Assessment of Pulmonary Arterial Hemodynamic and Vascular Changes by Pulmonary Pulse Transit Time in Patients with Human Immunodeficiency Virus Infection.

INTRODUCTION: Pulmonary arterial hypertension and human immunodeficiency virus (HIV) infection is a well-known association. Pulmonary pulse transit time (pPTT) is a recent echocardiographic marker that might be used for evaluation of pulmonary arterial stiffness (PAS) in patients with HIV infection. We aimed to investigate whether pPTT elevated in patients with HIV infection compared to healthy controls and its association with echocardiographic indices of right ventricular functions.
MATERIALS AND METHODS: Fifty HIV (+) patients from infectious disease outpatient clinics and fifty age- and sex-matched HIV (-) healthy volunteers were enrolled in this study. pPTT was measured from pulmonary vein flow velocity as the time interval between the R-wave in the electrocardiography and corresponding peak late systolic was then calculated as the mean from two separate pw-Doppler measurements.
RESULTS: pPTT, tricuspid annular peak systolic excursion (TAPSE) and right ventricle fractional area change (FAC) were significantly lower in patients with HIV than control patients (177.1 ± 34.9 vs. 215.7 ± 35.7 msn, P < 0.001; 2.33 ± 0.28 vs. 2.19 ± 0.22, P = 0.039; 45 [4.25] vs. 41.1 [4.0], P = 0.032, respectively). pPTT was positively correlated with FAC, TAPSE and cluster of differentiation 4 count (r = 0.210; P = 0.036, r = 0.256; P = 0.041, r = 0.304; P = 0.044, respectively).
CONCLUSION: Our study showed that pPTT, TAPSE, and right ventricle FAC levels were lower in patients with HIV infection. pPTT is an important predictor in patients with HIV expected to develop pulmonary vascular pathology. Copyright:

INTRODUCTION

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance (PVR), leading to right ventricular (RV) failure and premature death.[12] One of the causes of PAH is human immunodeficiency virus (HIV) infection, and survival is worse in patients with HIV-PAH, compared with either HIV-infected patients without PAH or patients with idiopathic PAH.[3] In this subset, early detection of PAH is essential, as it could be provide early treatment and improvement of the survival for patients.[4]

Transthoracic echocardiography represents an important diagnostic tool to diagnose PAH; various studies have been done to evaluate RV function in HIV-infected patients.[45] Most of the studies included traditional RV function parameters such as tricuspid annular peak systolic excursion (TAPSE), myocardial performance index.[6] Pulmonary pulse transit time (pPTT) is a surrogating echocardiographic marker for pulmonary hypertension[7] and might give valuable information about the stiffness of pulmonary vascular disease.[89] The objective of this study was to assess whether the pPTT level was different in HIV-infected patients and its relation with RV function.

MATERIALS AND METHODS

Study population

Fifty, HIV (+) patients from infectious disease outpatient clinic and fifty age- and sex-matched HIV (−) healthy volunteers were enrolled in this study. The exact diagnosis of HIV infection was established after documenting medical history and positive HIV antibody testing. The subjects with moderate-severe heart valve disease, heart failure (left ventricular [LV] ejection fraction [EF] below 50%), autoimmune disorders, malignancy, moderate-severe pulmonary disease, active infection, pregnancy, diabetes mellitus, hypertension, thyroid disorders, severe chronic obstructive pulmonary disease, rheumatologic disease, abnormal serum electrolyte values, kidney failure, incomplete/complete bundle branch block, atrial fibrillation, and paced rhythm were excluded. All patients underwent respiratory function tests to exclude subtle lung disease. Patients with concomitant hepatitis C and hepatitis B infection were also excluded. Duration of disease and duration of treatment was calculated for each patient. All patients were on highly active anti-retroviral (HAART) therapy and none of the patients was not AIDS. The study protocol was approved by the local ethics committee, and a written informed consent was obtained from each subject before the study.

Laboratory measurements

Blood samples were obtained from all participants in the morning after 8 h of fasting. The biochemical tests included the complete blood count and cluster of differentiation 4 (CD4) count. The weight and height of the participants were measured, and their body mass index (BMIs) (kg/m2) was calculated.

Transthoracic echocardiography

Transthoracic echocardiographic was performed with patients in the standard left lateral decubitus position using General Electric Vivid E95 echocardiographic imaging system (Horten, Norway) with a 2.5–5 MHz transducer. Examinations were performed by a two-experienced cardiologist who were blind to the characteristics of individuals. Pulmonary vein flow was obtained by Doppler of the right superior pulmonary vein from the apical four-chamber view according to guidelines of the American Society of Echocardiography.[10] Twelve patients whose right upper pulmonic vein flow Doppler cannot be obtained excluded from the study. Study patients had good enough images for analysis of pulmonary venous flow for the measurement. All patients were examined in the sinus rhythm and asymptomatic in terms of cardiac symptoms. The Nyquist limit was adjusted to 15–20 cm/s and the sweep speed was set to 50–100 mm/s to optimize the spectral display of myocardial velocities. pPTT was defined as the time interval between the R-wave in the electrocardiogram (ECG) and corresponding peak late systolic pulmonary vein flow velocity (R-PVs2 interval), was then calculated as the mean from 2 separate pw-Doppler measurements taken during the same examination.[7] A continuous one-lead ECG was obtained during all examinations. The blood pressure of all participants was measured before the examination. LV EF was estimated using the Simpson's rule. Basic echocardiographic measurement such as left atrium antero-posterior diameter, LV end-systolic, end-diastolic dimensions, diastolic ventricular septal, and diastolic LV posterior wall thickness were performed in the parasternal long-axis view. systolic pulmonary artery pressure (sPAP) was measured as the sum of caval breathing index using the Bernoulli equation and right atrial pressure value attained from the tricuspid valve pressure gradient. We performed sPAP, tricuspid annular peak systolic excursion (TAPSE), fractional area change (FAC), and tricuspid systolic annular velocity.

Statistical analysis

Continuous variables were expressed as mean ± standard deviation or median with interquartile range, and categorical variables were expressed as percentages and numbers. The normality of distributions of the parameters was assessed using the Kolmogorov–Smirnov test. Comparison between continuous variables was made by use of independent samples t-test for normally distributed variables, and Mann–Whitney U-test when the distribution was skewed. Pearson's correlation coefficients were used to assess the strength of the relationship between continuous variables, and Spearman correlation analysis was performed for non-continuous and categorical variables. All statistical procedures were performed using SPSS software version 20.0 (SPSS Inc., Chicago, IL, USA). A P < 0.05 was considered statistically significant.

RESULTS

Baseline clinical characteristics of the study groups are shown in Table 1. Gender, mean age, body mass index, lymphocyte count, and neutrophil count were not statistically different between the control and the HIV (+) patients. Hemoglobin levels were slightly higher but not statistically significant in HIV-positive patients than HIV negative patients (14.8 ± 1.3 vs. 13.9 ± 1.41 mg/dL, P = 0.055). Echocardiographic image and parameters are shown in Table 2 [Figure 1]. There were no significant differences between the control and the HIV (+) patients in terms of heart rate, LV end-diastolic dimension, LV end-systolic dimension, EF, diameter of the left atrium, diastolic interventricular septum diameter, and diastolic LV posterior wall diameter. RV functions and pPTT between HIV positive and control group are shown in Table 3. There were no differences between the control group and HIV-positive group in terms of basal RV diameter and pulmonary artery systolic pressure. pPTT, TAPSE, FAC were significantly lower in patients with HIV than control patients (177.1 ± 34.9 vs. 215.7 ± 35.7 msn, P < 0.001; 2.33 ± 0.28 vs. 2.19 ± 0.22, P = 0.039; 45 (4.25) vs. 41.1 (4.0), P = 0.032, respectively). pPTT was positively correlated with FAC, TAPSE, and CD4 count (r = 0.210; P = 0.036, r = 0.256; P = 0.041, r = 0.304; P = 0.044, respectively) [Table 4].

Table 1

Baseline clinical characteristics of patients and control subjects

	HIV NEGATİVE (n=50)	HIV POSITIVE (n=50)	P
Age, years	41.2±12.3	43.8±15.7	0.375
Male, n (%)	40 (80.0%)	42 (84.0%)	0.227
BMI, kg/m2	24.3±3.4	26.3±5.2	0.545
Hemoglobin, mg/dL	13.9±1.41	14.8±1.3	0.055
Neutrophil, x103/uL	4.41±1.89	3.83±1.48	0.193
Lymphocyte, x103/uL	1.90 (0.60)	1.85 (0.65)	0.503
CD4 count, cells/mm3	-	556.0±238.7	-

BMI, body mass index, P<0.05 statistically significant, mean±standard deviation, median (interquartile range)

Table 2

Echocardiographic features of the study and healthy subjects

	HIV NEGATİVE (n=50)	HIV POSITIVE (n=50)	P
Heart rate, bpm	74.5 (16.5)	75 (13.25)	0.546
LVIDd, mm	47.9±4.9	48.3±5.2	0.681
LVIDs, mm	31.1±4.7	31.9±4.0	0.363
LVEF, %	61 (3.5)	62 (3.0)	0.587
Diameter of left atrium, cm	3.10±0.30	3.20±0.36	0.664
IVSd, cm	0.99±0.10	0.96±0.15	0.261
LVPWd, cm	0.93±0.11	0.92±0.13	0.751

LVEF, left ventricular ejection fraction; LVIDd, left ventricular end diastolic dimension; LVIDs, left ventricular end systolic dimension; IVSd, diastolic interventricular septum diameter; LVPWd, diastolic left ventricular posterior wall diameter, P<0.05 statistically significant, mean±standart deviation, median (interquartile range)

Figure 1

pPTT was defined as the time interval between the R-wave in the electrocardiogram (ECG) and corresponding peak late systolic pulmonary vein flow velocity (R PVs2 interval)

Table 3

Right ventricular functions and pulmonary pulse transit time between HIV positive and control group

	HIV NEGATİVE (n=50)	HIV POSITIVE (n=50)	P
Basal RV diameter, cm	2.18±0.33	2.27±0.35	0.208
TAPSE, cm	2.33±0.28	2.19±0.22	0.039
sPAP, mmHg	23.4±3.9	23.9±5.2	0.593
FAC, %	45 (4.25)	41.1 (4.0)	0.032
Tricuspid Sm’, cm/s	12 (3)	11 (2)	0.847
pPTT, msn	215.7±35.7	177.1±34.9	<0.001

FAC, fractional area change; Sm, systolic tricuspid annular velocity; sPAP, pulmonary artery systolic pressure; pPTT, pulmonary pulse transit time; TAPSE, tricuspid annular plane systolic excursion. P<0.05 statistically significant, mean±standard deviation, median (interquartile range)

Table 4

Correlation analysis between pulmonary pulse transit time and variables

	Correlation coefficient (r)	P
Age	-0.094	0.254
CD4 count	0.304	0.044
BMI	0.007	0.965
Diameter of left atrium	0.095	0.522
Basal RV diameter	-0.050	0.540
Tricuspid Sm	0.067	0.416
sPAP	-0.155	0.228
FAC	0.210	0.036
LVEF	-0.093	0.295
TAPSE	0,256	0.041

BMI, body mass index; FAC, fractional area change; LVEF, left ventricular ejection fraction; sPAP, pulmonary artery systolic pressure; RV, right ventricle; TAPSE, tricuspid annular plane systolic excursion; Tricuspid Sm, systolic tricuspid annular velocity.

DISCUSSION

Our study demonstrated that a noninvasive and simple Doppler-derived marker called pPTT is a possible surrogate marker of pulmonary hemodynamic alterations and vascular stiffening in HIV-infected patients. pPTT was found significantly lower in patients with HIV-infected patients than in controls. On the other hand, pPTT was positively correlated with FAC, TAPSE, and CD 4 count.

HIV-related cardiac involvement is represented by asymptomatic right ventricle dysfunction (detectable only by advanced echocardiography), PAH and left ventricle dysfunction.[11] PAH caused by chronic obstruction of small pulmonary arteries and it eventually leads to RV failure and death. One of the established risk factors for the development of PAH is HIV infection.[1213] HIV-PAH is a rare entity; however, the prevalence was estimated to be approximately 0.5% in HIV-infected patients before the HAART therapy[14] but indicating that HAART has not made a great impact on the prevention of HIV-PAH.[3]

Diagnoses of HIV-related PAH are often beside on clinical doubt because of the main symptom of the disease is dyspnea and requires multidisciplinary approach. Recent studies have reported that >35%–57% of HIV-positive patients had systolic pulmonary arterial pressure (SPAP) >30 mmHg.[1516] Most of the HIV-positive patients with PAH are mostly diagnosed in the final stages of the disease.[17] It seems too important to diagnose HIV-related PAH in the early stages. The median time of diagnosis to death in these patients is approximately equal to 6 months; therefore, early diagnosis of PAH may provide to timely treatment and decrease in symptoms and rate of mortality.[4]

Previous studies have showed that pulse wave velocity (PWV) and the inversely related pulse transit time are physiologic measures and they have been identified as clinically important parameters in the evaluation of increased arterial stiffness in high blood pressure.[1819] PWV is a speed marker, and the pulse pressure wave travels along an arterial segment; however, pPTT refers to the time it takes the pulse pressure wave to travel from one arterial site to another.[718] While arterial stiffness and blood pressure increasing, PWV increases and pPTT shortens.[1820] It has been suggested that alterations in pulmonary vascular impedance resulting from vascular stiffening might have the potential to be a better predictor of prognosis and outcome than PVR.[2122] Wibmer et al. showed that a shortening of the interval between the R-wave in the ECG and the peak late systolic pulmonary vein flow velocity (R-PVs2) in patients with pulmonary hypertension.[7] In addition to these findings, Cerik et al. showed correlation between pulmonary arterial stiffness (PAS) and pulmonary acceleration time with HIV-infected patients.[23]

In the European Society of Cardiology/European Respiratory Society pulmonary hypertension guideline published in 2015, HIV infection and connective tissue disorder are included both in Group 1 (PAH) and in Group 1' pulmonary veno-occlusive disease as an etiopathological factor for PH.[24] There are similar pathological findings in patients with PAH. Intima, media and adventitia include hypertrophy, proliferation, and plexiform lesions. In the present study, pPTT levels in patients with HIV infection were lower than controls. SPAP was slightly higher in the HIV group, but it did not reach statistical significance. RV dysfunction can be seen in HIV-positive patients.[25] Virus-induced myocarditis, drug side effects, autonomic system disorders, and oxidative stress are some of them. In our study, the parameters associated with RV dysfunction (pPTT, TAPSE, RV FAC) were found to be statistically significantly lower in the HIV-positive arm, but no difference was found in sPAP. The sPAP calculation measured from the tricuspid regurgitation jet is based on the RV and right atrium (RA) gradient. In RV dysfunction, RA pressure rises. Consequently, the RV-RA gradient decreases and sPAP can be underestimated as in severe tricuspid regurgitation. This may explain why significant changes in pTT, TAPSE and RV FAC are not observed in the sPAP parameter. Recent study reported by Efe et al. has shown that TAPSE was positively correlated with pPTT and they found lower pPTT values in the patients with lupus.[26] Dogan et al. showed that pPTT and TAPSE were shorter in patients with systemic sclerosis as compared to the controls.[27] Our study showed that patients with HIV had shorter pPTT and its correlation with TAPSE. We also found that pPTT was positively correlated with FAC of the right ventricle. FAC is a relatively simple method for evaluating RV function and it is used as a quantitative method for estimating RV function via transthoracic echocardiography.[28] FAC reflects both the longitudinal and transverse movement of the RV and it might be more valuable than TAPSE in the assessment of RV functions.[2829]

CONCLUSION

pPTT is a simple and easily calculated echocardiographic marker for the evaluation of pulmonary hemodynamics. pPTT seems to be able to predict the possible development of pulmonary vascular disease in patients with HIV even when their pulmonary arterial pressure is still within the normal range.

Limitations

Main limitation of this study was absence of long-term follow-up data. We did not know whether the patients were developed PAH. The number of patients with HIV infection was relatively small. Non-HAART regimen patients were not included in this study, because of that we did not know the relation between HAART regimen and pulmonary hypertension.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.