Prognostic significance of insulin resistance in pulmonary hypertension

Introduction

Pulmonary arterial hypertension (PAH) is a disease of pulmonary vascular bed in which the remodelling, vasoconstriction, and increased thrombotic state in pulmonary vasculature lead to a progressive increase in pulmonary vascular resistance, right ventricular failure, and death.1

The pathophysiological mechanisms involved in the development and progression of PAH are complex and the role of many genetic and environmental factors have been suggested.2, 3

One of the recent advances in describing the pathophysiology of PAH is the presence of an association between insulin resistance (IR) and PAH.4-11

Our previous study6 indicated that the incidence of glucose intolerance and IR could be higher in patients with PAH. However, our study population was only composed of patients with class I of PAH. In addition, we did not directly assess IR and used triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C) ratio (TG/HDL-C) as a surrogate of IR in our study population.

The homeostasis model assessment-estimated insulin resistance (HOMA-IR), developed by Matthews et al., is a convenient method for estimation of IR and has been widely used in clinical and epidemiological researches.12, 13

In the present study, we aimed to assess HOMA-IR in patients with pulmonary hypertension (PH) in all PH classes [without a history of diabetes mellitus (DM)] and its prognostic significance in this group of patients.

Methods Patient selection

The study population was selected among patients scheduled for right heart catheterization (RHC) between March 2015 and March 2016 for evaluation of PH for the first time or at follow-up according to the following inclusion/exclusion criteria.

Inclusion criteria:

Presence of PH based on updated clinical classification of PH; a mean of pulmonary artery pressure (PAP) ≥ 25 mmHg in RHC

Age ≥ 18 years

Exclusion criteria:

Established DM

Under treatment for hyperlipidaemia

Presence of glucose intolerance [glycosylated haemoglobin (HbA1c) > 6%] or high blood sugar in favour of undiagnosed DM [fasting blood sugar (FBS) > 126 mg/dL or 2 h plasma glucose ≥ 200 mg/dL] in laboratory evaluations preceded RHC

A history of prednisolone intake or other corticosteroids

Decompensated right ventricular failure and/or overt fluid overload

Inability to perform 6 min walk test (6MWT)

Isolated postcapillary PH

Patients' evaluation and follow-up

Clinical history and a thorough physical examination were obtained from all the patients. The New York Heart Association (NYHA) functional class of all study population was assessed by the same investigator.

Body weight of the study population was measured with the subject wearing a hospital gown and their height was measured without shoes. Waist circumference was measured midway between the iliac crest and the lower rib margin.

Body mass index (BMI) was calculated by the weight divided by the square of the height.

The 6MWT was performed according to the protocol of Guyatt et al.14

All the blood analyses were performed at our laboratory on the day of RHC. Blood samples were collected from all study population after 12 h of overnight fasting. FBS was measured using enzymatic colorimetric method with glucose oxidase. HbA1c was assayed using high performance liquid chromatography (HPLC) by standardized laboratory protocol using a method certified by the National Glycohemoglobin Standardization Program. Fasting insulin was assayed by radioimmunoassay (Immunotech, Prague, Czech Republic) with a sensitivity of 0.5 μU/mL. HOMA-IR was calculated by the following formula: Fasting insulin (U/L) × FBS (mg/dL)/405, as described by Matthews et al.12, 13

Total cholesterol was measured using enzymatic colorimetric method with cholesterol esterase and cholesterol oxidase. HDL-C was measured after precipitation of the apolipoprotein B-containing lipoproteins with phosphotungstic acid. Serum TG level was measured using an enzymatic colorimetric method with glycerol phosphate oxidase.

Patients were defined to have IR or insulin sensitivity (IS) based on the HOMA-IR. The proposed value of HOMA-IR for distinction between IS and IR was considered according to what described in an Iranian study by Esteghamati et al.12 Accordingly, the HOMA-IR ≥ 1.775 was considered as IR in non-diabetic people. The cut point of HOMA-IR for IR in those who have metabolic syndrome features is 4.325.

As our previous study,6 we also checked the ratio of TG/HDL-C. We defined an individual as IS when TG/HDL-C ratio was <2.0 and IR when TG/HDL-C ratio was >3.0.

We also defined the metabolic syndrome in our study population according to the International Diabetes Federation (IDF).15

According to IDF definition, a person defined as having metabolic syndrome should have central obesity plus any two of the following: (i) fasting plasma glucose ≥ 100 mg/dL (or diabetes); (ii) TG ≥ 150 mg/dL; (iii) HDL < 40 mg/dL for men and <50 mg/dL for women; and (iv) systolic blood pressure ≥ 130 mmHg or diastolic blood pressure ≥ 85 mmHg.

The central obesity, based on cut-off points of the Iranian population, is defined as waist circumference > 90 cm in males and females.15

Using HOMA-IR cut-off, the prevalence of IR in those without and with IDF defined-metabolic syndrome is considered 24.1% and 42.5%, respectively, in Iranian population.12

Right heart catheterization was performed by standard method in all patients in catheterization laboratory. The following variables were measured for each patient: mean right atrial pressure (RAP); systolic and end-diastolic right ventricular pressure; systolic, diastolic, and mean PAP; pulmonary capillary wedge pressure (PCWP); and mixed venous oxygen saturation and cardiac output (CO) by the Fick method. The cardiac index (CI) was calculated by dividing CO to body surface area (BSA). The European Society of Cardiology 2015 guideline in diagnosis and management of PH was considered to define the presence of PH and determine the haemodynamic category (precapillary vs. postcapillary) as well as the PH World Health Organization (WHO) group of each patient.1

All selected patients were followed up until the end of 2019 for all causes of death by reviewing the hospital records or by contacting them on the phone.

This study was approved by the research and ethics committee of Rajaie Cardiovascular Medical and Research Center, and written informed consent was obtained from all patients.

Mortality risk assessment

For the mortality risk assessment of study participant, the simplified risk assessment tool as described by Boucly et al. was used.16

Four variables, namely, NYHA functional class, 6MWT distance, RAP, and CI, were considered for this risk stratification. The study participants were divided into low and high risk according to these criteria. The patients were categorized as low risk if they had three to four of four low-risk criteria.

Low-risk criteria:

NYHA class I–II

6MWT distance > 440 m

RAP < 8 mmHg

CI ≥ 2.5 L/min/m2

Study endpoints

The primary endpoint of the study was to determine the prevalence of IR in patients with PH and its different subgroups.

The secondary endpoint was the prevalence and the predictors of all causes of mortality and its relationship with IR.

Statistical analysis

IBM SPSS Statistics 19 (IBM SPSS Statistics for Windows, Version 19.0, Armonk, NY, USA: IBM Corp.) was used for all statistical analyses. The normality of distribution for all variables was verified by the one-sample Kolmogorov–Smirnov test. Categorical variables were reported as number (percentage), and quantitative variables were expressed as mean (standard deviation) or median (interquartile range, IQR) as appropriate. The Student's t-test, χ2 test, and Mann–Whitney test were used for comparisons and associations, as appropriate. Relationships were assessed using the Pearson or Spearman correlation coefficient depending on their distribution. P value < 0.05 was considered significant.

Results

Among 100 new and returning patients with PH scheduled for RHC between 2015 and 2016, a total of 59 patients (54.2% female) were enrolled according to our inclusion/exclusion criteria.

Table 1 depicts clinical, laboratory, and haemodynamic characteristics of all study participants, IR, and IS subgroups.

Table 1. Clinical, laboratory, and haemodynamic characteristics of all study participants, insulin resistance, and insulin sensitive subgroups, n = 59 Variables All study participants N = 59 Insulin resistance N = 16 Insulin sensitive N = 43 P valuea Sex (female), number (%) 32 (54.9) 9 (57) 23 (53) 0.02 Age, years, mean (SD) 45.9 (17.3) 46.2 (19.9) 45.8 (16.5) 0.1 Body mass index, kg/m2, mean (SD) 23.9 (4.9) 24.3 (5.8) 23.8 (4.6) 0.01 Waist circumference, cm, mean (SD) 83.8 (17.6) 84.7 (17) 82 (16) 0.4 History of hypertension, number (%) 10 (17) 2 (12.5) 8 (18.6) 0.5 Central obesity, number (%) 22 (37) 5 (31.2) 17 (39.5) 0.5 Metabolic syndrome, number (%) 6 (10.2) 2 (12.5) 4 (9.3) 0.7 Pulmonary hypertension class, number (%) Class I 28 (47.5) 11 (69) 17 (39.5) 0.05b Class II 17 (28.8) 1 (6.3) 16 (37.2) Class III 3 (5.1) 1 (6.3) 2 (4.7) Class IV 10 (16.9) 3 (19) 7 (16.3) Class V 1 (1.7) 0 1 (2.3) Pulmonary hypertension haemodynamic type 0.02 Precapillary 42 (71.2) 15 (25.4) 27 (45.7) Combined postcapillary 17 (28.8) 1 (1.7) 16 (27.1) NYHA functional class 0.5 I 1 (1.6) 0 1 (2.3) II 26 (44) 8 (50) 18 (42) III 29 (49.1) 8 (50) 21 (49) IV 3 (0.5) 0 3 (7) 6MWT, m, median (IQR) 330 (290–400) 375 (300–403) 330 (280–390) 0.3 FBS, mg/dL, mean (SD) 91.7 (10.7) 91.7 (10.4) 91.7 (10.9) 0.9 TG, mg/dL, mean (SD) 111 (42) 124 (50) 106 (38) 0.1 HDL, mg/dL, mean (SD) 39 (10) 38 (9.5) 40 (10) 0.6 Total cholesterol, mg/dL, mean (SD) 145 (41) 152 (42) 143 (41) 0.4 HbA1c, %, median (IQR) 5.0 (4.9–5.8) 5.02 (4.9–5.8) 5.2 (4.9–5.2) 0.9 TG/HDL, mg/dL, mean (SD) 2.8 (1.07) 3.2 (1.3) 2.7 (0.9) 0.1 Insulin level, mIU/L, median (IQR) 42.9 (20.9–104.9) 142 (117–207) 31 (20–51) <0.0001 HOMA-IR, median (IQR) 0.8 (0.4–1.9) 2.5 (2.2–3.7) 0.6 (0.4–1) <0.0001 Cardiac index, L/min/m2, mean (SD) 2.4 (0.6) 2.6 (0.6) 2.3 (0.6) 0.3 Right atrial pressure, mmHg, median (IQR) 10 (8–14) 8.5 (7–13) 11 (8–16) 0.1 Mean pulmonary artery pressure, mmHg, median (IQR) 40 (30–50) 33 (27–51) 42 (36–50) 0.2 High-risk criteria, number (%) 49 (83.1) 13 (81.3) 36 (83.7) 0.8 Mortality rate, number (%) 26 (44.1) 7 (43.8) 19 (44.2) 0.9 6MWT, 6 min walk test; FBS, fasting blood sugar; HbA1c, glycosylated haemoglobin; HDL, high-density lipoprotein; HOMA-IR, homeostasis model assessment of insulin resistance; IQR, interquartile range; NYHA, New York Heart Association; SD, standard deviation; TG, triglyceride.

The mean (standard deviation) of age was 45.9 (17.3) years. The majority of patients had NYHA class of II and III and considering the WHO PH classification, 47.5% were in class I (PAH), 28.8% class II (PH due to left heart), 5.1% class III (PH due to lung diseases), 16.9% class IV (chronic thromboembolic PH), and 1.7% class V (multifactorial PH including patients with haemolytic anaemias).

Regarding the haemodynamic classification of PH, 42 (71.2%) and 17 (28.8%) patients had precapillary PH and combined postcapillary PH, respectively.

The aetiological diagnoses in patients with class I of PH were idiopathic PAH and Eisenmenger syndrome in 11 and 17 patients, respectively. Ten (35%) patients had been evaluated as naïve PH and the rest of them were on specific PH therapy including phosphodiesterase 5-inhibitors (PDE5-I) and/or bosentan.

The most common aetiology for the patients in WHO PH group of II was dilated (ischaemic or non-ischaemic) cardiomyopathy.

Insulin resistance

As shown in Table 1, 16 (27.1%) patients had criteria of IR. Except one case who had combined postcapillary PH, and the rest of IR patients were in precapillary PH group. So we decided to analyse the significance of IR only in patients with precapillary PH.

Table 2 depicts the comparison of clinical, laboratory, and haemodynamic characteristics of IR and IS patients with precapillary PH (PAH).

Table 2. Comparison of clinical, laboratory, and haemodynamic characteristics of insulin resistance and insulin sensitive patients with precapillary pulmonary hypertension (PAH), n = 42 Variables All patients with precapillary PH N = 42 Insulin resistance N = 15 Insulin sensitive N = 27 P value Sex (female), number (%) 25 (59.5) 9 (59) 16 (60) 0.9 Age, years, mean (SD) 45.9 (17.3) 46.3 (20.6) 42.6 (16) 0.5 Body mass index, kg/m2, mean (SD) 23.9 (4.9) 24.2 (6) 23.1 (4.4) 0.4 Waist circumference, cm, mean (SD) 81 (17) 80 (18) 81 (16) 0.8 History of hypertension, number (%) 5 (11.9) 1 (6.7) 4 (14.8) 0.4 Central obesity, number (%) 12 (30) 4 (27) 8 (29) 0.8 Metabolic syndrome, number (%) 4 (9.5) 2 (13.3) 2 (7.4) 0.5 NYHA class 0.6 I 1 (2.4) 0 1 (3.7) II 24 (57.1) 8 (53) 16 (59) III 17 (40.5) 7 (47) 10 (37) IV 0 0 0 6MWT, m, median (IQR) 330 (290–400) 390 (300–405) 380 (310–410) 0.8 FBS, mg/dL, mean (SD) 91.7 (10.7) 92 (9.7) 89 (9.4) 0.5 TG, mg/dL, mean (SD) 113.7 (41) 128 (50) 105 (33) 0.09 HDL, mg/dL, mean (SD) 40 (10) 39 (9.5) 41 (11) 0.6 Total cholesterol, mg/dL, mean (SD) 146 (38) 156 (40) 141 (37) 0.2 HbA1c, %, median (IQR) 5.0 (4.9–5.8) 5.0 (4.9–5.8) 5.1 (4.8–5.9) 0.5 TG/HDL, mg/dL, mean (SD) 2.8 (1.07) 3.3 (1.3) 2.7 (0.9) 0.09 Insulin level, mIU/L, median (IQR) 42.9 (20.9–104.9) 148.8 (121–239) 31.3 (21–60) <0.0001 HOMA-IR, median (IQR) 0.8 (0.4–1.9) 3.2 (2.4–3.7) 0.6 (0.1–1.1) <0.0001 Cardiac index, L/min/m2, mean (SD) 2.4 (0.6) 2.6 (0.5) 2.5 (0.5) 0.6 Right atrial pressure, mmHg, median (IQR) 10 (8–14) 8 (7–13) 10 (8–12) 0.6 Mean pulmonary artery pressure, mmHg, median (IQR) 40 (30–50) 34 (27–52) 45 (30–55) 0.4 High-risk criteria, number (%) 33 (78.6) 12 (80) 21 (78) 0.8 Mortality rate, number (%) 14 (33.3) 7 (47) 7 (26) 0.1 6MWT, 6 min walk test; FBS, fasting blood sugar; HbA1c, glycosylated haemoglobin; HDL, high-density lipoprotein; HOMA-IR, homeostasis model assessment of insulin resistance; IQR, interquartile range; NYHA, New York Heart Association; PH, pulmonary hypertension; SD, standard deviation; TG, triglyceride.

Among 42 patients with precapillary PH, 4 patients showed the criteria of metabolic syndrome. As the patients with high fasting glucose level were excluded before enrolment, these 4 patients had central obesity plus a history of systemic hypertension or TG ≥ 150 mg/dL or HDL < 40 mg/dL for men and <50 mg/dL for women.

Thirteen of the remaining 38 patients had the criterion of IR, which means that the prevalence of IR (34.2%) in non-diabetic, non-metabolic syndrome PAH patients might be higher than Iranian general population.

As shown in Table 2, there was no statistically significant difference between the groups of IR and IS in terms of demographic, clinical, BMI, features of metabolic syndrome, and haemodynamic data.

The central obesity was observed in 30% of PAH group and according to the IDF, four (9.5%) of them fulfilled the criteria for the metabolic syndrome in which 50% had IR.

As HOMA-IR had a non-normal distribution, Spearman's rank correlation was used to show whether there was any correlation between HOMA-IR and TG/HDL ratio. We could not find any correlation between these two variables (Spearman's rho = 0.2, P value = 0.1); however, the TG/HDL ratio was higher in IR group and all the patients with metabolic syndrome features had a TG/HDL ratio more than 3. On the other hand, despite the fact that the difference was not statistically significant, both serum insulin levels [median (IQR) = 76 (25–149) mIU/L in those with TG/HDL > 3 vs. 56 (20–110) mIU/L in those with TG/HDL < 3, P = 0.5] and HOMA-IR [median (IQR) = 1.4 (0.5–2.8) in those with TG/HDL > 3 vs. 1 (0.4–1.9) in those with TG/HDL < 3, P = 0.5] were higher in those with a TG/HDL ratio more than 3.

There was also no statistically significant correlation between fasting insulin, HOMA-IR, and BMI or 6MWT distance.

Study outcomes Mortality risk assessment

Considering the simplified mortality risk assessment tool, 49 of 59 patients could be categorized as elevated risk.

In precapillary PH group, 33 of 42 patients were categorized as elevated risk.

There was no difference between IR and IS groups in terms of the risk category (P = 0.8). However, although the HOMA-IR level was not different in elevated risk and low-risk groups [the median (IQR) of HOMA-IR in elevated risk and low-risk groups was 0.9 (0.5–2) vs. 0.8 (0.4–1.9), respectively, P = 0.8], the TG/HDL ratio was significantly higher in elevated risk group (3.05 ± 0.15 vs. 2.1 ± 0.18 mg/dL in elevated risk and low-risk groups, respectively, P = 0.01).

Patient follow-up

There was no missed follow-up and we could find the destiny of all patients.

The mortality rate during a median (IQR) follow-up period of 48 (23–48) months was 44.1%. Nine patients (five precapillary) died within a year after the RHC. The survival rate was much better in patients with precapillary PH [48 (28.5–48) months] than combined postcapillary PH [24 (18–48) months] (P = 0.002).

Survival analysis in patients with precapillary pulmonary hypertension

As mentioned above and because of the low prevalence of IR in patients with combined postcapillary PH, the prognostic importance of IR in patients with precapillary PH was separately analysed.

At the end of the follow-up period, the mortality rate in this group of patients was 33.3%. There were 14 deaths in precapillary group, in which 6 of them was in class I and the rest were in other classes of PH.

The median (IQR) of survival in IR and IS patients was 48 (20–48) and 48 (36–48) months, respectively (P = 0.1).

Although the survival was not statistically different between the two IR and IS groups, the Kaplan–Meier curve of survival analysis showed less life span in IR patients (Figure 1).

image

The Kaplan–Meier curve of survival analysis in patients with insulin resistance compared with insulin sensitive patients.

Table 3 depicts univariate and multivariate analyses for predictors of mortality in patients with precapillary PH.

Table 3. Univariate and multivariate analyses for predictors of mortality in patients with precapillary pulmonary hypertension, n = 42 Characteristics Univariate analysis Multivariate analysis Beta P value OR (95% CI) Beta P value OR (95% CI) Age, years 0.094 0.001 1.1 (1.03–1.16) 0.15 0.005 1.1 (1.04–1.4) Sex, male −1.5 0.03 0.2 (0.06–0.87) −3.3 0.03 0.04 (0.002–0.8) Body mass index, kg/m2 0.18 0.03 1.2 (1.02–1.4) 0.35 0.02 1.4 (1.05–1.9) NYHA class 0.64 0.3 1.9 (0.5–6.5) Pulmonary hypertension class 0.5 0.04 1.6 (1.01–2.6) 6MWT, m −0.008 0.07 0.98 (0.99–1.001) FBS, mg/dL −0.01 0.7 0.99 (0.92–1.05) HbA1c 0.19 0.7 0.8 (0.3–2.4) TG/HDL, mg/dL 0.23 0.4 1.2 (0.7–2.2) Insulin level, mIU/L 0.008

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