In the last decade, with the advancement of antiretroviral therapy (ART), increased access to care for people living with human immunodeficiency virus (PLWH), and the introduction of preventive strategies such as pre-exposure prophylaxis, there has been significant progress in the control of HIV, resulting in a decline in new HIV infections of 32% and a decline in AIDS-related deaths of 52% since 2010 globally (1). With the increasing life expectancy of PLWH, the new challenge in the burden to the healthcare systems brought by HIV/AIDS has shifted to noncommunicable diseases, particularly cardiovascular diseases (CVD).

PLWH have been shown to have an increased risk for CVD, including acute myocardial infarction, ischemic stroke, and heart failure, which yielded as one of the most common causes of non-AIDS-related deaths among PLWH on ART (2–6). In addition to traditional CVD risk factors, HIV-related factors such as low CD4 cell count and high HIV viral loads can contribute to excess CVD risks in PLHIV (2). In addition, ART's side effects and toxicities may also increase the risk for metabolic syndrome, further increasing their CVD risk (2, 7, 8). For example, some ARTs have been reported to be associated with mitochondrial toxicity or cardiotoxicity, which may increase the risk of developing cardiac dysfunction (2). Due to the lack of appropriate screening, health education, and management protocols for cardiovascular risk modifications, PLWH may not receive timely diagnosis and optimal treatments to prevent advanced cardiovascular events (9). Therefore, early recognition of cardiac impairment in CVD management becomes crucial in parallel with the improved life expectancy of the HIV-infected population in the ART era (9–11).

Echocardiogram is a commonly used method to evaluate heart function with the advantages of safety, rapidness, and noninvasiveness (10). However, the conventional echocardiogram may not be sensitive enough to detect subtle regional myocardial abnormality and may, therefore, lead to delays in CVD preventive management. Speckle-tracking echocardiography (STE), a newer quantitative ultrasound technique, can detect early myocardial abnormality by measuring myocardial strain. It has been used to assess subclinical cardiac involvement and impairment in many diseases, such as CVD-free hypertensive and diabetic patients (12, 13). Previous STE studies showed reduced myocardial strains in PLWH compared to general populations, even given normal conventional echocardiography measurements. These findings provide supporting data on STE's capability in detecting subclinical myocardial abnormality in PLWH (14–19). Nevertheless, the small sample size and limited study population may influence the robustness of evidence to generalize the application of STE.

Since most studies mainly focused on comparing myocardial strain between people with and without HIV, the association between HIV-specific factors (such as CD4 cell counts, viral loads, and ART classes) and myocardial strains is underreported and inconsistent among these studies (16, 18). Due to these gaps and limitations, this study aimed to assess the effect of STE on detecting subclinical myocardial impairment and investigate the determinants associated with early cardiac dysfunction among Asian PLWH.

This cross-sectional study is significant as it is the first and the largest cohort using STE to investigate myocardial strain in Asian PLWH population. The results show that ART-experienced PLWH have reduced LVGLS than ART-naive PLWH, despite the younger age and lower traditional CVD risk in the ART-naive group. Multiple regression analysis revealed that hypertension, ART-naive status, and high viral loads are associated with reduced LVGLS in PLWH. However, the association between the ART categories and LVGLS change was insignificant in our analysis.

The mechanism underlying HIV-associated cardiomyopathy is typically multifactorial, resulting from direct HIV toxicity, opportunity infections, autoimmunity, severe immunosuppression, or nutritional deficiencies (23). Previous studies have shown that PLWH have a reduced LVGLS even in the absence of other risk factors and comorbidities (12–19). In our analysis, PLWH's layer-specific LV strain was −20.8%, −18.6%, and −16.6% at endo-, mid-, and epi-myocardium, respectively. These values were relatively reduced compared to those in the healthy Asian subjects, i.e., −22.8%, −20.0%, and −17.5% at endo-, mid-, and epi-myocardium, respectively (24). This finding was consistent with previous studies, demonstrating the asymptomatic reduction in myocardial deformation in PLWH even though they did not have CVDs (15–19). In addition, Mirea et al. and our study have both shown that the strain values decrease from the endocardium to the epicardium (19). The differences in layer-specific strain values may be due to the distribution of fiber angles of human heart, and the pattern of strain reduction may aid in distinguishing the determinant of myocardial impairment (25). For example, hypertension, hypercholesterolemia, and drug-related cardiotoxicity (such as anthracycline) can lead to a marked strain reduction in the endo-myocardium, while transmural infarction, diabetes, and hypertrophic cardiomyopathy have consistent decreases across all layers (24). Our study found that PLWH's layer-specific strains reduced similarly in each layer of the myocardium, irrespective of being ART-experienced or ART-naive. The finding suggests that HIV toxicity per se instead of ART-related cardiotoxicity or hypercholesterolemia is the primary factor causing cardiac impairment in PLWH.

In recent years, ART has considerably enhanced the life expectancy of PLWH. However, the prolonged use of certain ARTs raises concerns regarding the development of CVD, owing to their potential cardiac toxicity and increased risk of dyslipidemia (11, 23). Despite these reports, our subgroup analysis did not identify a correlation between specific ART types and myocardial strain. Furthermore, a previous study by Rodrigues et al. discovered that PLWH receiving ART exhibited a marginally smaller reduction in LVGLS compared to those not receiving ART (−18.4% and −17.7% in ART and non-ART groups, respectively) (17). In our study, with a larger sample size, we detected a significant association between improved LVGLS and ART use in PLWH. Notably, despite the higher age, BMI, and prevalence of hypertension and dyslipidemia in the ART-experienced group, they still demonstrated better myocardial strain than ART-naive individuals after adjusting for viral loads and CVD risk factors. These findings underscore the importance of timely ART administration upon HIV diagnosis and suggest that the benefits to myocardial health may outweigh the potential adverse effects of ART and other contributing factors.

On the other hand, although CD4 T-cell counts were reported to be negatively correlated with the reduction of myocardial strain (16, 18), we did not observe a significant association in our study, even when considering inflammatory markers like D-dimer and hsCRP. However, it is worth noting that previous studies did not consider the intermediate effects of CD4 count and viral loads. In our study, the majority of ART-experienced PLWH had normal-range CD4 counts, and the sample size with low counts might be too small to reach the power of statistical significance. While CD4 counts can fluctuate due to factors other than HIV treatment, viral load is widely regarded as a more critical measure of HIV status in individuals undergoing long-term ART treatment (26, 27). Likewise, our study found that change in myocardial strain was associated with PLWH's viral loads rather than CD4 counts, suggesting that viral loads may be a more meaningful indicator when evaluating HIV-associated cardiomyopathy. Therefore, maintaining undetectable viral loads may play a crucial role in preventing CVD among PLWH.

Recently, a systematic review showed that PLWH are at an increased risk of developing hypertension, with those on ART having a higher prevalence due to increasing age, BMI, and chronic inflammation (28). This is particularly concerning as hypertension is among the most significant risk factors for CVD, potentially leading to cardiac impairment and reduced myocardial strain (29). In our study, we observed that the impact of hypertension on myocardial function was noticeable even in a relatively young age, highlighting the importance of hypertension management in PLWH. Regular blood pressure measurements should be performed, and antihypertensive therapy with lifestyle modifications should be initiated if the blood pressure exceeds the target of 130/80 mmHg (30). However, whether prompt management of hypertension might improve myocardial strain requires further STE study to follow up the measurements in PLWH.

In a previous study, the prevalence of RV dysfunction in PLWH was 11% with the echocardiographic definition (31). It has been observed that early RV impairment can be detected in asymptomatic PLWH with significantly reduced RV free-wall longitudinal strain (16). Our results regarding RV were consistent with this previous study. While the mechanisms of isolated RV hypertension may be similar to those of LV, pulmonary hypertension is another known risk factor for RV dysfunction, and PLWH have an increased risk of developing pulmonary hypertension (31). In our analysis, the percentage of pulmonary hypertension was relatively high compared to previous studies, with an echocardiographic definition of RVSP greater than 25 mmHg (32). We applied a broader definition of pulmonary hypertension to understand the prevalence of mild or early pulmonary hypertension change in PLWH. Further studies are necessary to investigate whether the higher RVSP affects RV strain and whether it may progress into symptomatic pulmonary hypertension.

There are some limitations in this study. First, the image quality of STE is the primary technical limitation (33). Although operators and observers were trained and qualified, the blurred endocardial border and insufficiency to accurately capture all phases of the cardiac cycle due to low temporal and spatial resolution or inadequate frame rates may influence the result readings. Research-driven updating of both hardware and software is warranted to improve the feasibility. Second, healthy subjects were not enrolled for comparison in this study. This study aimed to provide the values of PLWH's myocardial strains and assess the causes associated with subclinical myocardial abnormality. Despite lacking a healthy control group, our data were more positive than the strain values of the healthy Asian subjects and consistent with the previous findings, which may strengthen the robustness of the results. Third, the causal relationship of the data should be cautiously interpreted in the cross-sectional study. Future research on the longitudinal trajectory of myocardial strain change after ART is needed to examine their relationship. Finally, although this study had a larger sample size of PLWH and presented the feasibility of detecting subclinical myocardial impairment among Asian PLWH, the relatively small sample size of the ART-naive group may limit the conclusions that can be drawn from multivariable analyses in this subgroup, which can be attributed to fewer newly diagnosed HIV-infected individuals remaining ART-naive, i.e., the advancement of ART, increased access to care for PLWH, and the introduction of preventive strategies such as pre-exposure prophylaxis. Future studies with larger sample sizes are needed to confirm our findings.

As the largest cohort investigating myocardial strain in the Asian PLWH population, our findings supported the application of STE in detecting subclinical myocardial impairment among PLWH and helped understand the relevant risk factors. Timely ART administration, viral load suppression, and hypertension control are crucial in preventing worsening myocardial function when making the management parallel with the improved life expectancy of the HIV-infected population in the ART era.