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ORIGINAL ARTICLE
Year : 2018  |  Volume : 11  |  Issue : 3  |  Page : 221-226  

Reversibility of echocardiographic changes in human immunodeficiency virus infection and acquired immune deficiency syndrome


1 Department of Cardiology, Command Hospital (Western Command), Panchkula, Haryana, India
2 Department of Medicine and Cardiology, Air Force Central Medical Establishment, Pune, Maharashtra, India
3 Military Hospital (CardioThoracic Centre), Pune, Maharashtra, India
4 Department of Cardiology, Base Hospital, Delhi Cantt, New Delhi, India

Date of Web Publication29-Jun-2018

Correspondence Address:
Keshavamurthy Ganapathy Bhat
Air Force Central Medical Establishment, Subroto Park, New Delhi - 110 010
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mjdrdypu.MJDRDYPU_202_17

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  Abstract 


Background: Echocardiographic abnormalities in patients with human immunodeficiency virus (HIV) infection have been well documented. However, their relation with CD4 count and reversibility with treatment has not been studied prospectively. We studied prevalence and nature of echocardiographic abnormalities in HIV-infected patients and prospectively correlated with their CD4 count. Materials and Methods: We studied 108 consecutive patients with HIV infection. Baseline CD4 cell count and two-dimensional echocardiography were done. The study participants were categorized into two; one with CD4 count <100/mm3 and the other with CD4 >100/mm3. They were followed up quarterly with CD4 count and repeat echocardiography for 1 year. Results: Abnormalities on echocardiography were noted in 36 of 108 patients (33.3%). Thirty-two patients (29.6%) were detected to have diastolic dysfunction of the left ventricle, ten patients (9.25%) left ventricular (LV) systolic dysfunction and eight patients (7.4%) pericardial effusion. Abnormalities were more frequent when CD4 was <100/c.mm. LV systolic dysfunction (and dilated cardiomyopathy) occurred exclusively in patients with CD4 <100/c.mm. As the CD4 count improved with treatment, many of the echocardiographic changes reversed. Conclusions: HIV-infected individuals frequently have asymptomatic and subclinical cardiac involvement. LV diastolic dysfunction, systolic dysfunction, and pericardial effusion are more common with lower CD4 cell count. With treatment, as the CD4 count improved, there was reversibility of systolic dysfunction, diastolic dysfunction, and pericardial effusion.

Keywords: Echocardiographic findings, reversibility, human immunodeficiency virus/acquired immune deficiency syndrome


How to cite this article:
Kumar A, Bhat KG, Swamy AJ, Kumar MN, Sharma P. Reversibility of echocardiographic changes in human immunodeficiency virus infection and acquired immune deficiency syndrome. Med J DY Patil Vidyapeeth 2018;11:221-6

How to cite this URL:
Kumar A, Bhat KG, Swamy AJ, Kumar MN, Sharma P. Reversibility of echocardiographic changes in human immunodeficiency virus infection and acquired immune deficiency syndrome. Med J DY Patil Vidyapeeth [serial online] 2018 [cited 2021 Jun 12];11:221-6. Available from: https://www.mjdrdypv.org/text.asp?2018/11/3/221/235560




  Introduction Top


As per the WHO estimates, there were 36.7 million people infected with human immunodeficiency virus (HIV) in the end 2015, but only 18.2 million were accessing antiretroviral therapy (ART).[1] People newly infected with HIV in 2015 were 2.1 million and 1.1 million deaths were attributed to acquired immune deficiency syndrome (AIDS). There has been no decline in new HIV infections among adults since 2010. However, AIDS-related deaths have reduced by 45% since 2005 resulting in increased number of people living with HIV and AIDS (PLHA). India has 2.1 million HIV-infected individuals out of which only 43% are receiving ART.[1] Cardiac manifestations are seen in 28%–73% of AIDS patients.[2] Cardiac complications are the direct cause of death in some. Varying cardiovascular manifestations have been noted in patients with HIV infection which include left ventricular (LV) dysfunction (both systolic and diastolic) with myocardial involvement, pericarditis and effusion, cardiomyopathy, endocardial involvement, pulmonary arterial hypertension, neoplasm, coronary artery disease, and drug-related cardiotoxicity.[3] However, ART influence on HIV-related cardiovascular disease is unclear. New-generation anti-HIV drugs are associated with metabolic abnormalities (e.g., dysglycemia and hyperlipidemia). There is a concern that this might accelerate the progression of the cardiovascular and cerebrovascular disease. However, a study at Veterans Affairs facilities which included more than 36,000 patients showed decreased mortality, and similar cardiovascular events.[4]

Cardiovascular manifestations in HIV infected individuals are often subclinical. LV diastolic dysfunction (LVDD), pericardial effusion and systolic dysfunction are more common. Such clinically covert but echocardiographically obvious abnormalities are often seen with opportunistic infections and low CD4 count.[5] The common cardiovascular manifestations among HIV-infected patients in India are LVDD and pericardial effusion.[6] Lower CD4 counts are more commonly associated with pericardial effusion. With advancement in the management of opportunistic infections, cardiac abnormalities are likely to be found with greater frequency in clinical practice.[6] Therefore, the echocardiographic evaluation of patients living with HIV and AIDS (PLHA) is assuming increasing significance.

Prognostication based on echocardiographic findings has not been accurate. LV dilatation and systolic dysfunction were considered a poor prognostic marker. However, clinical observation has shown that LV function, at least in some, improves with treatment as CD4 count improves. However, in India, there are no prospective studies which have correlated HIV associated cardiac manifestations with the CD4 count. We, therefore, studied HIV patients for echocardiographic abnormalities and studied their progression with serial echocardiography and CD4 count. The aim was to assess the prevalence of cardiovascular changes and more importantly, to study the evolution and possible reversibility of these abnormalities with ART.


  Materials and Methods Top


This is a prospective, observational case–control study.

Source of data

The study was conducted (at two centers) by enrolling consecutive patients who were detected to have HIV infection during routine evaluation or evaluation of symptoms at a zonal hospital and a tertiary care hospital.

Method of collection of data

One hundred and eight cases of seropositive HIV patients diagnosed by ELISA were selected for the study. A detailed clinical profile, including history and examination were done for each patient with emphasis on the cardiovascular system. Routine investigations such as blood counts and metabolic profile were obtained for all patients. All patients were subjected to cardiovascular investigations such as ECG and two-dimensional (2D) echocardiography. Chest X-ray was done where clinically indicated. All relevant findings of echocardiography like LV internal dimension (LVID) in systole LVID in diastole, interventricular septal thickness in systole and diastole, fractional shortening (FS), and ejection fraction (EF) were noted.

All patients were evaluated for their CD4 counts at baseline and quarterly for 1 year. 2D echocardiography was also done at 3 monthly intervals for 1 year. Findings were analyzed for various cardiac abnormalities and their evolution with time and CD4 count.

Patients were enrolled only after informed consent was obtained.

Inclusion criteria

Patients aged >18 years and confirmed to have HIV infection/AIDS (after confirmation by blood tests [standard deviation [SD] Bioline, Triline, and Trispot tests being positive]).

Exclusion criteria

  • Patients <18 years
  • Patients with the congenital cardiovascular disease
  • Patients with preexisting valvular heart disease
  • Patients with preexisting hypertension
  • Patients with preexisting diabetes mellitus
  • Patients expressing unwillingness/inability for follow-up for at least 1 year.


Sample size and design: a total of 108 HIV positive cases were studied prospectively. The study was approved by the ethical committee. Investigations were carried out to establish the diagnosis. CD4 cell count was done by the fluorescently activated cell sorter system. Screening for opportunistic infections was done. All patients were studied with 2D transthoracic echocardiography and color flow Doppler examination. Quantitative M – mode evaluation was done. The guidelines and standards of American Society of Echocardiography (ASE) were followed.[7],[8] LVEF ≥55% was considered normal, 45%–54% mild LV systolic dysfunction, 30%–44% moderate, and ≤30% as severe LV systolic dysfunction. Modified Simpson method was used to estimate LV function where exact values were critical. Diastolic function was determined by transmitral flow velocities and tissue Doppler study of the mitral annulus. Diastolic dysfunction was categorized into Grade I to Grade IV dysfunction as per guidelines of ASE.[8]

Statistical analysis

Patients were divided into two groups; Group A with CD4 count <100 and Group B with CD4 count >100/c.mm. All results were expressed as percentage of patients detected to have the given abnormality. The two groups were compared using Fisher's exact test.

Wilcoxon rank sum test was used to compare the median CD4 cell count of patients having echocardiographic abnormality with those not having echocardiographic abnormality. A P < 0.05 was considered statistically significant.


  Observations and Results Top


We studied 108 HIV-infected individuals; 78 males (72.22%) and 30 females (27.78%). Baseline characteristics of patients are given in [Table 1]. The mean age of the patients was 38.9 ± 6.36 years. Gender-wise, the mean age was 41 ± 6.36 years for males and 33 ± 5.6 years for females. There was no reported homosexuality or intravenous drug abuse. No patient was on ART at the time of initial enrolment. Patients were categorized into two groups based on initial CD4 count. Group A had CD4 count <100 and group B had CD4 count >100 [Table 1]. Median CD4 count in patients having echocardiographic abnormalities was 139.5 (95% confidence interval [CI] 38–235), whereas that in patients not having any echocardiographic abnormality was 363 (95% CI 215–666) with P < 0.0003.
Table 1: Baseline patient characteristics

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Echocardiographic findings

Echocardiographic abnormalities were found in 33.33% (36 out of 108 patients) [Table 2]. Fourteen patients out of 18 in Group A (78%) had abnormal findings compared to 22 out of 90 (24%) in Group B (P = 0.004). The most common echocardiographic abnormality found was LVDD in 29.6% (32 patients out of 108). In Group A with CD4 count <100, 12 out of 18 (66.7%) had diastolic dysfunction of LV and in Group B, it was found in 20 out of 90 (22.2%) patients (P = 0.014). LV systolic dysfunction was found in 10 out of 108 patients (9.25%) and pericardial effusion in eight patients (7.4%).
Table 2: Abnormal echocardiographic findings in the two groups at baseline

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LV systolic dysfunction (and dilated cardiomyopathy) was found exclusively in patients with CD4 <100; all 10 in Group A (10 out of 18, 55.56%, P < 0.0001). Pericardial effusion was noted in eight patients (7.4%); 6 in Group A (33.33%, 6 out of 18) compared to 2 in Group B (2.22%, 2 out of 90) with P = 0.012.

Right ventricular enlargement was noted in only two patients (1.8%). These patients belonged to low CD4 count group (2 out of 18, 11.11%, P = 0.167). Pulmonary hypertension was observed in four patients (4 out of 108, 3.7%), only in those with CD4 count <100 (4 out of 18, 22.22%, P = 0.025). Endocarditis was not observed in any of our patients.

Opportunistic infections were more common in Group A (67%) compared to Group B (9%). Echocardiographic abnormalities were more common in those with opportunistic infections than in those without (P < 0.001).

Four patients (3.7%), while on follow-up, developed coronary artery disease-acute Myocardial infarction (MI) - three male and one female patient, three in group, A and one in Group B. Primary angioplasty was done to female patient who had MI and she recovered without any complication. One male patient who suffered inferior wall MI presented after 1 week with the complication of ventricular septal rupture (VSR) and congestive heart failure. Device closure of VSR was attempted after discussion in the heart team conference but was unsuccessful due to friable margins. He succumbed to refractory heart failure. VSR in the setting of MI carries very high mortality rate.

Overall, clinically, overt cardiovascular findings were noted only in six patients (5.5%), all in Group A. In all others, the findings were subclinical and were detected on echocardiography.

Evolution of echocardiographic changes

LV systolic dysfunction was noted in ten patients [Table 3] and [Table 4], exclusively in those with CD4 count <100/c.mm (Group A) at the time of enrolment into the study. The mean LVEF in these patients was 45±3.5%. The mean CD4 count was 34±0.7. Out of these ten patients with LV systolic dysfunction, six improved with ART from a mean EF of 40% to 50%. The CD4 count in these six patients had increased from a mean of 34±5.6 to 357±22.6. In two patients, EF did not improve, remained static. Their CD4 count showed only marginal rise from 35 to 74 in one and 44–90 in other. Two patients with LV systolic dysfunction died due to pulmonary complications a few days after enrolment.
Table 3: Echocardiographic findings in Group A at baseline and at 1 year

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Table 4: Echocardiographic abnormalities in Group B at baseline and 1 year

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LVDD was noted in a total of 32 patients (29.62%) - 12 in Group A (66.67%) and 20 in Group B (22.22%). A total of 10 patients (10 out of 32, 31.25%) showed improvement in their diastolic dysfunction – 6 in Group A (6 out of 12, 50%) and 4 in Group B (4 out of 20, 20%). The increase in CD4 count in these patients who showed improvement in diastolic dysfunction in Group A was from a mean CD4 of 44.3±28.2 to 320±56.5 and in Group B was from 202±64.3 to 425±91.9 [Figure 1]. There was no improvement in diastolic dysfunction in 4 in Group A and 16 in Group B. Two patients in Group A died who also had severe LV systolic dysfunction.
Figure 1: Improvement in CD4 count in those who had reversal of left ventricular diastolic dysfunction. Group A: CD4 count <100/c.mm. Group B: CD4 count >100/c.mm.

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Pericardial effusion

Out of six pericardial effusions in Group A, two improved, two remained static and two patients died who also had severe LV systolic dysfunction. Only two patients in Group B had mild pericardial effusion which improved with institution of ART.

Pulmonary artery hypertension was noted in four patients, all in Group A (CD4 <100). Two improved (50%); the other two died.

Right ventricular enlargement was seen in two patients in Group A and none in Group B. These patients also had severe LV systolic dysfunction and they succumbed to their illness during the study.


  Discussion Top


Abnormalities on transthoracic echocardiography in HIV infected individuals were commonly detected in our study to the extent of 33.3%. Various studies have shown the cardiac involvement to be in the range of 28%–73%.[2] The most common echocardiographic manifestation found in our study was LVDD in 29.6% of patients. Aggarwal et al. found diastolic dysfunction in 19.2% of their patients [5] and Singh et al. in 8.9% of patients.[9] The increased prevalence of diastolic dysfunction in our study may partly be because a significant number of patients were above 40 years of age.

LV systolic dysfunction and global LV hypokinesia were seen in 9.25% of our patients. This is consistent with other Indian studies where LV systolic dysfunction was seen in 8.5%–19.2% of patients.[5],[9] In a study by Blanchard et al., LV dysfunction was seen in 14% in one group with AIDS or AIDS-related complex and 5% of asymptomatic HIV patients.[10] Although they have reported no significant correlation with CD4 count and LV dysfunction in their study, LV dysfunction was more frequent in AIDS patients than in asymptomatic HIV patients. Reduction in LV systolic function and FS can be explained by HIV-related myocardial involvement resulting in reduced contractility. Subclinical echocardiographic LV dysfunction possibly represents a mild form of cardiac involvement that may eventually end up with clinically manifest heart Failure.

Effusion in the pericardial cavity was noted in 7.4% of patients. Other Indian studies have documented pericardial effusion in 11.5%–17.4% of their patients.[5],[9] Often, the pericardial effusions are small without producing tamponade. However, generally, it is associated with low CD4 count,[10] and other complications such as infections and neoplasms seen in later stages of HIV infection. The prevalence of pericardial effusion in this study is low compared to other studies possibly because, smaller percentage of our patients were in advanced stage or with very low CD4 count. It was not part of the study to establish the exact etiology of pericardial effusion.

Pulmonary hypertension was found in 3.7% and right ventricular enlargement in 1.8%. In a study, Singh et al. found pulmonary hypertension in 11.4%.[9] Smaller percentage of advanced HIV infection in our study group accounts for these smaller percentages of pulmonary hypertension and right ventricular enlargement since these findings are generally seen in advanced HIV infection.

Early detection, prompt institution of ART and close follow-up of patients probably account for less number of advanced HIV infection in our study.

Median CD4 count was found to be 139 in patients with echocardiographic abnormalities, whereas it was 363 in patients without echocardiographic abnormalities (P < 0.0003). The study reaffirms the finding of various other studies that echocardiographic abnormalities develop as the CD4 count reduces in HIV infection, especially below 100.[5],[9]

HIV-related myocardial disease, according to some studies, is often seen when CD4 count goes below 100/mm 3 indicating severe immune suppression and hence portends bad prognosis.[11],[12] In our study, abnormalities including LV systolic dysfunction were more common (77.77%) when CD4 count was <100/mm 3 than when it was >100/mm 3 (24.44%) which was statistically significant (P = 0.004) unlike the results of study by Blanchard et al.[10] There was no patient with endocardial involvement (infective endocarditis) in our study possibly because no patient was abusing intravenous drug.

Reversibility of echocardiographic abnormalities

The salient feature of our study is the prospective evaluation of progression of HIV-related cardiac disease and correlation with CD4 count. Significant cardiac abnormalities were transient. LV dysfunction, in Group A with CD4 <100/c.mm, resolved in 60% of patients before follow-up echocardiogram after 9–12 months. Pericardial effusion improved in 50%. Only six patients (5.5%) had minor clinical symptoms (dyspnea) suggestive of possible cardiac involvement. There was no activity limiting symptom. No patient had symptoms of pericarditis or tamponade. Pericardial effusion was mild to moderate that resolved with ART and improvement in CD4 count.

Follow-up of Group A (CD4 <100) patients showed that initial LV systolic dysfunction did not necessarily imply unfavorable prognosis. LV dysfunction improved in 60% of Group A patients as their CD4 count improved. Objective standard measures were adapted to avert borderline findings being reported as abnormal and vice versa. Hence, it is unlikely that the results presented here are artifactual. In addition, the serial evolution of LV function was not minute: in first group with CD4 <100, average improvement in LV function was ten percent (from 40% to 50%). Similarly, the change in diastolic dysfunction was from Grade 1 LVDD to normal diastolic function. Recordings were objective and unlikely due to intraobserver variability with time.

Limitations

Relatively, a small sample size involving only two centers is a limitation of our study. Absence of matched controls makes the study a little weaker. Finally, as in all imaging assessments, intraobserver variability may limit the validity of our findings. However, observed change in LV function was not subtle, significantly greater than the intraobserver variability and the change was unequivocal in cases of pericardial effusion.

Clinical relevance and utility

Most of the echocardiographic abnormalities noted in our study patients were clinically unsuspected and most were asymptomatic for cardiovascular status. Hence, baseline transthoracic echocardiographic evaluation should be considered in all HIV infected individuals irrespective of presence or absence of cardiovascular symptoms. Second, serial echocardiography is more important than a single or point assessment. The presence of LV dilatation or systolic dysfunction on initial echocardiography is not as sinister as it was considered to be. Since LV dysfunction improved with ART concurrent with improvement in CD4 count, intervention with ART and serial echocardiography should be considered even in the presence of LV dysfunction. Finally, observation of reversibility of cardiac manifestations has important implication for future large scale; long-term studies in subjects with HIV associated heart disease.


  Conclusions Top


Our study suggests that echocardiographic abnormalities, particularly LV systolic dysfunction, are more common than clinically suspected in HIV-infected individuals, especially when CD4 count is below 100/mm 3. Routine echocardiographic evaluation in all HIV patients goes a long way in early detection and prompt treatment of HIV associated cardiac disease. Many of the cardiac abnormalities detected with low CD4 counts are reversible and completely disappear with ART and improvement in CD4 count. Larger and multicenter studies with a longer follow-up and histopathological correlation will throw further light on the issue of reversibility of echocardiographic findings and its mechanism.

Acknowledgement

Miss Nisha George, ST John's Research Institute, Bengaluru for performing statistical analysis of the study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
UNAIDS Fact Sheet November 2016. Global HIV Statistics. 08 December, 2016. p. 1-8. Available from: http://www.unaids.org/en/resources/fact-sheet. [Last retrieved on 2017 Oct 08].  Back to cited text no. 1
    
2.
Ippolito G, Galati V, Serraino D, Girardi E. The changing picture of the HIV/AIDS epidemic. Ann N Y Acad Sci 2001;946:1-2.  Back to cited text no. 2
    
3.
Rerkpattanapipat P, Wongpraparut N, Jacobs LE, Kotler MN. Cardiac manifestations of acquired immunodeficiency syndrome. Arch Intern Med 2000;160:602-8.  Back to cited text no. 3
    
4.
Bozzette SA, Ake CF, Tam HK, Chang SW, Louis TA. Cardiovascular and cerebrovascular events in patients treated for human immunodeficiency virus infection. N Engl J Med 2003;348:702-10.  Back to cited text no. 4
    
5.
Aggarwal P, Sharma A, Bhardwaj R, Raina R. Myocardial dysfunction in human immunodeficiency virus infection: An echocardiographic study. J Assoc Physicians India 2009;57:745-6.  Back to cited text no. 5
    
6.
Guha S, Pande A, Mookerjee S, Bhattacharya R, Pain S, Karmakar RN, et al. Echocardiographic profile of ART naïve human immunodeficiency virus (HIV) infected patients in a tertiary care hospital in Kolkata. Indian Heart J 2010;62:330-4.  Back to cited text no. 6
    
7.
Connolly HM, Oh JK. Echocardiography. In: Bonow RO, editor. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia: Elsevier Saunders; 2012. p. 200-69.  Back to cited text no. 7
    
8.
Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K, et al. Guidelines for the echocardiographic assessment of the right heart in adults: A report from the American society of echocardiography endorsed by the European association of echocardiography, a registered branch of the European society of cardiology, and the Canadian society of echocardiography. J Am Soc Echocardiogr 2010;23:685-713.  Back to cited text no. 8
    
9.
Singh A, Das S, Dalai RK. Study of cardiac manifestations in patients with HIV infection and their correlation with CD4 count in Indian population. Int J Clin Med 2012;3:178-83.  Back to cited text no. 9
    
10.
Blanchard DG, Hagenhoff C, Chow LC, McCann HA, Dittrich HC. Reversibility of cardiac abnormalities in human immunodeficiency virus (HIV)-infected individuals: A serial echocardiographic study. J Am Coll Cardiol 1991;17:1270-6.  Back to cited text no. 10
    
11.
Akhras F, Dubrey S, Gazzard B, Noble MI. Emerging patterns of heart disease in HIV infected homosexual subjects with and without opportunistic infections; a prospective colour flow Doppler echocardiographic study. Eur Heart J 1994;15:68-75.  Back to cited text no. 11
    
12.
Currie PF, Jacob AJ, Foreman AR, Elton RA, Brettle RP, Boon NA, et al. Heart muscle disease related to HIV infection: Prognostic implications. BMJ 1994;309:1605-7.  Back to cited text no. 12
    


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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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