted for publication March 22, 2000.
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