Echocardiographic Abnormalities and Associated Factors in a Cohort of Asymptomatic HIV-Infected Patients

Abstract

HIV patients have been reported to have a greater prevalence of echocardiographic abnormalities. We aimed to determine the prevalence of these abnormalities and their associated factors. This was an observational study of a cohort of asymptomatic HIV patients. Data were recorded on factors of cardiovascular interest and those related to HIV infection. All the subjects underwent a transthoracic echocardiogram. The study included 196 patients, 85.2% men, mean age 46.4 years, with a mean duration of HIV infection of 123.8 months and 27.6% with AIDS. Of the patients, 94.4% were on antiretroviral therapy and 92.5% of these had an undetectable viral load. The mean CD4 cell count was 544/mm³. The following echocardiographic abnormalities were found: left ventricular (LV) hypertrophy 28.6%, LV diastolic dysfunction 19.9%, left atrial (LA) dilatation 7.7%, right ventricular (RV) systolic dysfunction 6.1%, pulmonary hypertension 2.6%, RV dilatation 2%, and (LV) systolic dysfunction 1%. LV hypertrophy was associated with diabetes mellitus (OR 5.3, 95% CI 1.8–15.3; p=0.001), LV diastolic dysfunction with age (OR for each extra 5 years 4.4, 95% CI 4.2–4.6; p=0.0001), obesity (OR 4.07, 95% CI 1.6–10.0; p=0.02), alcohol consumption (OR 2.5, 95% CI 1.07–6.2; p=0.03) and lower CD4 cell count (OR for each 10 CD4 cells less 10.02, 95% CI 10.00–10.04; p=0.008), and RV systolic dysfunction with hypertension (OR 5.4, 95% CI 1.6–18.2; p=0.005). Echocardiographic abnormalities in HIV patients were common, especially LV hypertrophy and diastolic dysfunction. Prospective comparative studies involving the general population are needed to determine the prevalence of HIV infection and its treatment in these abnormalities.

Introduction

T he prognosis for patients with HIV infection has improved greatly with the introduction of antiretroviral therapy (ART) over 15 years ago.¹ The efficacy of ART and the resulting increase in survival have meant that HIV-infected patients now face different problems, including cardiovascular complications, which are of great importance given their associated morbidity and mortality.² A greater prevalence of heart disease, left ventricular (LV) systolic and diastolic dysfunction, LV hypertrophy, and pulmonary artery hypertension have all been described in the HIV-infected population as compared with similar patients without HIV infection.³ However, the etiology of these cardiac alterations is still being explored. Various different theories have been developed involving the HIV infection itself, inflammatory factors, ART,⁴ and classic cardiovascular risk factors that are heightened by the presence of the other factors.⁵ In the specific case of LV hypertrophy the data are contradictory, with some authors defending a lower ventricular mass in HIV-infected patients⁶ whereas others suggest the opposite.^7,8 LV hypertrophy and LV diastolic dysfunction are related to the development of heart failure in asymptomatic patients and have an important impact on morbidity and mortality in the general population.⁹ This might also be the case in persons with HIV. Few studies have evaluated echocardiographic abnormalities in asymptomatic HIV-infected patients in depth.

The aim, therefore, of this study was to determine the prevalence of echocardiographic abnormalities such as LV diastolic dysfunction, LV hypertrophy, left atrial (LA) dilatation, and right ventricular (RV) systolic dysfunction in a cohort of asymptomatic HIV-infected patients in our area, as well as the possible associated factors.

Materials and Methods

We undertook a cross-sectional observational study of a consecutive cohort of asymptomatic HIV-infected patients on regular follow-up by the Infectious Diseases Unit of our center and who attended for routine controls between April and July 2011. All the patients were older than 18 years of age. Patients were excluded if they had prior known structural heart disorders of any etiology or were pregnant or lactating. The study was approved by the hospital Ethics and Research Committee. All the patients were informed of the nature of the study and provided their consent to participate in the study.

A questionnaire was completed for all the patients about cardiovascular risk factors, smoking, alcohol and other drugs use, lung disease, medication, family history, and exercise tolerance according to the New York Heart Association (NYHA) classification.¹⁰ The patients also underwent a complete physical examination including measurements of weight, height, waist circumference, and blood pressure. HIV data collected included the route of transmission, the duration of the disease since diagnosis, AIDS events, viral load, nadir and current CD4 cell counts, ART and its duration, and coinfection with hepatitis B virus (HBV) and hepatitis C virus (HCV).

All the patients underwent an electrocardiogram and an echocardiogram. The transthoracic echocardiograms were performed by the same echocardiographist, blinded to the clinical history of the patients, who interpreted the results in real time following the protocol described in the clinical practice guidelines of the American Society of Echocardiography.^11

–14 The cardiovascular ultrasound system used was a Vivid S6, GE Healthcare.

The echocardiographic parameters measured were LV systolic function, by calculating the volumes and ejection fraction (EF) using the biplane Simpson method. Global systolic function was defined as preserved (EF ≥55%), mildly depressed (EF 45–54%), moderately depressed (EF 35–44%), or severely depressed (EF <35%). LV size was based on the end-diastolic diameter in M mode and indexed for body surface. LV size was defined as normal (22–31 mm/m²), mild dilatation (32–34 mm/m²), moderate dilatation (35–36 mm/m²), or severe dilatation (≥37 mm/m²). The degree of left ventricular hypertrophy was based on the calculation of the mass by M mode. This measurement was indexed for body surface. In men, mass was defined as normal (49–115 g/m²), mild hypertrophy (116–131 g/m²), moderate hypertrophy (132–148 g/m²), and severe hypertrophy (≥149 g/m²) and in women, a normal mass (43–95 g/m²), mild hypertrophy (96–108 g/m²), moderate hypertrophy (109–121 g/m²), and severe hypertrophy (≥122 g/m²). LV diastolic function was assessed according to the maximum mitral flow E and A wave velocities, deceleration time (DT), and lateral mitral annular velocity (E′) by tissue Doppler.

LV diastolic function was defined as normal (E/A 0.8–1.5, DT 160–200 ms, and E′ ≥10 cm/s), grade I diastolic dysfunction or disseminated relaxation pattern (E/A <0.8, DT >200 ms, and E/E′ ≤8), grade II or pseudonormal (E/A 0.8–1.5, DT 160–200 ms, and E/E′ 9–12), and grade III or restrictive (E/A >2, DT <160 ms, and E/E′ >12). The LA volume was also quantified and indexed according to the body surface. LA dilatation was defined as a volume >34 ml/m². RV systolic function was defined according to the tricuspid annular plane systolic excursion (TAPSE) by M mode and systolic maximum velocity (S′) of the tricuspid ring by tissue Doppler. RV systolic dysfunction was defined by a TAPSE <15 mm and/or S′ <10 cm/s. The RV size was quantified according to the baseline RV end-diastolic measurement in four-chamber plane. The RV was considered to be dilated if the diameter was >42 mm.

The qualitative variables are expressed in percentages and the associations were analyzed with the Chi square test (χ²) or Fischer's exact test. The quantitative variables are expressed as the mean±standard deviation and the differences were analyzed with the Student's t test after determining that the quantitative variables followed a normal distribution (Kolmogorov–Smirnov test). When there were more than two groups to compare, a one-way or more way analysis of variance (ANOVA) was used. The multivariate analysis for variables related to the events was done with the Cox proportional hazards model. The odds ratios were determined and the 95% confidence intervals calculated for the significant variables. In all cases two-tailed contrasts were conducted and significance was set at p<0.05. The analyses were done with SPSS 17.0.0 (SPSS, Inc., Chicago, IL).

Results

Of the 207 patients initially approached, 196 accepted and signed the consent form. The characteristics of these patients are shown in Table 1 and the echocardiographic findings in Table 2. Pulmonary hypertension was present in five patients (2.6%) and 14 were in the gray zone (PASP of 36–40 mm Hg); all data about pulmonary hypertension in this cohort have been detailed elsewhere.¹⁵ Concerning the LV parameters, the majority of the patients had a normal systolic function with normal chamber diameters. Of note, however, was the high percentage of patents with ventricular hypertrophy (28.6%) and diastolic dysfunction (19.9%). In an attempt to determine the percentage of patients with LV diastolic dysfunction with no evident cardiac cause we adjusted for age all the diastolic dysfunction parameters used according to the limits recommended by the American Association of Echocardiography for the various age groups. In addition, we also eliminated from the analysis all those patients with LV hypertrophy of whatever degree. Even so, 9.2% of the sample had diastolic dysfunction. LA dilatation was found in 15 patients.

Table 1.

Characteristics of Patients (n=196)

Characteristic
Age (years)	46.39±9.46
Sex (male)	167 (85.2)
White race	188 (95.9)
Hypertension	34 (17.4)
Diabetes mellitus	17 (8.7)
Dyslipidemia	38 (19.5)
Previous cardiovascular disease	7 (3.6)
Pulmonary disease	25 (12.8)
Functional class NYHA I	165 (84.2)
Smoking
Current smoker	113 (57.7)
Nonsmoker	46 (23.5)
Ex smoker	37 (18.9)
Alcohol^a	43 (21.9)
Other drugs	27 (13.8)
HCV coinfection^b	53 (27.2)
HIV transmission
Homosexual	95 (48.5)
Heterosexual	57 (29.1)
Parenteral drugs	42 (21.4)
Time since HIV infection diagnosis (months)	123.76±88.42
Nadir CD4 lymphocyte/mm³	212.69±154.51
AIDS	54 (27.6)
Antiretroviral therapy	185 (94.4)
Time with antiretroviral therapy (months)	85.25±67.83
Current CD4 lymphocyte/mm³	544.01±258.93
Undetectable viral load (<50 cop/ml)^c	173 (93.5)

Cut-off limit: ≥2 drinks/day for men, ≥1 drinks/day for women.

18.9% of them were F4 by elastometry.

Patients with antiretroviral therapy. Quantitative variables are expressed as mean±standard deviation and qualitative variables are expressed as n (%).

HCV, hepatitis C virus; HIV, human immunodeficiency virus; NYHA, New York Heart Association.

Table 2.

Echocardiographic Parameters (n=196)

Parameters
LV ejection fraction (%)	72.18±6.47
LV systolic dysfunction (EF < 55%)	2 (1)
LVEDD indexed (mm/m²)	25.92±2.56
LV dilatation	1 (0.5)
LV mass indexed (g/m²)	100.22±22.95
LV hypertrophy
No	140 (71.4)
Mild/moderate/severe	35 (17.9)/12 (6.1)/9 (4.6)
Mitral E/A ratio	1.22±0.42
E wave DT (ms)	218.19±48.20
Mitral E/E′ ratio	5.73±1.96
LV diastolic dysfunction
No	157 (80.1)
Grade I/Grade II/Grade III	31 (15.8)/8 (4.1)/0 (0)
LA volume (ml/m²)	24.16±7.21
LA dilatation	15 (7.7)
RVEDD basal (mm)	34.42±4.29
RV dilatation	4 (2)
TAPSE (mm)	24.08±4.24
Tricuspid annular S′ velocity (cm/s)	12.80±2.30
RV systolic dysfunction	12 (6.1)

DT, deceleration time; EF, ejection fraction; LA, left atrium; LV, left ventricle; LVEDD, left ventricular end-diastolic diameter; RV, right ventricle; RVEDD, right ventricular end-diastolic diameter; TAPSE, tricuspid anular plane systolic excursion. Quantitative variables are expressed as mean±standard deviation and qualitative variables are expressed as n (%).

Tables 3 –5 show the factors associated with LV hypertrophy, LV diastolic dysfunction, and RV dilatation and dysfunction, respectively. The multivariate analysis showed that the only factor associated with LV hypertrophy was diabetes mellitus (OR 5.3, 95% CI 1.8–15.3; p=0.001). In the multivariate analysis for LV diastolic dysfunction, the following factors remained significant: age (OR for each 5 years extra 4.4, 95% CI 4.2–4.6; p=0.0001), obesity (OR 4.07, 95% CI 1.6–10.0; p=0.02), alcohol consumption (OR 2.5, 95% CI 1.07–6.2; p=0.03), and CD4 cell count (OR for each 10 CD4 cells less 10.02, 95% CI 10.00–10.04; p=0.008). LA dilatation was detected in 15 (7.6%) patients and was associated with LV hypertrophy, with a higher percentage of patients with LV hypertrophy among those who had LA dilatation (60% vs. 26%; p=0.005). Finally, in the multivariate analysis RV systolic dysfunction was related to hypertension (OR 5.4, 95% CI 1.6–18.2; p=0.005).

Table 3.

Left Ventricular Hypertrophy and Associated Factors (n=196)

Factors	LVH (n=56)	Non-LVH (n=140)	p
Diabetes mellitus	11 (19.6)	6 (4.3)	0.001
ART	56 (100)	129 (92.1)	0.031
Age (years)	49.23±9.87	45.26±9.10	0.008
LA dilatation	9 (16.1)	6 (4.3)	0.005

LVH, left ventricular hypertrophy; ART, antiretroviral therapy; LA, left atrium. Quantitative variables are expressed as mean±standard deviation and qualitative variables are expressed as n (%).

Table 4.

Left Ventricular Diastolic Dysfunction and Associated Factors (n=196)

Factors	DD (n=39)	Non-DD (n=157)	p
Age (years)	53.27±8.43	44.69±9.46	0.0001
Alcohol	14 (35.9)	29 (18.5)	0.019
Hypertension	15 (38.5)	19 (12.2)	0.0001
Renal failure	4 (10.2)	2 (1.3)	0.004
CD4 lymphocyte/mm³	454.41±201.68	566.27±267.20	0.015
Obesity	15 (38.5)	25 (15.9)	0.002

DD, diastolic dysfunction. Quantitative variables are expressed as mean±standard deviation and qualitative variables are expressed as n (%).

Table 5.

Right Ventricular Dilatation and Systolic Dysfunction and Associated Factors (n=196)

Factors	RV systolic dysfunction (n=12)	RV with no systolic dysfunction (n=184)	p
Age (years)	52.33±7.26	45.95±9.47	0.023
Hypertension	6 (50.0)	28 (15.4)	0.002

	RV dilatation (n=4)	Nondilatated RV (n=192)
Drugs	2 (50.0)	25 (13.0)	0.034
DM	2 (50.0)	15 (7.8)	0.003
HBV	1 (25.0)	5 (2.6)	0.010

RV, right ventricle; DM, diabetes mellitus; HBV, hepatitis B virus. Quantitative variables are expressed as mean±standard deviation and qualitative variables are expressed as n (%).

Discussion

In this series of asymptomatic HIV-infected patients with good immunovirological status, we found a high prevalence of echocardiographic abnormalities, mainly LV hypertrophy and diastolic dysfunction. The prevalence of LV hypertrophy was greater than that reported for the general population of European patients (12%) with similar percentages of patients and ages to our series.¹⁶ This result coincides with recent data on north American people reported by Hsue et al.,⁷ though earlier studies had found a lower LV mass in HIV-infected patients related to nutritional status.⁶ LV hypertrophy in the general population is related to age, hypertension, and certain inflammatory states. The only factor in our study associated with this echocardiographic finding was diabetes mellitus. Diabetes has been described as a predictive factor of LV hypertrophy in both the general population and in HIV-infected patients.^7,17 Two recent studies related the use of ART with LV hypertrophy.^17,18 Though we did not find this association in our series, it is nevertheless true that the 11 patients without ART did not present LV hypertrophy. Hsue et al.⁷ noted that a poor immunological control can be related to this echocardiographic finding; the high levels of inflammation found in these patients could, in theory, contribute to the increased myocardial mass.⁷

The prevalence of LV diastolic dysfunction in our study was 19.9%, mainly grade I (relaxation alteration). A large European study in the general population including 647 patients with preserved global systolic function reported a prevalence of relaxation alteration of 2.5%, and 0.5% after adjusting for age.¹⁹ In our population, even after adjusting for age and LV hypertrophy, the prevalence of LV diastolic dysfunction was 9.2%. The HIV-infected population has been reported to have this greater prevalence of LV diastolic dysfunction.^20
–22 The factors associated with diastolic dysfunction were age, obesity, alcohol consumption, and a low CD4 cell count. Both age and obesity are classically related to LV diastolic dysfunction. In the specific case of the HIV-infected population, both immunological control²³ and ART²⁴ have been related to this echocardiographic finding. The relation between a low CD4 cell count and LV diastolic dysfunction supports an inflammatory cause of the condition, similar to recent findings in an HIV population with pulmonary hypertension²⁵ and in patients with chronic inflammatory disorders.²⁶ The prevalence of LA dilatation in our patients was slightly lower than that reported elsewhere,¹⁷ though this difference is partly related to the cutoff point selected for its definition.

No current data in the era of the extended use of ART are available about RV systolic function as assessed by echocardiography and the few data that are available using tissue Doppler, cardiac magnetic resonance, and radionuclide ventriculography studies are not conclusive.^27
–29

The limitations of this study concern the lack of a control group and its cross-sectional design. The absence of a control group could be overcome by the amount of data in the literature concerning the prevalence of echocardiographic abnormalities, in both the guidelines and in European studies with a population comparable to that of this study. The cross-sectional design of the study limits analysis of the weight of exposure to the different factors studied in the development of these abnormalities. Nevertheless, despite these limitations, our series, with a considerable number of patients and characteristics similar to any current HIV cohort in developed countries, provides interesting information in relation to previously published studies, which in some cases involved a small sample or were undertaken before the era of the generalized use of ART, or used different echocardiographic techniques, or were based on echocardiographic criteria that are now obsolete.

In summary, echocardiographic abnormalities in HIV-infected patients were frequent, especially LV hypertrophy and diastolic dysfunction. Nonetheless, prospective comparative studies involving the general population are needed to determine the weight of the HIV infection and its treatment in these abnormalities.

Footnotes

Author Disclosure Statement

No conflicts of interest exist.

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