HIV Reports
Cardiac Function in Vertically HIV-infected Children and Adolescents in the Era of Highly Active Antiretroviral Therapy Talía Sainz, MD, PhD,*††† María Álvarez-Fuente, MD,‡ Rodrigo Fernández-Jiménez, MD,§ María Isabel González-Tomé, MD, PhD,¶ María Isabel de José, MD, PhD,‖ José Tomás Ramos, MD, PhD,** María Luisa Navarro, MD, PhD,†† Jorge Martínez, MD,‡‡ Milagros García-Hortelano, MD, PhD,§§ Constancio Medrano, MD,‡ María Ángeles Muñoz-Fernández, PhD,*† and María José Mellado, MD, PhD,§§ on Behalf of the Madrid Cohort of HIV-Infected Children and Adolescents Integrated in the Pediatric Branch of the Spanish National AIDS Network (CoRISpeS) Background: Previous studies have demonstrated increased risk of adverse cardiac outcomes in adults with HIV infection. However, few studies have addressed this problem in vertically HIV-infected children and adolescents, and the long-term cardiac health of this unique population in the antiretroviral therapy era is still unknown. Methods: Ventricular function was evaluated cross-sectionally in a group of HIV-infected children and adolescents and healthy controls, using conventional echocardiography along with tissue Doppler imaging and strain analysis by speckle tracking. Simultaneously, measurements of carotid intima-media thickness were performed. Results: A total of 64 cases and 58 controls were included, mean age was 13.6 ± 5.4 years and 64% were females. All but 2 patients were on antiretroviral treatment, and 64% had undetectable viral load. HIV-infected patients showed higher intima-media thickness (0.425 ± 0.019 vs. 0.415 ± 0.019 mm, P = 0.003). Statistically significant differences were found between groups in ejection fraction and fractional shortening (66.1% and 36.2% in the HIVAccepted for publication October 9, 2014. From the *Laboratorio de Inmunobiología Molecular, Hospital General Universitario Gregorio Marañón; †Instituto de Investigación Sanitaria Gregorio Marañón; ‡Unidad de Cardiología Infantil, Hospital General Universitario Gregorio Marañón; §Imaging in Experimental Cardiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III; ¶Unidad de Inmunodeficiencias, Servicio de Pediatría, Hospital Universitario Doce de Octubre; ‖Servicio de Pediatría, Hospital Universitario La Paz; **Servicio de Pediatría, Hospital de Getafe; ††Unidad de Enfermedades Infecciosas, Servicio de Pediatría, Hospital General Universitario Gregorio Marañón; ‡‡Servicio de Pediatría, Hospital Universitario Niño Jesús; and §§Servicio de Pediatría, Hospital Carlos III and Servicio de Pediatría, Hospital La Paz, Madrid, Spain. Both Talía Sainz and María Álvarez-Fuente contributed equally to this work. Partial/final results of this work have been presented at the following meetings: 20th Conference on Retrovirus and Opportunistic Infections (CROI), Poster, Atlanta, WA, March 5–9, 2013 (ref. V-111); 31st Congress of the European Society of Pediatric Infectious Diseases (ESPID), Oral poster, Milan, Italy, 31 May to 1, June, 2013 (ref. 967); 47th Annual Meeting of the Association for European Pediatric and Congenital Cardiology (AEPC), Oral presentation, London, UK, May 22–25, 2013 (ref. 06-4). This work was partially supported by a Small Grant Award from the European Society of Pediatric Infectious Diseases (ESPID), by the Spanish Ministry of Science and Innovation (FIS, Grant no. PI12/01483) and Red Española de Investigación en SIDA (RIS) [AIDS Research Network; grant numbers RD06/0006/0035, RD12/0017/0037, RD12/0017/31, RD12/0017/35, RD12/0017/16 and RD09/0076/00103]. Philips Healthcare kindly provided portable ultrasound equipment for the purpose of the study. T.S. and R.FJ. are funded by grants from the Spanish Ministry of Science and Innovation (Ayudas para Contratos de Formación en Investigación Río Hortega). The Madrid Cohort of HIV-infected Children is supported by Fundación para la investigación y prevención del SIDA en España (FIPSE; Grant no. 360829-09). The authors have no conflicts of interest to disclose. Address for correspondence: Talía Sainz Costa, MD, PhD, Laboratorio de Inmunobiología Molecular, Hospital Gregorio Marañón, C/ Dr Esquerdo 46, 28007, Madrid, Spain, E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0891-3668/15/3405-e125 DOI: 10.1097/INF.0000000000000634
infected group vs. 71.5% and 40.8% in the control group, respectively, P = 0.001), although individual values fell within or near normal ranges. There were no significant differences in diastolic function, tissue Doppler imaging or cardiac strain (longitudinal and rotational) between both groups. No associations were identified between echocardiographic parameters and current CD4+ T-lymphocyte counts, CD4+ T-lymphocyte nadir, HIV viral load, duration or type of antiretroviral treatment regimens. Conclusions: In a context of highly effective antiretroviral treatment, no differences were found regarding cardiac abnormalities using conventional and advanced ultrasound imaging techniques in this cohort of vertically HIVinfected children and adolescents, when compared with healthy controls. Key Words: HIV, children and adolescents, cardiac function, echocardiography, speckle tracking, IMT (Pediatr Infect Dis J 2015;34:e125–e131)
E
ffective, early treatment of vertically HIV-infected children enables them to live for many years, as HIV infection has turned into a chronic condition. However, they are at high risk for complications associated with a lifelong exposure to antiretroviral treatment (ART).1 Among other aging-associated diseases, HIV infection in adults confers an increased cardiovascular risk, and the prevalence of cardiovascular disease is likely to rise as patients continue to age.2 There is evidence that the atherogenic process described in HIV-infected adults starts early in childhood, and that vertically infected adolescents already have increased intima-media thickness (IMT).3–5 Although its relation to premature atherosclerosis remains uncertain, ventricular dysfunction has also been described both in adults and in children with HIV infection.6–8 Most of the evidences regarding the presence of cardiac abnormalities in vertically HIV-infected children come from the pre-ART era. Echocardiographic abnormalities were common, persistent and often progressive, and these abnormalities included dilated cardiomyopathy with depressed left ventricle (LV) contractility and LV dilation, heart failure and aortic dilation.6,7,9 These findings were associated with overall higher risk of all-cause mortality.9–11 Based on results from a large, cross-sectional analysis comparing cardiac status of HIV-infected children in the pre-ART and post-ART era and HIV-uninfected controls,12 symptomatic cardiac disease associated with HIV infection has shifted with highly effective ART to a mild and mostly asymptomatic condition. Over the past decades, novel and increasingly automated techniques for sophisticated analysis of cardiac mechanics have emerged. Among them, speckle-tracking echocardiography (STE) has been suggested to be a more sensitive, load-independent and angle-independent measure that allows functional analysis of the myocardium and ability to detect cardiac dysfunction at an early stage.13 A recent report by Sims et al14 supports the use of these new
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technologies to achieve an earlier detection of cardiac dysfunction specifically in HIV-infected children. In this study, we aimed to perform a thorough evaluation of cardiac status using conventional echocardiography along with speckle tracking in vertically HIV-infected children and adolescents and HIV-uninfected controls. We simultaneously evaluated cardiovascular risk by means of IMT and analyzed the impact that ART exposure, as well as clinical and immunovirologic variables, may have on cardiac function.
METHODS Study Design and Eligibility Criteria We performed a cross-sectional analysis from an ongoing prospective, longitudinal and multicenter observational study evaluating cardiovascular risk.5 Between June and December 2011, HIV-infected children and adolescents attending the clinics of the 6 participating hospitals were prospectively enrolled. Exclusion criteria included acute infection, chronic conditions and family history of premature cardiovascular disease.5 Uninfected children born to HIV-infected mothers, children attending the clinics for a routine cardiac examination and healthy adolescents from a high school in the same urban area were enrolled as controls. Additional exclusion criteria for healthy controls included current infectious or inflammatory illnesses, chronic conditions and use of medications. Unmatched controls were included with the goals of achieving a group with similar age, sex, ethnicity and body mass index (BMI; ±1 kg/m2). The study was reviewed and approved by the Ethics Committee and Clinical Research of the 6 participating Hospitals. All participants, parents or legal guardians and children older than 12 years, gave written informed consent to take part in the study.
Clinical Assessments All participants underwent physical examination, including anthropometric and blood pressure measurements according to recommendations of the American Heart Association,15 performed by the same trained technician. Elevated blood pressure was defined according to the 95th percentile, adjusted by age and height.16 ART history and immunovirologic variables were recorded from the
Pediatric HIV database. To assess the effect of treatment, years of antiretroviral exposure were analyzed as a continuous variable.
Echocardiographic Measurements Resting cardiac echocardiography was performed by a single certified sonographer, blind to the HIV status, using a CX50 portable equipment equipped with an S5 multifrequency probe (Philips Medical Systems, Inc., Eindhoven, The Netherlands), in the supine position. Classic measures of LV systolic function, such as ejection fraction (EF) and fractional shortening (FS), as well as indicators of diastolic function, such as mitral inflow E/A ratio and tissue Doppler-derived E/E′ ratio, were evaluated. Parameters acquired from M-mode echocardiography included LV end-diastolic and endsystolic diameters, as well as septal and posterior wall thicknesses. Values of systolic pulmonary pressure were noninvasively estimated using the maximum velocity of the tricuspid regurgitant jet.17 Parameters that reflect right ventricular performance, such as tricuspid annular plane systolic excursion and tissue Doppler-derived tricuspid annular systolic peak velocity, were also evaluated. Tissue Doppler velocities were assessed as the mean of 3 successive cardiac cycles. All measurements were performed according to the American Society of Echocardiography recommendations18 and were subsequently normalized by Z score when needed.19 Quantification of myocardial deformation (strain and torsion) by 2-dimensional STE was performed following consensus by the American and European Associations of Echocardiography.13 LV deformation parameters were analyzed offline by a blind trained cardiologist using 2-dimensional speckle-tracking echo software (QLAB Advanced Quantification Software version 7.1; Philips Medical Systems, Inc.). Definition of these parameters has been described elsewhere.13 In our study, global longitudinal strain was obtained by averaging all segmental longitudinal strain curves computed from the conventional apical 2-chamber, 3-chamber and 4-chamber views, as it has been described.20–22 LV twist was assessed from basal and apical short-axis views using the same frame rate and was defined as the net difference between apical rotation and basal rotation at the maximal deformation point (Fig. 1). As STE relies on good image quality and high temporal resolution, images that did not meet these criteria were excluded from strain-specific analysis.
FIGURE 1. Assessment of LV rotation by 2-dimensional speckle-tracking analysis. LV rotation time curves (bottom, both panels) derived from 2-dimensional speckle-tracking analysis of the short-axis views at the base (top, panel A) and at the apex (top, panel B) of the LV.
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The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
Carotid Artery Ultrasound IMT was examined simultaneously using the same CX50 portable equipment and specific IMT detection software—Qlab (Philips Medical Systems, Inc.). Measurements were made bilaterally at the common carotid artery (1–2 cm proximal to the bulb), as previously described5 and digitalized. Images were read by an experienced cardiologist, blind to HIV status, and the mean value of the right and left measurements was then calculated and used for the analysis.
Laboratory Assays Fasting blood samples were drawn for real-time measurements of glucose levels and lipid profile [total cholesterol, highdensity lipoprotein cholesterol (HDLc) and low-density lipoprotein cholesterol] that were determined in the different participating hospitals using standard enzymatic methods. In the HIV-infected group, plasma HIV-1 viral load (VL) was quantified using the Cobas TaqMan HIV-1 assay (Roche Diagnostics Systems, Inc., Branchburg, NJ) with a detection limit of 50 copies/mL. Absolute and percentage CD4 T-lymphocyte (CD4) counts were measured with standard flow cytometric methods.
Data Analyses Normally distributed quantitative variables were described as mean and standard deviation (SD), whereas continuous nonnormally distributed variables were reported as median and
Cardiac Function
interquartile ranges. Weight, height, BMI and hypertension were adjusted using Z score according to age and gender,16,23 as well as ventricular dimensional parameters.19 Means for variables with a normal distribution were compared using the Student t test and Fisher test when appropriate. Nonparametric variables were examined using the Mann–Whitney and Kruskal–Wallis tests. Simultaneous independent associations between parameters of cardiac function and HIV-related variables were evaluated by logistic regression analysis. Statistical analyses were performed using Stata v. 12.0 (StataCorp LP, College Station, TX).
RESULTS Study Population and Between Group Comparison of Clinical Characteristics A total of 64 HIV-infected children and adolescents and 58 healthy volunteers underwent echocardiography, including tissue Doppler imaging and LV rotational analysis. Two patients were excluded because of known history of premature cardiovascular disease, and 2 were excluded because of acute infection. Main characteristics of both cohorts are summarized in Table 1. Globally, mean age was 13.6 ± 5.4 years. Most subjects were female (64%) and of Caucasian origin (74%). All had acquired HIV from mother-to-child transmission except for 3 patients who had been diagnosed very
TABLE 1. Main Characteristics of Both Cohorts
Demographic data Age (years) Female, n (%) Caucasian, n (%) Clinical variables Heart rate (beats/min) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Blood pressure over 95th percentile, n (%) Smokers, n (%) BMI (kg/m2) Z score BMI* Waist (cm) Hip (cm) Waist-to-hip ratio Laboratory measurements Glycemia (mg/dL) Total cholesterol (mg/dL) HDLc (mg/dL) LDLc (mg/dL) Total cholesterol/HDLc Triglycerides (mg/dL)* IMT (mm) HIV-related parameters On ART, n (%) Vertical transmission, n (%) Hepatitis virus C coinfection, n VL 70%) for many of the uninfected patients also supports this hypothesis. Deterioration of standard echocardiographic measures of EF and FS is generally considered a late stage of cardiac dysfunction in clinically asymptomatic patients. In an attempt to overcome this fact, measurements of longitudinal strain and rotational motion analysis were included in our cardiac evaluation, and again no differences were found in ventricular function. A previous study published in 2012 by Sims et al,14 including 28 ART-treated HIV-infected subjects, report mild cardiac impairment missed by conventional echocardiography but detected by cardiac strain analysis. The mean age of the subjects included in the mentioned study was 18 ± 4 years (range 7–29), whereas the mean age in our cohort is 14 ± 5 (range 2.5–22). We hypothesize that this small difference in age between the two studies may reflect big differences in terms of timing and effectiveness of ART. Most participants in our study were treated early and frequently achieved and maintained undetectable VLs at least until adolescence, and they had an overall better disease control compared with their peers born 5 years before. Nevertheless, as impairment of cardiac function appears progressively, it is also possible that mild abnormalities that are not yet present during adolescence might become apparent in young adults. Although no clinically significant differences in cardiac function were found between groups, we explored relationships between HIV-related variables and echocardiographic parameters. According to the literature, disease severity appears to be the main factor related to abnormalities on cardiac structure and function.35 In this study, no correlation was found between traditional echocardiographic parameters and detectable VLs, CD4 counts or CD4 nadir. Our findings are consistent with the last study published by Lipshultz et al12 describing an association between CD4 nadir and cardiac function in the pre-ART era but no association in early treated patients. www.pidj.com | e129
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We present here data from a cross-sectional analysis, so no causal inferences can be made. The rather small sample size of the study obviously limits our ability to measure the contribution of HIV-related variables on cardiac function. Larger studies would potentially allow us to deepen associations between ventricular function and particular antiretroviral drugs, which may help to identify optimal combinations in terms of protecting long-term cardiac health. Characteristics of the control group are another main limitation of the study. HIV-exposed but uninfected children were included in the study, as they have historically been considered as the optimal control group to assess cardiovascular risk. However, some studies suggest that intrauterine exposure to HIV and ART may have impact on cardiac status, and these findings put into question the appropriateness of this population as a reference.6,36 To further confirm our findings, we repeated the analyses restricting the control group to HIV-unexposed subjects, and results were consistent with previous findings. Although previous data and our data suggest that ART has a protective effect on cardiac health, vertically HIV-infected individuals may benefit from cardiac evaluation for a prompt diagnosis and management of abnormalities. The optimal timing for a cardiac study is unclear, but according to the findings from the previously mentioned studies and the data provided in this work, the end of adolescence might be the ideal time to perform a follow-up echocardiogram.
ACKNOWLEDGMENTS We acknowledge all patients and healthy volunteers as well as their families for their participation in this study. We thank all the professionals involved in the study and especially those integrating the Spanish Pediatric HIV-infection Network (CoRISpeS). REFERENCES 1. Agwu AL, Fairlie L. Antiretroviral treatment, management challenges and outcomes in perinatally HIV-infected adolescents. J Int AIDS Soc. 2013. 16:1–13 2. d’Arminio A, Sabin CA, Phillips AN, et al; Writing Committee of the D:A:D: Study Group. Cardio- and cerebrovascular events in HIV-infected persons. AIDS. 2004;18:1811–1817. 3. Charakida M, Donald AE, Green H, et al. Early structural and functional changes of the vasculature in HIV-infected children: impact of disease and antiretroviral therapy. Circulation. 2005;112:103–109. 4. McComsey GA, O’Riordan M, Hazen SL, et al. Increased carotid intima media thickness and cardiac biomarkers in HIV infected children. AIDS. 2007;21:921–927. 5. Sainz T, Álvarez-Fuente M, Navarro ML, et al; Madrid Cohort of HIVInfected Children and Adolescents Integrated in the Pediatric Branch of the Spanish National AIDS Network (CoRISPE). Subclinical atherosclerosis and markers of immune activation in HIV-infected children and adolescents: the CaroVIH Study. J Acquir Immune Defic Syndr. 2014;65:42–49. 6. Lipshultz SE, Easley KA, Orav EJ, et al; Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection (P(2)C(2) HIV) Study Group. Cardiovascular status of infants and children of women infected with HIV-1 (P(2)C(2) HIV): a cohort study. Lancet. 2002;360:368–373. 7. Starc TJ, Lipshultz SE, Easley KA, et al. Incidence of cardiac abnormalities in children with human immunodeficiency virus infection: the prospective P2C2 HIV study. J Pediatr. 2002;141:327–334. 8. Barbarinia G, Barbaro G. Incidence of the involvement of the cardiovascular system in HIV infection. AIDS. 2003;17(suppl 1):S46–S50. 9. Lipshultz SE, Easley KA, Orav EJ, et al. Cardiac dysfunction and mortality in HIV-infected children: the prospective P2C2 HIV multicenter study. Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection (P2C2 HIV) Study Group. Circulation. 2000;102:1542–1548.
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10. Currie PF, Jacob AJ, Foreman AR, et al. Heart muscle disease related to HIV infection: prognostic implications. BMJ. 1994;309:1605–1607. 11. Lipshultz SE. Dilated cardiomyopathy in HIV-infected patients. N Engl J Med. 1998;339:1153–1155. 12. Lipshultz SE, Williams PL, Wilkinson JD, et al; Pediatric HIV/AIDS Cohort Study (PHACS). Cardiac status of children infected with human immunodeficiency virus who are receiving long-term combination antiretroviral therapy: results from the Adolescent Master Protocol of the Multicenter Pediatric HIV/AIDS Cohort Study. JAMA Pediatr. 2013;167:520–527. 13. Mor-Avi V, Lang RM, Badano LP, et al. Current and evolving echocardiographic techniques for the quantitative evaluation of cardiac mechanics: ASE/EAE consensus statement on methodology and indications endorsed by the Japanese Society of Echocardiography. Eur J Echocardiogr. 2011;12:167–205. 14. Sims A, Frank L, Cross R, et al. Abnormal cardiac strain in children and young adults with HIV acquired in early life. J Am Soc Echocardiogr. 2012;25:741–748. 15. Urbina EM, Williams RV, Alpert BS, et al; American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee of the Council on Cardiovascular Disease in the Young. Noninvasive assessment of subclinical atherosclerosis in children and adolescents: recommendations for standard assessment for clinical research: a scientific statement from the American Heart Association. Hypertension. 2009;54:919–950. 16. Blood Pressure Tables for Children and Adolescents from the Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents of the national Institute for Health, USA. Available at: http://www.nhlbi.nih.gov/guidelines/hypertension/child_tbl. htm. Accessed 31 May 2013. 17. Yock PG, Popp RL. Noninvasive estimation of right ventricular systolic pressure by Doppler ultrasound in patients with tricuspid regurgitation. Circulation. 1984;70:657–662. 18. Lopez L, Colan SD, Frommelt PC, et al. Recommendations for quantification methods during the performance of a pediatric echocardiogram: a report from the Pediatric Measurements Writing Group of the American Society of Echocardiography Pediatric and Congenital Heart Disease Council. J Am Soc Echocardiogr. 2010;23:465–495. 19. Park MK. ed. Cardiología Pediátrica. 3rd ed. Madrid: Elsevier España; 2003. p. 55–66. 20. Macron L, Lairez O, Nahum J, et al. Impact of acoustic window on accuracy of longitudinal global strain: a comparison study to cardiac magnetic resonance. Eur J Echocardiogr. 2011;12:394–399. 21. Mollema SA, Delgado V, Bertini M, et al. Viability assessment with global left ventricular longitudinal strain predicts recovery of left ventricular function after acute myocardial infarction. Circ Cardiovasc Imaging. 2010;3:15–23. 22. Nahum J, Bensaid A, Dussault C, et al. Impact of longitudinal myocardial deformation on the prognosis of chronic heart failure patients. Circ Cardiovasc Imaging. 2010;3:249–256. 23. WHO Child Growth Standards: Methods and development: length/heightfor-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age. Available at: http://www.who.int/childgrowth/publications/technical_report_pub/en/index.html. Accessed 24 May 2013. 24. Opravil M, Pechère M, Speich R, et al. HIV-associated primary pulmonary hypertension. A case control study. Swiss HIV Cohort Study. Am J Respir Crit Care Med. 1997;155:990–995. 25. Domanski MJ, Sloas MM, Follmann DA, et al. Effect of zidovudine and didanosine treatment on heart function in children infected with human immunodeficiency virus. J Pediatr. 1995;127:137–146. 26. Frerichs FC, Dingemans KP, Brinkman K. Cardiomyopathy with mitochondrial damage associated with nucleoside reverse-transcriptase inhibitors. N Engl J Med. 2002;347:1895–1896. 27. Meng Q, Lima JA, Lai H, et al. Use of HIV protease inhibitors is associated with left ventricular morphologic changes and diastolic dysfunction. J Acquir Immune Defic Syndr. 2002;30:306–310. 28. Pugliese A, Isnardi D, Saini A, et al. Impact of highly active antiretroviral therapy in HIV-positive patients with cardiac involvement. J Infect. 2000;40:282–284. 29. Melek M, Esen O, Esen AM, et al. Tissue Doppler evaluation of tricuspid annulus for estimation of pulmonary artery pressure in patients with COPD. Lung. 2006;184:121–131. 30. McMurray JJ, Adamopoulos S, Anker SD, et al; ESC Committee for Practice Guidelines. ESC guidelines for the diagnosis and treatment of
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acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33:1787–1847. 31. Yingchoncharoen T, Agarwal S, Popović ZB, et al. Normal ranges of left ventricular strain: a meta-analysis. J Am Soc Echocardiogr. 2013;26:185–191. 32. Notomi Y, Srinath G, Shiota T, et al. Maturational and adaptive modulation of left ventricular torsional biomechanics: Doppler tissue imaging observation from infancy to adulthood. Circulation. 2006;113:2534–2541.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
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33. Takeuchi M, Nakai H, Kokumai M, et al. Age-related changes in left ventricular twist assessed by two-dimensional speckle-tracking imaging. J Am Soc Echocardiogr. 2006;19:1077–1084. 34. Blessberger H, Binder T. Non-invasive imaging: two dimensional speckle tracking echocardiography: basic principles. Heart. 2010;96:716–722. 35. Hsue PY, Hunt PW, Ho JE, et al. Impact of HIV infection on diastolic function and left ventricular mass. Circ Heart Fail. 2010;3:132–139. 36. Wilkinson JD, Williams PL, Leister E, et al; Pediatric HIVAIDS Cohort Study (PHACS). Cardiac biomarkers in HIV-exposed uninfected children. AIDS. 2013;27:1099–1108.
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Cardiac Function in Vertically HIV-infected Children and Adolescents in the Era of Highly Active Antiretroviral Therapy Talía Sainz, MD, PhD,*††† María Álvarez-Fuente, MD,‡ Rodrigo Fernández-Jiménez, MD,§ María Isabel González-Tomé, MD, PhD,¶ María Isabel de José, MD, PhD,‖ José Tomás Ramos, MD, PhD,** María Luisa Navarro, MD, PhD,†† Jorge Martínez, MD,‡‡ Milagros García-Hortelano, MD, PhD,§§ Constancio Medrano, MD,‡ María Ángeles Muñoz-Fernández, PhD,*† and María José Mellado, MD, PhD,§§ on Behalf of the Madrid Cohort of HIV-Infected Children and Adolescents Integrated in the Pediatric Branch of the Spanish National AIDS Network (CoRISpeS) Background: Previous studies have demonstrated increased risk of adverse cardiac outcomes in adults with HIV infection. However, few studies have addressed this problem in vertically HIV-infected children and adolescents, and the long-term cardiac health of this unique population in the antiretroviral therapy era is still unknown. Methods: Ventricular function was evaluated cross-sectionally in a group of HIV-infected children and adolescents and healthy controls, using conventional echocardiography along with tissue Doppler imaging and strain analysis by speckle tracking. Simultaneously, measurements of carotid intima-media thickness were performed. Results: A total of 64 cases and 58 controls were included, mean age was 13.6 ± 5.4 years and 64% were females. All but 2 patients were on antiretroviral treatment, and 64% had undetectable viral load. HIV-infected patients showed higher intima-media thickness (0.425 ± 0.019 vs. 0.415 ± 0.019 mm, P = 0.003). Statistically significant differences were found between groups in ejection fraction and fractional shortening (66.1% and 36.2% in the HIVAccepted for publication October 9, 2014. From the *Laboratorio de Inmunobiología Molecular, Hospital General Universitario Gregorio Marañón; †Instituto de Investigación Sanitaria Gregorio Marañón; ‡Unidad de Cardiología Infantil, Hospital General Universitario Gregorio Marañón; §Imaging in Experimental Cardiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III; ¶Unidad de Inmunodeficiencias, Servicio de Pediatría, Hospital Universitario Doce de Octubre; ‖Servicio de Pediatría, Hospital Universitario La Paz; **Servicio de Pediatría, Hospital de Getafe; ††Unidad de Enfermedades Infecciosas, Servicio de Pediatría, Hospital General Universitario Gregorio Marañón; ‡‡Servicio de Pediatría, Hospital Universitario Niño Jesús; and §§Servicio de Pediatría, Hospital Carlos III and Servicio de Pediatría, Hospital La Paz, Madrid, Spain. Both Talía Sainz and María Álvarez-Fuente contributed equally to this work. Partial/final results of this work have been presented at the following meetings: 20th Conference on Retrovirus and Opportunistic Infections (CROI), Poster, Atlanta, WA, March 5–9, 2013 (ref. V-111); 31st Congress of the European Society of Pediatric Infectious Diseases (ESPID), Oral poster, Milan, Italy, 31 May to 1, June, 2013 (ref. 967); 47th Annual Meeting of the Association for European Pediatric and Congenital Cardiology (AEPC), Oral presentation, London, UK, May 22–25, 2013 (ref. 06-4). This work was partially supported by a Small Grant Award from the European Society of Pediatric Infectious Diseases (ESPID), by the Spanish Ministry of Science and Innovation (FIS, Grant no. PI12/01483) and Red Española de Investigación en SIDA (RIS) [AIDS Research Network; grant numbers RD06/0006/0035, RD12/0017/0037, RD12/0017/31, RD12/0017/35, RD12/0017/16 and RD09/0076/00103]. Philips Healthcare kindly provided portable ultrasound equipment for the purpose of the study. T.S. and R.FJ. are funded by grants from the Spanish Ministry of Science and Innovation (Ayudas para Contratos de Formación en Investigación Río Hortega). The Madrid Cohort of HIV-infected Children is supported by Fundación para la investigación y prevención del SIDA en España (FIPSE; Grant no. 360829-09). The authors have no conflicts of interest to disclose. Address for correspondence: Talía Sainz Costa, MD, PhD, Laboratorio de Inmunobiología Molecular, Hospital Gregorio Marañón, C/ Dr Esquerdo 46, 28007, Madrid, Spain, E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0891-3668/15/3405-e125 DOI: 10.1097/INF.0000000000000634
infected group vs. 71.5% and 40.8% in the control group, respectively, P = 0.001), although individual values fell within or near normal ranges. There were no significant differences in diastolic function, tissue Doppler imaging or cardiac strain (longitudinal and rotational) between both groups. No associations were identified between echocardiographic parameters and current CD4+ T-lymphocyte counts, CD4+ T-lymphocyte nadir, HIV viral load, duration or type of antiretroviral treatment regimens. Conclusions: In a context of highly effective antiretroviral treatment, no differences were found regarding cardiac abnormalities using conventional and advanced ultrasound imaging techniques in this cohort of vertically HIVinfected children and adolescents, when compared with healthy controls. Key Words: HIV, children and adolescents, cardiac function, echocardiography, speckle tracking, IMT (Pediatr Infect Dis J 2015;34:e125–e131)
E
ffective, early treatment of vertically HIV-infected children enables them to live for many years, as HIV infection has turned into a chronic condition. However, they are at high risk for complications associated with a lifelong exposure to antiretroviral treatment (ART).1 Among other aging-associated diseases, HIV infection in adults confers an increased cardiovascular risk, and the prevalence of cardiovascular disease is likely to rise as patients continue to age.2 There is evidence that the atherogenic process described in HIV-infected adults starts early in childhood, and that vertically infected adolescents already have increased intima-media thickness (IMT).3–5 Although its relation to premature atherosclerosis remains uncertain, ventricular dysfunction has also been described both in adults and in children with HIV infection.6–8 Most of the evidences regarding the presence of cardiac abnormalities in vertically HIV-infected children come from the pre-ART era. Echocardiographic abnormalities were common, persistent and often progressive, and these abnormalities included dilated cardiomyopathy with depressed left ventricle (LV) contractility and LV dilation, heart failure and aortic dilation.6,7,9 These findings were associated with overall higher risk of all-cause mortality.9–11 Based on results from a large, cross-sectional analysis comparing cardiac status of HIV-infected children in the pre-ART and post-ART era and HIV-uninfected controls,12 symptomatic cardiac disease associated with HIV infection has shifted with highly effective ART to a mild and mostly asymptomatic condition. Over the past decades, novel and increasingly automated techniques for sophisticated analysis of cardiac mechanics have emerged. Among them, speckle-tracking echocardiography (STE) has been suggested to be a more sensitive, load-independent and angle-independent measure that allows functional analysis of the myocardium and ability to detect cardiac dysfunction at an early stage.13 A recent report by Sims et al14 supports the use of these new
The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
www.pidj.com | e125
The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
Sainz et al
technologies to achieve an earlier detection of cardiac dysfunction specifically in HIV-infected children. In this study, we aimed to perform a thorough evaluation of cardiac status using conventional echocardiography along with speckle tracking in vertically HIV-infected children and adolescents and HIV-uninfected controls. We simultaneously evaluated cardiovascular risk by means of IMT and analyzed the impact that ART exposure, as well as clinical and immunovirologic variables, may have on cardiac function.
METHODS Study Design and Eligibility Criteria We performed a cross-sectional analysis from an ongoing prospective, longitudinal and multicenter observational study evaluating cardiovascular risk.5 Between June and December 2011, HIV-infected children and adolescents attending the clinics of the 6 participating hospitals were prospectively enrolled. Exclusion criteria included acute infection, chronic conditions and family history of premature cardiovascular disease.5 Uninfected children born to HIV-infected mothers, children attending the clinics for a routine cardiac examination and healthy adolescents from a high school in the same urban area were enrolled as controls. Additional exclusion criteria for healthy controls included current infectious or inflammatory illnesses, chronic conditions and use of medications. Unmatched controls were included with the goals of achieving a group with similar age, sex, ethnicity and body mass index (BMI; ±1 kg/m2). The study was reviewed and approved by the Ethics Committee and Clinical Research of the 6 participating Hospitals. All participants, parents or legal guardians and children older than 12 years, gave written informed consent to take part in the study.
Clinical Assessments All participants underwent physical examination, including anthropometric and blood pressure measurements according to recommendations of the American Heart Association,15 performed by the same trained technician. Elevated blood pressure was defined according to the 95th percentile, adjusted by age and height.16 ART history and immunovirologic variables were recorded from the
Pediatric HIV database. To assess the effect of treatment, years of antiretroviral exposure were analyzed as a continuous variable.
Echocardiographic Measurements Resting cardiac echocardiography was performed by a single certified sonographer, blind to the HIV status, using a CX50 portable equipment equipped with an S5 multifrequency probe (Philips Medical Systems, Inc., Eindhoven, The Netherlands), in the supine position. Classic measures of LV systolic function, such as ejection fraction (EF) and fractional shortening (FS), as well as indicators of diastolic function, such as mitral inflow E/A ratio and tissue Doppler-derived E/E′ ratio, were evaluated. Parameters acquired from M-mode echocardiography included LV end-diastolic and endsystolic diameters, as well as septal and posterior wall thicknesses. Values of systolic pulmonary pressure were noninvasively estimated using the maximum velocity of the tricuspid regurgitant jet.17 Parameters that reflect right ventricular performance, such as tricuspid annular plane systolic excursion and tissue Doppler-derived tricuspid annular systolic peak velocity, were also evaluated. Tissue Doppler velocities were assessed as the mean of 3 successive cardiac cycles. All measurements were performed according to the American Society of Echocardiography recommendations18 and were subsequently normalized by Z score when needed.19 Quantification of myocardial deformation (strain and torsion) by 2-dimensional STE was performed following consensus by the American and European Associations of Echocardiography.13 LV deformation parameters were analyzed offline by a blind trained cardiologist using 2-dimensional speckle-tracking echo software (QLAB Advanced Quantification Software version 7.1; Philips Medical Systems, Inc.). Definition of these parameters has been described elsewhere.13 In our study, global longitudinal strain was obtained by averaging all segmental longitudinal strain curves computed from the conventional apical 2-chamber, 3-chamber and 4-chamber views, as it has been described.20–22 LV twist was assessed from basal and apical short-axis views using the same frame rate and was defined as the net difference between apical rotation and basal rotation at the maximal deformation point (Fig. 1). As STE relies on good image quality and high temporal resolution, images that did not meet these criteria were excluded from strain-specific analysis.
FIGURE 1. Assessment of LV rotation by 2-dimensional speckle-tracking analysis. LV rotation time curves (bottom, both panels) derived from 2-dimensional speckle-tracking analysis of the short-axis views at the base (top, panel A) and at the apex (top, panel B) of the LV.
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The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
Carotid Artery Ultrasound IMT was examined simultaneously using the same CX50 portable equipment and specific IMT detection software—Qlab (Philips Medical Systems, Inc.). Measurements were made bilaterally at the common carotid artery (1–2 cm proximal to the bulb), as previously described5 and digitalized. Images were read by an experienced cardiologist, blind to HIV status, and the mean value of the right and left measurements was then calculated and used for the analysis.
Laboratory Assays Fasting blood samples were drawn for real-time measurements of glucose levels and lipid profile [total cholesterol, highdensity lipoprotein cholesterol (HDLc) and low-density lipoprotein cholesterol] that were determined in the different participating hospitals using standard enzymatic methods. In the HIV-infected group, plasma HIV-1 viral load (VL) was quantified using the Cobas TaqMan HIV-1 assay (Roche Diagnostics Systems, Inc., Branchburg, NJ) with a detection limit of 50 copies/mL. Absolute and percentage CD4 T-lymphocyte (CD4) counts were measured with standard flow cytometric methods.
Data Analyses Normally distributed quantitative variables were described as mean and standard deviation (SD), whereas continuous nonnormally distributed variables were reported as median and
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interquartile ranges. Weight, height, BMI and hypertension were adjusted using Z score according to age and gender,16,23 as well as ventricular dimensional parameters.19 Means for variables with a normal distribution were compared using the Student t test and Fisher test when appropriate. Nonparametric variables were examined using the Mann–Whitney and Kruskal–Wallis tests. Simultaneous independent associations between parameters of cardiac function and HIV-related variables were evaluated by logistic regression analysis. Statistical analyses were performed using Stata v. 12.0 (StataCorp LP, College Station, TX).
RESULTS Study Population and Between Group Comparison of Clinical Characteristics A total of 64 HIV-infected children and adolescents and 58 healthy volunteers underwent echocardiography, including tissue Doppler imaging and LV rotational analysis. Two patients were excluded because of known history of premature cardiovascular disease, and 2 were excluded because of acute infection. Main characteristics of both cohorts are summarized in Table 1. Globally, mean age was 13.6 ± 5.4 years. Most subjects were female (64%) and of Caucasian origin (74%). All had acquired HIV from mother-to-child transmission except for 3 patients who had been diagnosed very
TABLE 1. Main Characteristics of Both Cohorts
Demographic data Age (years) Female, n (%) Caucasian, n (%) Clinical variables Heart rate (beats/min) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Blood pressure over 95th percentile, n (%) Smokers, n (%) BMI (kg/m2) Z score BMI* Waist (cm) Hip (cm) Waist-to-hip ratio Laboratory measurements Glycemia (mg/dL) Total cholesterol (mg/dL) HDLc (mg/dL) LDLc (mg/dL) Total cholesterol/HDLc Triglycerides (mg/dL)* IMT (mm) HIV-related parameters On ART, n (%) Vertical transmission, n (%) Hepatitis virus C coinfection, n VL 70%) for many of the uninfected patients also supports this hypothesis. Deterioration of standard echocardiographic measures of EF and FS is generally considered a late stage of cardiac dysfunction in clinically asymptomatic patients. In an attempt to overcome this fact, measurements of longitudinal strain and rotational motion analysis were included in our cardiac evaluation, and again no differences were found in ventricular function. A previous study published in 2012 by Sims et al,14 including 28 ART-treated HIV-infected subjects, report mild cardiac impairment missed by conventional echocardiography but detected by cardiac strain analysis. The mean age of the subjects included in the mentioned study was 18 ± 4 years (range 7–29), whereas the mean age in our cohort is 14 ± 5 (range 2.5–22). We hypothesize that this small difference in age between the two studies may reflect big differences in terms of timing and effectiveness of ART. Most participants in our study were treated early and frequently achieved and maintained undetectable VLs at least until adolescence, and they had an overall better disease control compared with their peers born 5 years before. Nevertheless, as impairment of cardiac function appears progressively, it is also possible that mild abnormalities that are not yet present during adolescence might become apparent in young adults. Although no clinically significant differences in cardiac function were found between groups, we explored relationships between HIV-related variables and echocardiographic parameters. According to the literature, disease severity appears to be the main factor related to abnormalities on cardiac structure and function.35 In this study, no correlation was found between traditional echocardiographic parameters and detectable VLs, CD4 counts or CD4 nadir. Our findings are consistent with the last study published by Lipshultz et al12 describing an association between CD4 nadir and cardiac function in the pre-ART era but no association in early treated patients. www.pidj.com | e129
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We present here data from a cross-sectional analysis, so no causal inferences can be made. The rather small sample size of the study obviously limits our ability to measure the contribution of HIV-related variables on cardiac function. Larger studies would potentially allow us to deepen associations between ventricular function and particular antiretroviral drugs, which may help to identify optimal combinations in terms of protecting long-term cardiac health. Characteristics of the control group are another main limitation of the study. HIV-exposed but uninfected children were included in the study, as they have historically been considered as the optimal control group to assess cardiovascular risk. However, some studies suggest that intrauterine exposure to HIV and ART may have impact on cardiac status, and these findings put into question the appropriateness of this population as a reference.6,36 To further confirm our findings, we repeated the analyses restricting the control group to HIV-unexposed subjects, and results were consistent with previous findings. Although previous data and our data suggest that ART has a protective effect on cardiac health, vertically HIV-infected individuals may benefit from cardiac evaluation for a prompt diagnosis and management of abnormalities. The optimal timing for a cardiac study is unclear, but according to the findings from the previously mentioned studies and the data provided in this work, the end of adolescence might be the ideal time to perform a follow-up echocardiogram.
ACKNOWLEDGMENTS We acknowledge all patients and healthy volunteers as well as their families for their participation in this study. We thank all the professionals involved in the study and especially those integrating the Spanish Pediatric HIV-infection Network (CoRISpeS). REFERENCES 1. Agwu AL, Fairlie L. Antiretroviral treatment, management challenges and outcomes in perinatally HIV-infected adolescents. J Int AIDS Soc. 2013. 16:1–13 2. d’Arminio A, Sabin CA, Phillips AN, et al; Writing Committee of the D:A:D: Study Group. Cardio- and cerebrovascular events in HIV-infected persons. AIDS. 2004;18:1811–1817. 3. Charakida M, Donald AE, Green H, et al. Early structural and functional changes of the vasculature in HIV-infected children: impact of disease and antiretroviral therapy. Circulation. 2005;112:103–109. 4. McComsey GA, O’Riordan M, Hazen SL, et al. Increased carotid intima media thickness and cardiac biomarkers in HIV infected children. AIDS. 2007;21:921–927. 5. Sainz T, Álvarez-Fuente M, Navarro ML, et al; Madrid Cohort of HIVInfected Children and Adolescents Integrated in the Pediatric Branch of the Spanish National AIDS Network (CoRISPE). Subclinical atherosclerosis and markers of immune activation in HIV-infected children and adolescents: the CaroVIH Study. J Acquir Immune Defic Syndr. 2014;65:42–49. 6. Lipshultz SE, Easley KA, Orav EJ, et al; Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection (P(2)C(2) HIV) Study Group. Cardiovascular status of infants and children of women infected with HIV-1 (P(2)C(2) HIV): a cohort study. Lancet. 2002;360:368–373. 7. Starc TJ, Lipshultz SE, Easley KA, et al. Incidence of cardiac abnormalities in children with human immunodeficiency virus infection: the prospective P2C2 HIV study. J Pediatr. 2002;141:327–334. 8. Barbarinia G, Barbaro G. Incidence of the involvement of the cardiovascular system in HIV infection. AIDS. 2003;17(suppl 1):S46–S50. 9. Lipshultz SE, Easley KA, Orav EJ, et al. Cardiac dysfunction and mortality in HIV-infected children: the prospective P2C2 HIV multicenter study. Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection (P2C2 HIV) Study Group. Circulation. 2000;102:1542–1548.
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10. Currie PF, Jacob AJ, Foreman AR, et al. Heart muscle disease related to HIV infection: prognostic implications. BMJ. 1994;309:1605–1607. 11. Lipshultz SE. Dilated cardiomyopathy in HIV-infected patients. N Engl J Med. 1998;339:1153–1155. 12. Lipshultz SE, Williams PL, Wilkinson JD, et al; Pediatric HIV/AIDS Cohort Study (PHACS). Cardiac status of children infected with human immunodeficiency virus who are receiving long-term combination antiretroviral therapy: results from the Adolescent Master Protocol of the Multicenter Pediatric HIV/AIDS Cohort Study. JAMA Pediatr. 2013;167:520–527. 13. Mor-Avi V, Lang RM, Badano LP, et al. Current and evolving echocardiographic techniques for the quantitative evaluation of cardiac mechanics: ASE/EAE consensus statement on methodology and indications endorsed by the Japanese Society of Echocardiography. Eur J Echocardiogr. 2011;12:167–205. 14. Sims A, Frank L, Cross R, et al. Abnormal cardiac strain in children and young adults with HIV acquired in early life. J Am Soc Echocardiogr. 2012;25:741–748. 15. Urbina EM, Williams RV, Alpert BS, et al; American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee of the Council on Cardiovascular Disease in the Young. Noninvasive assessment of subclinical atherosclerosis in children and adolescents: recommendations for standard assessment for clinical research: a scientific statement from the American Heart Association. Hypertension. 2009;54:919–950. 16. Blood Pressure Tables for Children and Adolescents from the Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents of the national Institute for Health, USA. Available at: http://www.nhlbi.nih.gov/guidelines/hypertension/child_tbl. htm. Accessed 31 May 2013. 17. Yock PG, Popp RL. Noninvasive estimation of right ventricular systolic pressure by Doppler ultrasound in patients with tricuspid regurgitation. Circulation. 1984;70:657–662. 18. Lopez L, Colan SD, Frommelt PC, et al. Recommendations for quantification methods during the performance of a pediatric echocardiogram: a report from the Pediatric Measurements Writing Group of the American Society of Echocardiography Pediatric and Congenital Heart Disease Council. J Am Soc Echocardiogr. 2010;23:465–495. 19. Park MK. ed. Cardiología Pediátrica. 3rd ed. Madrid: Elsevier España; 2003. p. 55–66. 20. Macron L, Lairez O, Nahum J, et al. Impact of acoustic window on accuracy of longitudinal global strain: a comparison study to cardiac magnetic resonance. Eur J Echocardiogr. 2011;12:394–399. 21. Mollema SA, Delgado V, Bertini M, et al. Viability assessment with global left ventricular longitudinal strain predicts recovery of left ventricular function after acute myocardial infarction. Circ Cardiovasc Imaging. 2010;3:15–23. 22. Nahum J, Bensaid A, Dussault C, et al. Impact of longitudinal myocardial deformation on the prognosis of chronic heart failure patients. Circ Cardiovasc Imaging. 2010;3:249–256. 23. WHO Child Growth Standards: Methods and development: length/heightfor-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age. Available at: http://www.who.int/childgrowth/publications/technical_report_pub/en/index.html. Accessed 24 May 2013. 24. Opravil M, Pechère M, Speich R, et al. HIV-associated primary pulmonary hypertension. A case control study. Swiss HIV Cohort Study. Am J Respir Crit Care Med. 1997;155:990–995. 25. Domanski MJ, Sloas MM, Follmann DA, et al. Effect of zidovudine and didanosine treatment on heart function in children infected with human immunodeficiency virus. J Pediatr. 1995;127:137–146. 26. Frerichs FC, Dingemans KP, Brinkman K. Cardiomyopathy with mitochondrial damage associated with nucleoside reverse-transcriptase inhibitors. N Engl J Med. 2002;347:1895–1896. 27. Meng Q, Lima JA, Lai H, et al. Use of HIV protease inhibitors is associated with left ventricular morphologic changes and diastolic dysfunction. J Acquir Immune Defic Syndr. 2002;30:306–310. 28. Pugliese A, Isnardi D, Saini A, et al. Impact of highly active antiretroviral therapy in HIV-positive patients with cardiac involvement. J Infect. 2000;40:282–284. 29. Melek M, Esen O, Esen AM, et al. Tissue Doppler evaluation of tricuspid annulus for estimation of pulmonary artery pressure in patients with COPD. Lung. 2006;184:121–131. 30. McMurray JJ, Adamopoulos S, Anker SD, et al; ESC Committee for Practice Guidelines. ESC guidelines for the diagnosis and treatment of
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acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33:1787–1847. 31. Yingchoncharoen T, Agarwal S, Popović ZB, et al. Normal ranges of left ventricular strain: a meta-analysis. J Am Soc Echocardiogr. 2013;26:185–191. 32. Notomi Y, Srinath G, Shiota T, et al. Maturational and adaptive modulation of left ventricular torsional biomechanics: Doppler tissue imaging observation from infancy to adulthood. Circulation. 2006;113:2534–2541.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
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33. Takeuchi M, Nakai H, Kokumai M, et al. Age-related changes in left ventricular twist assessed by two-dimensional speckle-tracking imaging. J Am Soc Echocardiogr. 2006;19:1077–1084. 34. Blessberger H, Binder T. Non-invasive imaging: two dimensional speckle tracking echocardiography: basic principles. Heart. 2010;96:716–722. 35. Hsue PY, Hunt PW, Ho JE, et al. Impact of HIV infection on diastolic function and left ventricular mass. Circ Heart Fail. 2010;3:132–139. 36. Wilkinson JD, Williams PL, Leister E, et al; Pediatric HIVAIDS Cohort Study (PHACS). Cardiac biomarkers in HIV-exposed uninfected children. AIDS. 2013;27:1099–1108.
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