|Year : 2014 | Volume
| Issue : 1 | Page : 8-12
Left ventricular mass and diastolic dysfunction in children infected with the human immunodeficiency virus
Olukemi O Ige, Stephen Oguche, Christopher S Yilgwan, Fidelia Bode-Thomas
Department of Pediatrics, University of Jos, Jos, Nigeria
|Date of Web Publication||7-Apr-2014|
Department of Paediatrics, Jos University Teaching Hospital, PMB 2076, Jos
Source of Support: None, Conflict of Interest: None
Background: Increased left ventricular mass (LVM) and diastolic dysfunction are associated with higher morbidity and mortality among adult patients with human immunodeficiency virus (HIV) infection.
Objective: The objective of the following study is to determine the prevalence of increased LVM and diastolic dysfunction in Nigerian children infected with HIV.
Methods: Cross-sectional comparative study of LVM and left ventricular (LV) diastolic function of 150 HIV-positive children and controls asymptomatic for cardiac disease.
Results: Mean LVM was larger in subjects than controls - 66.5 (95% confidence interval, 63.7-69.3) versus 56.9 (54.1-59.7) g/m 2 respectively - P < 0.001. An increased LVM was present in 21 (14.0%) subjects and 4 (2.7%) controls - P < 0.001. Mean mitral valve peak flow velocities and pressure gradients for the early and late diastolic waves were higher among HIV positive children than controls (P < 0.001). LV diastolic dysfunction was present in 46 (30.7%) subjects and 19 (12.7%) controls (P < 0.001). Subjects with increased LVM were younger and had more severe disease than those with normal LVM. Subjects and controls were similar with respect to their clinical and immunological stages of disease and use of nucleoside reverse transcriptase inhibitors.
Conclusion: Increased LVM and diastolic dysfunction are significantly more common in HIV-infected children compared with controls and occur in asymptomatic subjects.
Keywords: Children, diastolic dysfunction, human immunodeficiency virus, left ventricular mass
|How to cite this article:|
Ige OO, Oguche S, Yilgwan CS, Bode-Thomas F. Left ventricular mass and diastolic dysfunction in children infected with the human immunodeficiency virus. Nig J Cardiol 2014;11:8-12
|How to cite this URL:|
Ige OO, Oguche S, Yilgwan CS, Bode-Thomas F. Left ventricular mass and diastolic dysfunction in children infected with the human immunodeficiency virus. Nig J Cardiol [serial online] 2014 [cited 2020 Sep 23];11:8-12. Available from: http://www.nigjcardiol.org/text.asp?2014/11/1/8/130044
| Introduction|| |
There have been several reports on the spectrum of cardiovascular complications of the human immunodeficiency virus (HIV) infection in adults but fewer in children. ,, Many of these studies have found HIV infection to be associated with a higher prevalence of cardiomyopathy and increased left ventricular mass (LVM). ,, An increase in LVM may be associated with left ventricular (LV) diastolic dysfunction and both have been shown to increase morbidity and mortality in both adults and children, with increased predisposition to ventricular arrhythmias, severe heart failure, myocardial infarction and cerebrovascular accidents. ,,
The pathogenesis of increased LVM which often underlies diastolic dysfunction, may be related to an increase in sympathetic tone, a manifestation of autonomic dysfunction, which in turn raises the concentration of catecholamines, leading eventually to myocardial hypertrophy. , HIV infected adults receiving nucleoside reverse transcriptase inhibitors (NRTI) have been found to have higher LVM compared with controls.  Higher LVM has also been shown to be more common in older HIV-infected children and those with opportunistic infections and malnutrition. ,
The cause of LV diastolic dysfunction in HIV infected individuals is still uncertain, but possible etiologic factors have been proposed. Higher levels of inflammatory markers such as high sensitivity C-reactive protein have been linked to LV diastolic dysfunction in the general population.  In HIV infected individuals, the HIV virions and other viruses infect the myocardial cells directly, leading to the local release of cytokines. Cytokines act by down-regulating the sarcoendoplasmic reticulum Ca 2+ -ATPase pumps which results in a slower removal of cytosolic calcium. This could lead to a prolonged and incomplete diastolic phase and consequently, diastolic dysfunction. , Hsue et al.  in their study have reported that the use of NRTI and lower CD4 counts were associated with LV diastolic dysfunction, while a decrease in CD4+ T cell count of <100 cell/mm 3 resulted in an increase in the mean LVM by 1.3 g.
LV diastolic dysfunction is known to precede systolic dysfunction in most cardiac diseases and has also been reported in HIV-infected children. ,,, Very few studies on the myocardial function of such children have emanated from sub-Saharan Africa, where the greatest burden of the disease lies and none of these has focused on diastolic function. , Okoromah et al.  in South-west Nigeria showed that the mean LVM was significantly higher in HIV-infected children compared with controls, but did not assess their diastolic function. The current report aims to determine the prevalence of increased LVM and diastolic dysfunction in Nigerian African children infected with HIV and their possible associated factors.
| Materials and Methods|| |
A total of 150 children with confirmed HIV infection attending the pediatric infectious disease clinic (PIDC) of the Jos University Teaching Hospital (JUTH) were systematically sampled and enrolled into the study. Age-and sex-matched HIV-negative children of the same number, with no acute or chronic illnesses were recruited from the pediatric out-patients department and the PIDC and constituted the control group. Socio-economic status of all the participants was determined according to the method described by Olusanya et al. 
Written informed consent was obtained from each child's parent or guardian, while approval was obtained from the Ethics Committee of JUTH before commencement of the study.
Two-dimensional, M-mode and Doppler echocardiograms were performed on all subjects and controls using an Acuson ® Cypress ® Ultrasound System (Siemens Medical, Germany, 2004) with 3.5 MHz and 7.5 MHz transducers for older and younger children respectively. Our observations on the LV systolic function of the study population have been previously reported. 
End-diastolic measurements of the left ventricular internal dimension (LVID), interventricular septal thickness (IVST) and posterior wall thickness (PWT) - all measured according to the guidelines of the American Society of Echocardiography  were used to calculate LV mass using the formula:
Anatomic LVM = 1.04 ([LVID + PWT + IVST] 3 − [LVID] 3 ) - 13.6 g. 
LVM was indexed to the body surface area in m 2 , compared with published normal values for age and adjudged to be increased if above the normal range for age. 
LV diastolic function was assessed using pulsed wave Doppler flow velocities across the mitral valve. The peak velocity (V max ) and peak pressure gradient (∆P max ) across the mitral valve in early and late diastole corresponding to the early (E) and atrial (A) waves were measured and the E/A ratio calculated. LV diastolic dysfunction was adjudged present if the mitral valve E/A wave ratio was <1 (slow-relaxation pattern) or above 2.5 (restrictive pattern). 
| Results|| |
The children were aged between 7 months and 14 years with a mean of 5.59 (5.2-6.0) years for the HIV positive subjects and 5.6 (5.0-6.2) years for the controls and a male to female ratio of 1.1:1. Subjects differed from the controls with respect to their socio-economic status [Table 1]. The most likely route of acquisition of the HIV infection was maternal to child (vertical) transmission in the majority (95.3%) of cases, followed by blood transfusion in 6 (4.0%). In 1 (0.7%) patient, the route of transmission could not be ascertained. This was a 13-year-old boy whose mother was HIV negative and who had no history of blood transfusion, sexual contact, traditional circumcision, uvulectomy or scarification marks. Features suggestive of encephalopathy were present in only one patient [Table 1].
|Table 1: Clinical characteristics of HIV positive subjects, age and socio-economic status distribution of subjects and controls|
Click here to view
The mean LVM was 66.5 (63.7-69.3) g/m 2 in HIV-infected subjects compared with 56.9 (54.1-59.7) g/m 2 in HIV negative controls. The difference was statistically significant - P < 0.001 [Table 2]. Excessive LVM was present in 21 (14.0%) subjects compared with 4 (2.7%) controls - P < 0.001. Subjects with increased LVM were younger and had more severe disease than those with a normal LVM. There was no significant difference between subjects with excessive LVM compared with subjects without, in terms of their immunological stages of disease and the use of NRTI [Table 3].
|Table 2: Mean LVM and mitral valve flow parameters in HIV-positive subjects compared with HIV-negative controls|
Click here to view
|Table 3: Increased LVM and the clinical characteristics of HIV positive subjects|
Click here to view
LV diastolic dysfunction
The mean mitral valve V max and ∆P max for the early diastolic waves (E waves) were significantly higher in HIV-infected children (91.1 (90.2-92.0) cm/s and 3.3 (3.2-3.4) mmHg) than in controls (85.4 (84.3-86.6) cm/s and 3.0 (2.9-3.1) mmHg) respectively - P < 0.001 in each case. In late diastole during active atrial contraction, the mean A wave V max and ∆P max were also significantly higher in HIV-infected subjects than in HIV-negative controls - P < 0.001 in each case [Table 2].
LV diastolic dysfunction (of the restrictive pattern in all cases) was present in 46 (30.7%) subjects compared with 19 (12.7%) controls (P < 0.001). Although subjects with LV diastolic dysfunction were older than those without (6.0 (5.1-6.9) and 5.4 (5.1-5.7) years respectively), the difference was not statistically significant (P = 0.36). There was also no significant difference between subjects with LV diastolic dysfunction compared with subjects without the abnormality with respect to their clinical and immunological stages of disease and the use of NRTI [Table 4]. Multiple linear regression analysis revealed no significant correlation between diastolic dysfunction and factors such as tachycardia (P = 0.41), fever (P = 0.71), hypertension (P = 0.30) or hypotension (P = 0.34).
|Table 4: Left ventricular diastolic dysfunction with respect to clinical characteristics of HIV-positive subjects|
Click here to view
| Discussion|| |
The impact of HIV infection on LV diastolic function has not been previously described in children in sub-Saharan Africa even though HIV is a common cause of morbidity and mortality in the region. Our study demonstrates that HIV infection is associated with both increased LV mass index and diastolic dysfunction.
We found a larger mean LVM among the HIV-positive children in this study compared with controls - similar to findings by others. , Immune activation in HIV-infected adults is postulated to contribute to the observed increase in LVM in a similar manner as with systemic lupus erythematosus, rheumatoid arthritis and other chronic inflammatory conditions in adults without HIV infection. , Our finding of a more advanced immunological stage of disease in those with larger muscle mass supports this hypothesis. In addition, tachycardia has been typically reported along with increased LVM in HIV-infected children, suggesting that the increased LVM may be as a result of autonomic dysfunction.  This has also been likened to the increase in heart muscle mass in response to the physical and metabolic stresses that are associated with chronic diseases and malnutrition.  We found no correlation between the presence of diastolic dysfunction and tachycardia in the HIV-infected children we studied. However, we did not further assess for autonomic dysfunction by evaluating heart rate variation during deep breathing and its response to postural changes, as has been done in adult subjects. 
Our study shows that LV diastolic dysfunction using pulse wave Doppler flow velocities across the mitral valve is significantly more common in HIV subjects compared with controls. Nearly 30.7% of our subjects had diastolic dysfunction, a figure similar to the 26% detected in adults by Mondy et al.  in the United States but higher than the 10% reported by Kumar et al.  in children. The latter assessed LV diastolic dysfunction using the E/A ratio as in the present study, while Mondy et al.  in addition to the E/A ratio also assessed the mitral inflow deceleration time and the lateral mitral annular velocity using tissue Doppler. It is possible that we might have found a higher prevalence of LV diastolic dysfunction if we had also utilized these or other additional parameters.
HIV-associated cardiac dysfunction is said to be of multifactorial origin. The HIV or other associated viral infection may directly attack cardiac myocytes and thus impinge on myocardial function. The detection of HIV-1 in endomyocardial biopsy specimens of HIV patients with LV dysfunction and the detection of HIV-1 sequences in the myocytes of HIV patients undergoing autopsy provide some evidence for this.  Furthermore, ischemic heart disease may play a role - as suggested by the finding that HIV-positive adults have a demonstrable increase in their carotid artery intima-media thickness (IMT), which suggests subclinical atherosclerosis.  HIV-infected children have similarly been shown to have increased carotid artery IMT compared with healthy controls and this may also predispose them to diastolic dysfunction. 
We found no association between diastolic dysfunction in our HIV-infected children and the stage of their disease. Longo-Mbenza et al.  found a higher prevalence of diastolic dysfunction in adults with acquired immunodeficiency syndrome (stage IV disease). In contrast, only four children in our study had stage IV disease and none of them had diastolic dysfunction. However, we did not assess for the pseudo normalization pattern using mitral inflow deceleration time, which has been shown to correlate directly to LVM in adults. 
A longitudinal study design would have enabled us to monitor progression of LVM and LV diastolic dysfunction in our subjects and hence to determine the natural history of these conditions in children with HIV infection. The present study however has further shown the existence of these cardiac abnormalities in Nigerian children infected with HIV, thus strengthening the case for echocardiographic screening in these patients.
| References|| |
|1.||Longo-Mbenza B, Seghers LV, Vita EK, Tonduangu K, Bayekula M. Assessment of ventricular diastolic function in AIDS patients from Congo: A Doppler echocardiographic study. Heart 1998;80:184-9. |
|2.||Meng Q, Lima JA, Lai H, Vlahov D, Celentano DD, Strathdee S, et al. Use of HIV protease inhibitors is associated with left ventricular morphologic changes and diastolic dysfunction. J Acquir Immune Defic Syndr 2002;30:306-10. |
|3.||Mansoor A, Golub ET, Dehovitz J, Anastos K, Kaplan RC, Lazar JM. The association of HIV infection with left ventricular mass/hypertrophy. AIDS Res Hum Retroviruses 2009;25:475-81. |
|4.||Barbaro G, Di Lorenzo G, Grisorio B, Barbarini G. Incidence of dilated cardiomyopathy and detection of HIV in myocardial cells of HIV-positive patients. Gruppo Italiano per lo Studio Cardiologico dei Pazienti Affetti da AIDS. N Engl J Med 1998;339:1093-9. |
|5.||Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham heart study. N Engl J Med 1990;322:1561-6. |
|6.||Verdecchia P, Porcellati C, Reboldi G, Gattobigio R, Borgioni C, Pearson TA, et al. Left ventricular hypertrophy as an independent predictor of acute cerebrovascular events in essential hypertension. Circulation 2001;104:2039-44. |
|7.||Kardys I, Deckers JW, Stricker BH, Vletter WB, Hofman A, Witteman JC. Echocardiographic parameters and all-cause mortality: The Rotterdam study. Int J Cardiol 2009;133:198-204. |
|8.||Fisher SD, Easley KA, Orav EJ, Colan SD, Kaplan S, Starc TJ, et al. Mild dilated cardiomyopathy and increased left ventricular mass predict mortality: The prospective P2C2 HIV Multicenter Study. Am Heart J 2005;150:439-47. |
|9.||Himelman RB, Chung WS, Chernoff DN, Schiller NB, Hollander H. Cardiac manifestations of human immunodeficiency virus infection: A two-dimensional echocardiographic study. J Am Coll Cardiol 1989;13:1030-6. |
|10.||Hsue PY, Hunt PW, Ho JE, Farah HH, Schnell A, Hoh R, et al. Impact of HIV infection on diastolic function and left ventricular mass. Circ Heart Fail 2010;3:132-9. |
|11.||Ganau A, Devereux RB, Roman MJ, de Simone G, Pickering TG, Saba PS, et al. Patterns of left ventricular hypertrophy and geometric remodeling in essential hypertension. J Am Coll Cardiol 1992;19:1550-8. |
|12.||Frerichs FC, Dingemans KP, Brinkman K. Cardiomyopathy with mitochondrial damage associated with nucleoside reverse-transcriptase inhibitors. N Engl J Med 2002;347:1895-6. |
|13.||Gardin JM, Wagenknecht LE, Anton-Culver H, Flack JM, Gidding S, Wong ND, et al. Relationship of race, sex, systolic blood pressure levels, and body mass to left ventricular mass in healthy young adults: The CARDIA study. Circulation 1991;84:133. |
|14.||Miller TL, Orav EJ, Colan SD, Lipshultz SE. Nutritional status and cardiac mass and function in children infected with the human immunodeficiency virus. Am J Clin Nutr 1997;66:660-4. |
|15.||Michowitz Y, Arbel Y, Wexler D, Sheps D, Rogowski O, Shapira I, et al. Predictive value of high sensitivity CRP in patients with diastolic heart failure. Int J Cardiol 2008;125:347-51. |
|16.||Ju H, Scammel-La Fleur T, Dixon IM. Altered mRNA abundance of calcium transport genes in cardiac myocytes induced by angiotensin II. J Mol Cell Cardiol 1996;28:1119-28. |
|17.||Hilal-Dandan R, He H, Martin JL, Brunton LL, Dillmann WH. Endothelin downregulates SERCA2 gene and protein expression in adult rat ventricular myocytes: Regulation by pertussis toxin-sensitive Gi protein and cAMP. Am J Physiol Heart Circ Physiol 2009;296:H728-34. |
|18.||Gomez-Marin O, Mas MS. Diastolic cardiac dysfunction precedes systolic dysfunction in pediatric HIV infected patients. Pediatr Res 1996;39:36. |
|19.||Yamamoto K, Redfield MM, Nishimura RA. Analysis of left ventricular diastolic function. Heart 1996;75:27-35. |
|20.||Lipshultz SE, Fisher SD, Miller TL, Sharma TS, Milton AN. The cardiovascular manifestations of HIV infection. Dialog Cardiovasc Med 2007;12:5-23. |
|21.||Okoromah CA, Ojo OO, Ogunkunle OO. Cardiovascular dysfunction in HIV-infected children in a Sub-Saharan country: Comparative cross-sectional observational study. J Trop Paediatr 2012;58:3-11. |
|22.||Ige OO, Oguche S, Bode-Thomas F. Left ventricular systolic function in Nigerian children with human immunodeficiency virus infection. Congenit Heart Dis 2012;7:417-22. |
|23.||Olusanya O, Okpere E, Ezimokhai M. The importance of social class in fertility control in a developing country. West Afr J Med 1985;4:205-12. |
|24.||Lai WW, Geva T, Shirali GS, Frommelt PC, Humes RA, Brook MM, et al. Guidelines and standards for performance of a pediatric echocardiogram: A report from the Task Force of the Pediatric Council of the American Society of Echocardiography. J Am Soc Echocardiogr 2006;19:1413-30. |
|25.||Devereux RB, Reichek N. Echocardiographic determination of left ventricular mass in man. Anatomic validation of the method. Circulation 1977;55:613-8. |
|26.||Vogel M, Staller W, Bühlmeyer K. Left ventricular myocardial mass determined by cross-sectional echocardiography in normal newborns, infants, and children. Pediatr Cardiol 1991;12:143-9. |
|27.||Spirito P, Maron BJ, Bonow RO. Noninvasive assessment of left ventricular diastolic function: Comparative analysis of Doppler echocardiographic and radionuclide angiographic techniques. J Am Coll Cardiol 1986;7:518-26. |
|28.||Lipshultz SE, Easley KA, Orav EJ, Kaplan S, Starc TJ, Bricker JT, et al. Left ventricular structure and function in children infected with human immunodeficiency virus: The prospective P2C2 HIV multicenter study. Pediatric pulmonary and cardiac complications of vertically transmitted HIV infection (P2C2 HIV) study group. Circulation 1998;97:1246-56. |
|29.||Barbaro G, Barbarini G, Di Lorenzo G. Early impairment of systolic and diastolic function in asymptomatic HIV-positive patients: A multicenter echocardiographic and echo-doppler study. The Gruppo Italiano Per lo Studio Cardiologico dei Pazienti Affetti da AIDS. AIDS Res Hum Retroviruses 1996;12:1559-63. |
|30.||Pieretti J, Roman MJ, Devereux RB, Lockshin MD, Crow MK, Paget SA, et al. Systemic lupus erythematosus predicts increased left ventricular mass. Circulation 2007;116:419-26. |
|31.||Wislowska M, Jaszczyk B, Kochmañski M, Sypu³a S, Sztechman M. Diastolic heart function in RA patients. Rheumatol Int 2008;28:513-9. |
|32.||Rossi MA, Oliveira JS, Zucoloto S, Pissaia O, Costa RS. Effect of protein-calorie malnutrition on catecholamine levels and weight of heart in rats. J Neural Transm 1980;48:85-99. |
|33.||Nzuobontane D, Ngu BK, Christopher K. Cardiovascular autonomic dysfunction in Africans infected with human immunodeficiency virus. J R Soc Med 2002;95:445-7. |
|34.||Mondy KE, Gottdiener J, Overton ET, Henry K, Bush T, Conley L, et al. High prevalence of echocardiographic abnormalities among HIV-infected persons in the era of highly active antiretroviral therapy. Clin Infect Dis 2011;52:378-86. |
|35.||Kumar P, Hemal A, Pensi T, Kumar D, Nath R, Khurana R. Cardiovascular manifestation of HIV infected children: A cross-sectional study. (Poster Presentation at the 49 th National Conference of Indian Academy of Pediatrics, January 18-22, 2012). |
|36.||Grody WW, Cheng L, Lewis W. Infection of the heart by the human immunodeficiency virus. Am J Cardiol 1990;66:203-6. |
|37.||Hsue PY, Hunt PW, Sinclair E, Bredt B, Franklin A, Killian M, et al. Increased carotid intima-media thickness in HIV patients is associated with increased cytomegalovirus-specific T-cell responses. AIDS 2006;20:2275-83. |
|38.||Giuliano Ide C, de Freitas SF, de Souza M, Caramelli B. Subclinic atherosclerosis and cardiovascular risk factors in HIV-infected children: PERI study. Coron Artery Dis 2008;19:167-72. |
|39.||de Simone G, Kitzman DW, Palmieri V, Liu JE, Oberman A, Hopkins PN, et al. Association of inappropriate left ventricular mass with systolic and diastolic dysfunction: The HyperGEN study. Am J Hypertens 2004;17:828-33. |
[Table 1], [Table 2], [Table 3], [Table 4]