Thrombosis Research 129 (2012) 86–88

Contents lists available at SciVerse ScienceDirect

Thrombosis Research

j ourna l homepage: www.e lsev ie r .com/ locate / thromres

Letter to the Editors-in-Chief

Hyperlipidemia is associated with a higher pulmonary arterysystolic pressure in patients after pulmonary embolism

Dear Editors,

Chronic thromboembolic pulmonary hypertension (CTEPH) is acomplication after pulmonary embolism (PE). The incidence ofCTEPH within two years after acute PE described in the literature sofar is between 1% and 8% [1]. The exact reason for the developmentof CTEPH is still unclear. It seems that emboli of patients are orga-nized, leading to obstruction and narrowing of pulmonary arteries[2]. Impaired fibrinolysis could be one reason for the developmentof organized thrombi. However, although abnormalities of the fibri-nolytic system have been described in CTEPH-patients, the exact rea-son for the described impairment of fibrinolysis in these patients isstill unclear [3].

The screening method of choice for CTEPH is transthoracicechocardiography in order to evaluate the pulmonary artery sys-tolic pressure (PAP). In case of a pathological PAP computed to-mographic angiography (CTA), ventilation-perfusion lungscanning or pulmonary angiography is performed to confirmCTEPH by typical radiological findings. Up to now it is still unclearwhich patients should be screened for CTEPH. In the studies pub-lished so far recurrent PE, massive PE, and idiopathic PE were riskfactors for the development of CTEPH within two years after acutePE [1,4,5].

One aim of our study was to evaluate the incidence of pathologicalPAP in our patients after PE. Our second goal was to evaluate comor-bididies associated with the development of CTEPH in order to char-acterize patients at high risk for CTEPH after PE.

For the presented study we screened patients hospitalized for afirst episode of PE at the department of angiology of the medicaluniversity of Graz, Austria between the years 2005 and 2008.The diagnosis of PE was based exclusively on positive results ofhigh-resolution spiral computed tomography. PE was classified asidiopathic if it was not proceeded within 90 days by major trauma,surgery, immobilization of three days or more, distant travel (N8hours), or associated with childbirth, oral contraceptive use orpregnancy.

We excluded patients with massive PE requiring fibrinolytic ther-apy because according to the literature these patients are at a lowerrisk to develop CTEPH [6]. We further excluded patients withknown chronic obstructive pulmonary disease, valvular heart dia-sease, and dilated cardiomyopathy as in these patients transthoracicechocardiography was assumed to be pathological for other reasonsthan CTEPH.

Abbreviations: CTEPH, chronic thromboembolic pulmonary hypertension;VTE, ve-nous thromboembolism;PE, pulmonary embolism;CTA, computed tomographic angi-ography;PAP, pulmonary artery systolic pressure;DVT, deep vein thrombosis;TTE,transthoracic echocardiography;IVC, inferior vena cava.

0049-3848/$ – see front matter © 2011 Elsevier Ltd. All rights reserved.doi:10.1016/j.thromres.2011.09.018

PE-patients described above who met no exclusion criterion werecontacted by phone call at least one year after acute PE and wereasked for a visit in our outpatient clinic in order to perform a trans-thoracic echocardiography. Ninety-nine patients were included inour study.

All 99 patients underwent transthoracic echocardiography for theevaluation of the systolic and mean PAP. Systolic PAP was calculatedas the transtricuspid pressure gradient. A normal PAP was definedas a transtricuspid pressure gradient of ≤30 mm Hg [7]. We furtherdocumented the diameter of the inferior vena cava (IVC), of the he-patic veins, of the right atrium, the right ventricle, the left ventricle,and the systolic and diastolic right ventricular area as possible param-eters for pulmonary hypertension.

Comorbodities at time of hospitalization for the episode of acutePE were documented. Arterial hypertension was defined as hyperten-sion requiring antihypertensive therapy. Hyperlipidemia was definedas LDL cholesterol level N160 mg/dl. Lipid lowering therapy wasdocumented. Thrombophilia screening has been performed in eachof our patients during hospital stay as a regular procedure in ourPE-patients. This screening involved deficiency of antithrombin, pro-tein C, or protein S, factor V Leiden mutation, prothrombin G20210Amutation, lupus anticoagulant, and anti-cardiolipin or anti-beta-2-glycoprotein I IgG and IgM antibodies.

Differences between means of groups and proportions of patientswere calculated with t-test and with Fisher´s exact test respectivelyusing SPSS 17.0. A p value less than 0.05 was considered statisticalsignificant. The p values calculated with t-test were further adjustedfor sex, age, and lipid lowering therapy in a binary logistic regressionmodel.

Characteristics of patients including data of the thrombophiliascreening are shown in Table 1.

In the 99 patients included in the study we found a pathologicalPAP in three patients. Characteristics of these patients are shown inTable 2.

Two of the patients with pathological PAP had peripheral PE andone patient suffered a central PE. As a massive central PE is describedas a risk factor for the development of CTEPH in the literature [1,4] wecompared means of parameters measured with transthoracic echo-cardiography between our patients with central PE and peripheralPE. Mean PAP was higher in patients with peripheral PE comparedto patients with central PE (15.8±8.9 vs. 12.1±8.7). However, thedifference did not reach statistical significance. Regarding othertransthoracic echocardiography-parameters we were not able tofind statistical significant differences between central-PE andperipheral-PE patients.

As all three patients with pathological PAP had an idiopathic eventand as an idiopathic PE-event is also described as a risk factor for thedevelopment of CTEPH in the literature [1] we compared means ofparameters measured with transthoracic echocardiography betweenpatients with idiopathic PE and those with provoked PE. Mean PAPwas higher in idiopathic PE patients compared to provoked PE pa-tients (16.0±11.6 vs. 13.7±6.4), however the difference did notreach statistical significance. Similar to the central and peripheral PE

Table 1Characteristics of patients including thrombophilia screening.

Patients (f/m) 99(41/58)

Age mean±SD 56±17BMI kg/m2 mean±SD 26.5±7.5Central PE n(%) 34(34.3)Peripheral PE n(%) 56(56.6)Idiopathic PE n(%) 42(42.4)Art. Hypertension n(%) 41(41.4)Hyperlipidemia n(%) 33(33.3)VKA therapy n(%) 42(42.4)Prothrombin G20210A Mutation n(%)-heterozygous n(%) 7(7.1)Factor V Leiden Mutation n(%)-heterozygous n(%) 12(12.1)-homozygous n(%) 1(1)

Table 3Echocardiographic measurements in patients with hyperlipidemia compared withpatients without hyperlipidemia.

Hyperlipidemia NoHyperlipidemia

pvalue

PAP mean±SD 18.9±11.6 12.6±6.7 b0.05Right atrium diameter in cmmean±SD

4.1±0.6 3.9±0.5 ns

IVC diameter in cm mean±SD 1.6±0.3 1.6±0.3 nsLiver vein diameter in cm mean±SD 0.7±0.2 0.7±0.2 nsRight ventricular diameter in cmmean±SD

2.4±0.5 2.2±0.5 ns

Left ventricular diameter in cmmean±SD

4.4±0.7 4.5±0.6 ns

Diastolic right ventricular area in cm2

mean±SD19.5±4.2 18.9±3.9 ns

Systolic right ventricular area in cm2

mean±SD13.6±3.7 13.1±3.6 ns

Pathological PAP, n(%) 3(9.1) 0 b0.05

Abbreviations used in tablesSD: standard deviation.PE: pulmonary embolism.VKA: vitamin K antagonist.PAP: pulmonary artery systolic pressure.

87Letter to the Editors-in-Chief

patients we were not able to find a statistical significant difference inthe other transthoracic echocardiography-parameters measured inthe study.

As all three of our patients with pathological PAP suffered fromhyperlipidemia we tried to find differences in the transthoracicechocardiography-parameters between patients with hyperlipidemiaand patients without hyperlipidemia. We found statistical significantdifferences for the PAP between patients with hyperlipidemia andpatients without hyperlipidemia (18.9±11.6 vs. 12.6±6.7; pb0.05).This p value was still statistical significant after adjustment for sex,age, and lipid lowering therapy (Table 3). Concerning other transtho-racic echocardiography-parameters measured we were not able tofind statistical significant differences between hyperlipidemic patientsand those without hyperlipidemia (Table 3).

Using a Fisher´s exact test we compared the proportion of patientswith pathological PAP in hyperlipidemic patients (3 out of 33 patients)and patients without hyperlipidemia (0 out of 66 patients). Witha p value of 0.04 this difference reached statistical significance(Table 3).

The data on dyslipidemia as an independent risk factor for VTE areconflicting. Some publications show interaction of elevated triglyc-erides, elevated small LDL particles and low HDL cholesterol levelswith the coagulation system leading to an increased risk for VTE[8,9]. Other publications were not able to find an association of ele-vated total cholesterol or LDL cholesterol levels and an increasedVTE-risk [10,11]. A possible contribution to an increased VTE-riskdue to hyperlipidemia could be the recently published data concern-ing the influence of statin therapy on VTE-risk. Even big meta-analyses suggest that statin therapy may lower the VTE-risk [12].

Possible mechanisms behind elevated VTE-risk in hyperlipidemicpatients might be the interaction of parameters of the lipid metabo-lism and fibrinolysis. In obese patients impairment of fibrinolysis isalready described in the literature [13]. We know that triglycerideenriched lipoproteins are accompanied by elevation of PAI1 and in-creased viscosity of blood and plasma [14].

In CTEPH patients the thrombotic emboli are organized after theacute setting of PE, leading to obstruction and narrowing of pulmo-nary arteries [2]. This leads to an increase in pulmonary hypertensionand thus to CTEPH. Impaired fibrinolysis could be one reason for the

Table 2Characteristics of patients with pathological PAP (N30 mmHg).

Age inyrs.

Sex PE Art.Hypertension

Hyperlipidemia IdiopathicPE

80 male peripheral Yes yes yes62 female peripheral Yes yes yes63 male central No yes yes

development of organized thrombi. Moser et al. was able to induceCTEPH in dogs treated with tranexamic acid already twenty yearsago due to experimental impairment of fibrinolysis [15]. However, al-though abnormalities of the fibrinolytic system were described inCTEPH patients, the exact reason for this phenomenon is still unclear[3]. Neither a high resting plasma PAI 1 activity nor a blunted re-sponse to t-PA to venous occlusion was found as a possible reasonfor the development of CTEPH [3].

Our three patients with a pathological PAP were patients suffer-ing from hyperlipidemia. As already described above lipid parame-ters seem to have a relevant influence on the fibrinolytic system.We hypothesize that patients suffering from hyperlipidemia areat high risk to develop CTEPH due to impaired fibrinolysis. Theexact mechanism how lipid parameters interact with the fibrino-lytic system is still unclear. In the literature interacation withPAI1 through trigyzerides was described [14]. Changes in PAI1 ac-tivity were investigated in CTEPH patients [3]. However, as alreadystated above, there were no changes concerning this parameter ofthe fibrinolytic system.

Our study has some limitations: We did not measure parametersof the fibrinolytic system to underline our hypothesis that hyperlipi-demic patients are at high risk for CTEPH. The second limitation isthe small sample size.

Nevertheless we were able to show that hyperlipidemic patientsseem to be at higher risk for the development of pathological PAPafter a first episode of VTE. This might be due to an impaired fibrino-lysis caused by elevated LDL cholesterol. Our findings should be prop-erly assessed in a prospective randomized study.

Conflicts of interest statement

Our study was funded by a scientific grant provided by ActelionPharmaceuticals Ltd..The authors have no further conflicts of interestto declare.

Acknowledgements

Our study was funded by a scientific grant provided by ActelionPharmaceuticals Ltd.. The sponsor had no involvement in study design,collection, analysis and interpretation of data, further no involvement inwriting themanuscript and in the decision to submit themanuscript forpublication.

88 Letter to the Editors-in-Chief

References

[1] Pengo V, Lensing AW, PrinsMH, Marchiori A, Davidson BL, Tiozzo F, et al. Incidenceof chronic thromboembolic pulmonary hypertension after pulmonary embolism.N Engl J Med 2004;350:2257–64.

[2] Moser KM, AugerWR, Fedullo PF. Chronic major-vessel thromboembolic pulmonaryhypertension. Circulation 1990;81:1735–43.

[3] Olman MA, Marsh JJ, Lang IM, Moser KM, Binder BR, Schleef RR. Endogenousfibrinolytic system in chronic large-vessel thromboembolic pulmonary hypertension.Circulation 1992;86:1241–8.

[4] Otero R, Oribe M, Ballaz A, Jimenez D, Uresandi F, Nauffal D, et al. Echocardiographicassessment of pulmonary arterial pressure in the follow-up of patients withpulmonary embolism. Thromb Res 2011;127:303–8.

[5] Becattini C, Agnelli G, Pesavento R, Silingardi M, Poggio R, Taliani MR, et al.Incidence of chronic thromboembolic pulmonary hypertension after a firstepisode of pulmonary embolism. Chest 2006;130:172–5.

[6] Kline JA, Steuerwald MT, Marchick MR, Hernandez-Nino J, Rose GA. Prospectiveevaluation of right ventricular function and functional status 6 months afteracute submassive pulmonary embolism: frequency of persistent or subsequentelevation in estimated pulmonary artery pressure. Chest 2009;136:1202–10.

[7] McQuillan BM, Picard MH, Leavitt M, Weyman AE. Clinical correlates and referenceintervals for pulmonary artery systolic pressure among echocardiographicallynormal subjects. Circulation 2001;104:2797–802.

[8] Doggen CJ, Smith NL, Lemaitre RN, Heckbert SR, Rosendaal FR, Psaty BM. Serumlipid levels and the risk of venous thrombosis. Arterioscler Thromb Vasc Biol2004;24:1970–5.

[9] Deguchi H, Pecheniuk NM, Elias DJ, Averell PM, Griffin JH. High-density lipoproteindeficiency and dyslipoproteinemia associated with venous thrombosis in men.Circulation 2005;112:893–9.

[10] Ageno W, Becattini C, Brighton T, Selby R, Kamphuisen PW. Cardiovascular riskfactors and venous thromboembolism: a meta-analysis. Circulation 2008;117:93–102.

[11] Holst AG, Jensen G, Prescott E. Risk factors for venous thromboembolism: resultsfrom the Copenhagen City Heart Study. Circulation 2010;121:1896–903.

[12] Squizzato A, Galli M, Romualdi E, Dentali F, Kamphuisen PW, Guasti L, et al. Statins,fibrates, and venous thromboembolism: a meta-analysis. Eur Heart J 2010;31:1248–56.

[13] Salobir B, Sabovic M. A metabolic syndrome independent association betweenoverweight, fibrinolysis impairment and low-grade inflammation in youngwomen with venous thromboembolism. Blood Coagul Fibrinolysis 2006;17:551–6.

[14] Rosenson RS, Lowe GD. Effects of lipids and lipoproteins on thrombosis andrheology. Atherosclerosis 1998;140:271–80.

[15] Moser KM, Cantor JP, Olman M, Villespin I, Graif JL, Konopka R, et al. Chronicpulmonary thromboembolism in dogs treated with tranexamic acid. Circulation1991;83:1371–9.

Thomas Gary⁎Ina Starz

Klara BelajKarin Steidl

Franz HafnerHarald Froehlich

Ernst PilgerMarianne Brodmann

Division of Angiology, Medical University Graz, Austria⁎Corresponding author at: Division of Angiology, Medical University

Graz, Auenbruggerplatz 15, 8036 Graz, Austria. Tel.: +43 316 38581795; fax: +43 316 385 13788.

E-mail address: thomas.gary@medunigraz.at(T. Gary).

13 May 2011