Primary pulmonary arterial hypertension with preserved right ventricular function leads to lower extremity venous insufficiency

Abstract

Objectives

Pulmonary hypertension with heart failure is related to venous insufficiency. However, there is no clear data whether pulmonary arterial hypertension with preserved right ventricular function cause venous insufficiency. In this study, we aim to investigate the relation between pulmonary arterial pressure with venous insufficiency in pulmonary arterial hypertension patients with preserved right ventricular function.

Methods

Between January 2012 and October 2014, 38 patients with a diagnosis of pulmonary arterial hypertension and 47 control group patients were included. Venous disability score and venous segmental disease score of both groups were calculated in order to measure venous insufficiency. The relationship between venous disability score and venous segmental disease scores and mean pulmonary arterial pressure and World Heart Organization functional capacity was examined.

Results

Total venous segmental disease score (5 ± 3.9 vs. 2 ± 1.8 p < 0.001), right venous segmental disease score (2.6 ± 2.2 vs. 1 ± 0.9 p < 0.001), left venous segmental disease score (2.4 ± 2.2 vs. 1 ± 0.9 p < 0.001), and venous disability scores (2.2 ±1 vs. 1.6 ± 0.7 p < 0.001) of patients with pulmonary arterial hypertension were higher than the control group. While the total venous segmental disease score was highly related to mean pulmonary arterial pressure (r = 0.829, p < 0.001), the venous disability score was only weakly related (r = 0.343, p = 0.037). Total venous segmental disease score (r = 0.606, p < 0.001) and venous disability scores (r = 0.601, p < 0.001) were moderately related with World Health Organization functional capacity intensity.

Conclusions

The degree of venous insufficiency increase in accordance with the mean pulmonary arterial pressure even in patients with preserved right ventricular function.

Keywords

Pulmonary hypertension venous insufficiency Doppler ultrasonography

Introduction

Venous insufficiency (VI) is a commonly seen pathology with 9.4% of men and 6.6% of women.¹ Venous insufficiency is a stepwise developing, complicated and multifactorial disorder in which blood return from the legs to the right heart is impaired.² Although its etiology is multifactorial, reflux through incompetent venous valves is the major mechanism of the pathophysiology.³

Venous hypertension is the main cause of pathological changes in the wall of the lower limb veins.⁴ Venous hypertension results from reflux of blood through incompetent valves mainly caused by previous deep vein thrombosis (DVT).⁵ However, external compression such as is the case in obesity with increased intraabdominal pressure may also cause venous hypertension and VI.⁶ Increased intraabdominal pressure in obese patients would have an impairing effect on venous function and, in particular, venous return, and possibly increase the rate of reflux.

Increased central venous pressure may also be related with cardiac disease. Cardiac disease with increased central venous pressure has also been studied recently with respect to the pathogenesis of venous valve incompetence resulting in venous hypertension and insufficiency. Previous studies showed that increased central venous pressure induced by pulmonary hypertension (PH) causes internal jugular vein valve incompetence.⁷ In addition, VI of the lower extremity appears more frequent in patients with chronic obstructive pulmonary disease (COPD) leading to right heart failure and increased central venous pressure.⁸ However, there is no study to directly investigate the effect of pulmonary arterial hypertension (PAH) with preserved right ventricular function on lower limb VI.

Although there has always been a consideration among vascular surgeons that a relation exists between lower extremity venous disease and PH, to the best of our knowledge, no study has been done to investigate the impact of PAH on venous function of the leg. The aim of this study was to examine the relationship between PAH and impaired venous function of the lower limbs.

Methods

After approval by the local ethics committee of the university, we screened the computerized database of the cardiology department of the university for 45 patients diagnosed and treated as having PAH between January 2012 and October 2014. A written informed consent was obtained from every patient. Patients who had PAH with reduced right and left ventricular dysfunction, secondary PH (other than PAH), coronary artery disease (evaluated by history, physical examination, electrocardiography, or previous coronary angiography), heart failure, atrial fibrillation, significant valve disease, or venous disease of the lower limbs, history of DVT, previous or current long-term anticoagulation therapy, history of lower extremity fracture, major abdominal or pelvic surgery, or history of COPD and those who declined to participate were excluded from study. We conducted the study with the remaining 38 patients.

All the patients with PAH underwent right heart catheterization, essential for the diagnosis of PAH, before the study. Therefore, pulmonary pressure values were present before those who underwent color duplex examinations. We acquired the pulmonary arterial pressure (PAP) values retrospectively from patient data registries. The study was continued with the functional classification for PH of the World Health Organization (WHO) from class I to class IV and color duplex examination of lower leg veins.

The control group of 76 patients was composed of patients who applied to the radiology department for any reason except pulmonary, cardiac, or venous disease. Written informed consent was also obtained from every patient in the control group. Twenty-three patients of the control group were excluded from the study for the same exclusion criteria mentioned above in addition to being in functional class II–IV. The remaining 53 patients in the control group were subjected to echocardiographic examination. In six patients of the control group, we detected systolic PAP (sPAP) > 36 mmHg or severe valve disease. After excluding these six patients, the remaining 47 patients in the control group were also subjected to color duplex examination of the lower leg veins.

All the patients in the PH and control groups were evaluated for venous disability score (VDS). The VDS quantifies physical limitations due to chronic venous disease. Score = 0, asymptomatic; score = 1, symptomatic but able to carry out usual activities without compression therapy; score = 2, symptomatic but able to carry out usual activities only with compression therapy or limb elevation; and score = 3, symptomatic but unable to carry out usual activities even with compression therapy or limb elevation.⁹

All the patients were subjected to transthoracic echocardiographic examination. Echocardiographic studies were performed using Philips HD11XE equipment, and subjects were requested to rest for at least 5 min before examination. All echocardiographic data were calculated based on the American Society of Echocardiography Guidelines.¹⁰ We used apical four-chamber view and M-mode scanning to measure the tricuspid annular plane systolic excursion (TAPSE). The right ventricle performance index (Tei index) has been calculated with tissue Doppler recordings from the lateral mitral annulus. Right ventricular Tei index was calculated as (A−B)/B, where A is the period is the sum of the isovolumetric contraction time, systolic contraction (S), and the isovolumetric relaxation time. B is defined as the systolic contraction time alone¹¹

Right heart catheterization was performed according to guidelines on Guidelines on Diagnosis and Treatment of Pulmonary Hypertension to confirm the diagnosis of PAH and to assess the severity mean PAP.¹²

All color duplex examinations of lower leg veins were made by the same radiologist, who was blinded to the absence or presence of PH using the HI VISION Ascendus system (HITACHI ALOKA Medical, Tokyo, Japan) with a high-frequency linear surface probe (7.5–10 MHz). Bilateral major venous segments of the lower extremity of all participants were examined in both B-mode gray scale and color duplex ultrasound. The patients who had any thrombotic material in lower leg veins were excluded from the study. In examination of VI, we examined vessels both spontaneously and during a valsalva maneuver. We evaluated venous reflux using spectral Doppler examination in the major venous segments and reflux longer than 1 s was defined as VI.⁶ Patients were scored using the venous segmental disease score (VSDS). Major venous segments were evaluated for the presence of reflux. The relative importance of each anatomic segment was weighted, with a maximum score of 10 for reflux—Thigh veins (small saphenous vein, 0.5 points; great saphenous vein, 1 point; perforator in thigh, 0.5 points; popliteal vein, 2 points; superficial femoral vein, 1 point; deep femoral vein, 1 point; common femoral vein or above, 1 point) and Calf veins (posterior tibial alone, 1 point; more than one calf vein, 2 points; perforator in calf, 1 point).

The correlation of VSDS and VDS score with mean PAP and WHO functional capacity was also investigated.

Statistical analysis

Analysis of the variables was done with the SPSS (version 15.0, SPSS Inc., Chicago, Illinois) program. Continuous variables are given as mean± standard deviation (mean± SD) and categorical variables are given as percent. Kolmogrov–Smirnov test was used to evaluate the distribution of variables. Continuous variables that had an even distribution were analyzed with Student’s t test and variables that had a non-normal distribution were evaluated with Mann–Whitney U test. While investigating the associations between mPAP, WHO functional capacity and VSDS and VDS score, the correlation coefficients (rho), and their significance were calculated using Spearman test. p < 0.05 was considered as statistically significant.

Results

Basic clinical properties of patients with PAH and the control group including patients without PH are shown in Table 1. Right ventricle Tei index (26.8 ± 3 vs. 27.1±.8 p > 0.05) and TAPSE (18.3 ± 2.4 vs. 18.9 ± 2.6 p > 0.05) were in normal range and similar between PAH patients and control group, respectively. Both groups had similar clinical features. VDS and VSDS scores of the PAH group and control group are compared in Table 2. It was observed that VDS and VSDS (right, left, and total) scores were higher in the PAH group (p < 0.001).

Table 1.

Comparison of patients with pulmonary arterial hypertension and control groups with regard to demographic and clinical properties.

	PAH group(n = 38)	Control group (n = 47)	p
Age (Year)	61 ± 10	59 ± 11	0.573
Male	40%	47%	0.498
DM	21%	32%	0.262
HT	32%	23%	0.399
Smoking	26%	26%	0.935
Height (cm)	166 ± 7.7	166 ± 6.9	0.806
Weight (kg)	68 ± 9.2	74 ± 12	0.012
BMI (kg/m²)	25 ± 3.1	26 ± 4.2	0.77

DM: diabetes mellitus; HT: hypertension; BMI: body mass index; PAH: pulmonary arterial hypertension; SD: standard deviation.

Values are presented as n, n (%), or mean ± SD.

Table 2.

VDS and VSDS points in pulmonary arterial hypertension and control group.

	PAH group(n = 38)	Control group (n = 47)	p
VDS	2.2 ± 1.0	1.6 ± 0.7	<0.001
VSDS
Left	2.4 ± 2.0	1 ± 1.0	<0.001
Right	2.6 ± 2.2	0.9 ± 1.0	<0.001
Total	5 ± 3.9	2 ± 1.8	<0.001

VDS: venous disability score, VSDS: venous segmental disease score; PH: pulmonary arterial hypertension.

n: Number, mean ± standard deviation (mean ± SD).

It was found that VDS scores were weakly related to mPAP (r = 0.343, p = 0.037). However, total VSDS score was well related to mPAP (r = 0.829, p < 0.001); also right and left VSDS scores were well related to mPAP (respectively, r = 0.791, p < 0.001, r = 0.750, p < 0.001). Figure 1 shows the correlation of total VSDS, right and left VSDS scores with mPAP.

Figure 1.

Correlation between total VSDS score (a), right lower limb VSDS score (b), and left lower limb VSDS score (c) and systolic pulmonary arterial pressure in scatter plot analyses. VSDS: venous segmental disease score; mPAP: mean pulmonary arterial pressure.

While VDS score (r = 0.601, p < 0.001), total VSDS score (r = 0.606, p < 0.001), and left VSDS score (r = 0.503, p < 0.001) were observed to be correlated to WHO functional capacity score at an acceptable degree, the correlation of right VSDS with WHO functional capacity was observed to be significant (r = 0.621, p < 0.001).

Discussion

In our study, we found that VI in the lower extremities was more common among patients with PAH than in a control group. The severity of VI also increased in relation to the severity of PH. To our knowledge, this is the first study investigating the relationship between PAH and lower limb VI.

VI of the lower limbs, including venous dilatation, incompetent venous valves, and ultimate venous hypertension, give rise to a broad spectrum of clinical consequences, such as edema, skin changes, and ulcerations.¹³ Older age, female sex, obesity, prolonged standing, and smoking are some of the well-documented risk factors of VI.¹⁴ Prolonged exposure to venous hypertension caused by valvular incompetence has a major role in the symptoms of VI.¹⁵ Progression of venous hypertension is caused by retrograde blood flow within the deep veins, superficial veins, and perforator veins of the lower limbs through incompetent venous valves.¹⁶

Although the relationship between VI and the risk factors mentioned above and the pathophysiological explanations is well defined, it is not clearly defined whether the mechanical and functional disorders of the heart might affect the formation of VI. The fact that the blood pumping power of the ventricle alone cannot be sufficient for venous return has been understood with time. It is well known that the mean circulatory filling pressure in the blood, central venous pressure, and vascular resistance are the main factors defining the return of venous blood.¹⁷ Two other basic forces have also been shown to provide venous blood return to the atrium from lower limb veins. The first one is the contraction of calf muscles and¹⁸ the second one is the pressure change due to respiratory changes.¹⁹ However, the effect of the atrium on venous return could not be explained. It has always been thought that the atrium plays a passive role in venous return. However, Rai et al.,^20,21 published a study and showed that the opening and closing function of venous valves are synchronous with the cardiac cycle. Venous valves open at the same time with atrial diastole following ventricular systole and close at the same time with atrial systole. On the other hand, a study on dogs suggested that the main mechanism is the suction power of the atrium besides other factors like skeletal muscle contraction and respiratory functions for the transfer of peripheral venous blood to the heart.²² The negative pressure in the atrium during atrial diastole producing a suction effect pulls the blood up in the vena cava, so the venous valves open by the effect of this negative pressure. Opposite to that, during atrial systole, negative pressure disappears and also by the effect of gravity, the atrium loses suction power and the venous valves close to avoid backflow of the blood. As a result, the atrial effect is not just a reservoir but it has an active role in venous return.²² According to these data and information, we have set a hypothesis that the clinical disorders leading to increased atrial pressure may cause venous valvular insufficiency because of the loss of suction effect due to negative pressure in the atrium. Thus, Doepp et al.,²³ have demonstrated that jugular venous valve insufficiency developed in all of five cases with primary PH, in 60% of 30 COPD cases and in 27% of control group patients. Especially in patients with PH and COPD, VI rates are much higher than in control groups. Regardless of the underlying causes, it was found that PAP elevation is correlated with the degree of internal jugular venous valvular insufficiency. In these two groups of patients, it was suggested that PH causes an increase in right atrial pressure and this causes venous VI by increasing central blood pressure. Similarly, Erdogmus et al.⁸ suggested that the prevalence of VI in patients with COPD is higher than the control group, independently of other risk factors. They determined that the prevalence rate of VI increased as the severity of COPD increased. Indeed, VI was observed in all patients with PH and cor pulmonale. But in this study, the relationship between PH and VI was not directly examined. Our study is the first one evaluating the direct relationship between pulmonary pressure elevation and lower limb VI after matching conventional risk factors. In our study, a very good correlation was observed between sPAP elevation and VSDS score showing the severity of peripheral VI. Much more objective data on the degree and severity of VI were obtained in our study using quantitative evaluation by VSDS scoring of all venous valves in the calf and hip regions. When we bring together the data of our study and the other mentioned clinical studies and trials, it can be considered that elevation of right atrium pressure and increased central venous blood pressure due to increase in sPAP causes a decline in suction power formed during right atrial diastole. This may lead to insufficiency of venous system valves reaching the heart through the inferior vena cava. In this context, PAP plays a direct role in the pathophysiology of VI.

Limitations of the study

Although the relationship between mPAP and VI was clearly shown in this study, an increase in the number of patients with PH would add much more value to the study.

Conclusion

VDS and VSDS scores that show VI are higher in patients with PAH. The degree of peripheral VI is correlated with WHO functional capacity and mPAP even in normal right ventricular function. Therefore, in patients suffering from venous insufficiency, it is recommended to investigate pulmonary arterial hypertension as another etiology of it.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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