In Portugal the incidence of HIV infection is increasing, with more than 6000 new cases per year, and mortality is decreasing (less than 500 deaths).1 With greater longevity, mostly due to newer and more effective antiretroviral therapies and antimicrobial prophylaxis, mortality and morbidity have shifted from opportunistic illness toward a variety of other medical conditions,2–5 including cardiovascular disease,6–10 which occur later in the course of HIV infection.11–13

Cardiovascular disease in HIV infection is diverse. Myocarditis, pericarditis, pleural effusion or neoplastic invasion may be due to opportunistic infections and tumors,14 directly dependent on immunological status. On the other hand, coronary artery disease has a complex and multifactorial pathogenesis, and the role of HIV infection is less clear. Possible mechanisms such as immune activation, inflammation, coagulation disturbances, lipoprotein particle changes,15 antiretroviral toxicity,10 and direct or immune-mediated damage of endothelial and myocardial cells, are less well established and require validation.16

Ventricular filling abnormalities and diastolic dysfunction are the first manifestations of myocardial injury irrespective of the cause,17,18 and are widely reported in HIV-infected populations with and without antiretroviral treatment or without established cardiovascular disease.19

It is not known whether cardiac disease can be diagnosed in the early stages prior to established diastolic dysfunction. Most myocardial pathologic processes are usually regional before becoming widespread, and local ventricular mechanics can be accurately assessed using strain and strain rate (SR).

The aim of this study was to reveal abnormalities in cardiac function due to HIV infection using strain and strain rate analysis in infected subjects without cardiovascular disease.

A total of 200 patients were screened in the outpatient clinic for study inclusion and 80 were potentially eligible. Three were excluded because of hypertension at the clinical exam, one had severe aortic stenosis, and 26 refused to provide written informed consent. Overall 50 patients were included, mean age 41±6 years, 64% male. All the electrocardiograms were normal.

Table 1 summarizes the characteristics of the HIV-infected population. One patient has been infected for 30 years, and another less than a year. There was a high prevalence of smokers (74%, 37 patients).

Seven (14%) patients were not under active antiretroviral treatment: four did not fulfill clinical or laboratory criteria to start drugs, two were not compliant and the other presented an acute infection and started medication at the selection visit. Patients were taking a mean of 3.3 antiretroviral drugs, 66% were taking three, 16% four and 4% five drugs. Most were taking two antiretroviral classes, except two who were taking three classes.

CD4 count was 579±285 cells/mm3; maximum viral load was 463 000 copies and minimum was <20 copies. Fifteen patients (30%) had detectable viral load, of whom eight were under active treatment – six (75%) with ‘blips’ (intermittent episodes of detectable low-level HIV1), and two (25%) were frequently non-compliant.

Comparing the HIV population to controls, there were no differences in demographic and clinical data between groups except for diastolic blood pressure and smoking (37 smokers in the HIV group and none in the control group, p<0.0001) (Table 2).

Intra-observer and inter-observer variability and reproducibility

These are shown in Figures 1–12.

Figure 1.

Bland-Altman plot of intra-observer variability in global longitudinal strain. x axis: global longitudinal strain; y axis: difference between observations.

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Figure 2.

Bland-Altman plot of intra-observer variability in mean radial strain. x axis: mean radial strain; y axis: difference between observations.

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Figure 3.

Bland-Altman plot of intra-observer variability in mean circumferential strain. x axis: mean circumferential strain; y axis: difference between observations.

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Figure 4.

Bland-Altman plot of intra-observer variability in mean systolic strain rate. x axis: mean systolic strain rate; y axis: difference between observations.

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Figure 5.

Bland-Altman plot of intra-observer variability in mean early diastolic strain rate. x axis: mean early diastolic strain rate; y axis: difference between observations.

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Figure 6.

Bland-Altman plot of intra-observer variability in mean late diastolic strain rate. x axis: mean late diastolic strain rate; y axis: difference between observations.

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Figure 7.

Bland-Altman plot of inter-observer variability in global longitudinal strain. x axis: global longitudinal strain; y axis: difference between observations.

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Figure 8.

Bland-Altman plot of inter-observer variability in mean radial strain. x axis: mean radial strain; y axis: difference between observations.

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Figure 9.

Bland-Altman plot of inter-observer variability in mean circumferential strain. x axis: mean circumferential strain; y axis: difference between observations.

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Figure 10.

Bland-Altman plot of inter-observer variability in mean systolic strain rate. x axis: mean systolic strain rate; y axis: difference between observations.

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Figure 11.

Bland-Altman plot of inter-observer variability in mean early diastolic strain rate. x axis: mean early diastolic strain rate; y axis: difference between observations.

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Figure 12.

Bland-Altman plot of inter-observer variability in mean late diastolic strain rate. x axis: mean late diastolic strain rate; y axis: difference between observations.

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Our study excluded patients with comorbidities, particularly established cardiovascular disease, that could cause myocardial damage and abnormal cardiac mechanics.

Although there was a high prevalence of smokers, the population was relatively healthy (systolic blood pressure 122±12 mmHg, blood glucose 97±13 mg/dl, LDL-cholesterol 115±28 mg/dl, 90% with CD4 count >200 cells/mm3, only 32% with detectable viral load, and 86% under antiretroviral treatment), a representative sample of HIV-infected populations in developed countries,25 potentially achieving a normal life expectancy.26

Previous echocardiographic studies in HIV-infected populations have focused on systolic and diastolic function assessed by 2D and spectral Doppler echocardiography, only the most recent17,19,27,28 using pulsed tissue Doppler, but none had classified and graded diastolic dysfunction according to the current guidelines.21

In our study there were no differences in systolic or diastolic function between groups when assessed with conventional echocardiography and pulsed tissue Doppler. Previous studies also showed no systolic abnormalities, but reported a high prevalence of diastolic dysfunction. This difference can be explained by comparing the studied populations. Our is a relatively healthy and young sample with no comorbidities, unlike the larger sample (689 patients) studied by Reinsch et al.19 in the HIV-Heart Study, who were older (44±10 years, p=0.04), 60% had dyslipidemia, 7% had diabetes and one third had hypertension. They used pulsed tissue Doppler and transmitral pulsed Doppler to assess diastolic dysfunction, which was present in 48% of the patients. Blood pressure, hyperlipidemia, diabetes, body mass index and age were different between groups with and without diastolic dysfunction, but infection-related conditions were similar (duration of infection, CD4 count, viral load and treatment). Two other smaller studies using pulsed tissue Doppler17,28,29 came to the same conclusions concerning a high prevalence of relaxation abnormalities, but again the classification and grading were not performed as recommended. In a sub-analysis30 of the SUN study with 659 patients, diastolic dysfunction correlated with high-sensitivity C-reactive protein and the presence of hypertension. Hsue et al.27 obtained similar results, the HIV-infected group having significantly more hypertension (26% vs. 6%), and in multivariate analysis, hypertension, age and HIV infection increased the risk for diastolic dysfunction (neither CD4 count, viral load, nor type of treatment increased the risk when adjusted for age and hypertension).

To summarize, our results, which are not in agreement with previous studies, can be explained by the fact that our HIV population were healthier compared with other, more heterogeneous HIV populations.

The population studied by Oliviero et al.31 was similar to ours in age and blood pressure but had a better metabolic status (blood glucose, p<0.001 and cholesterol, p=0.001), a shorter infection duration and were not under active antiretroviral therapy. They reported an abnormal relaxation pattern in 30% of patients, but compared with our results there were no differences in diastolic parameters (e’ 0.13±0.08 vs. 0.12±0.03, p=0.4; E/e’ 6.6±3.5 vs. 5.7±1.8, p=0.12).

Speckle tracking is a recent echocardiographic technology that analyzes motion by tracking natural acoustic reflections with relative angle independence, less noise interference and substantially lower intra-observer and inter-observer variability. Strain and strain rate are dimensionless measurements of deformation (degree of shortening or stretching of fibers). The degree of shearing increases toward the subendocardium. The subendocardial region that is assessed by longitudinal strain is the most vulnerable component of left ventricular mechanics and therefore most sensitive to the presence of myocardial disease. A transmural insult or progression of disease results in concomitant midmyocardial and subepicardial dysfunction, leading to a reduction in circumferential and radial strain.32

Our study was the first to assess strain and strain rate33 in a HIV-infected population without established cardiovascular disease or risk factors. Although the mean strain and strain rate obtained in the HIV group were in the normal range according to the latest ASE/EAE Consensus Statement,23 global longitudinal strain, SRS and SRE were statistically lower compared with the control group, revealing early abnormalities. It is important to note that diastolic dysfunction was not detected with conventional echocardiography but the presence of lower SRE reveals abnormalities in myocardial relaxation.

In the present study viral load had no impact on myocardial performance, probably because only 30% had detectable virus in blood samples, but circumferential strain differed according to immunological status (more than half of the patients had CD4 >500 cells/mm3), which is in agreement with the findings of previous studies that reported myocardial injury mediated by the non-myocyte pool, especially in patients with low CD4 count.34

Antiretroviral therapy is usually assumed to be toxic (particularly protease inhibitors associated with lipodystrophy leading to metabolic disorders including insulin resistance and dyslipidemia15,34,35), but in our sample the drugs had no perceptible impact when studied individually or in combination, probably because of the small number of patients enrolled.

Although we believe our data are relevant, not only because they were obtained with strain and strain rate methodology, but also because our population was healthy, we do acknowledge some limitations, including the small number of participants, the fact that it was an observational study, and the absence of biomarker assessment.

In conclusion, diastolic dysfunction assessed as recommended by the latest guidelines is not prevalent in a relatively healthy HIV-infected population without cardiovascular disease or risk factors. Although strain and strain rate are able to detect the first signs of myocardial mechanics abnormalities, because these techniques are still in the research stage, we consider it premature to recommend routine screening echocardiograms in HIV-infected adults without cardiovascular disease, mostly because the prognostic impact of these findings is unknown.

The authors have no conflicts of interest to declare.