This study represents the longest prospective outcome investigation of subclinical LVSD detected by speckle-tracking echocardiography in RA patients with preserved LV EF and without overt cardiac disease. Key findings include: 1) nearly one-fourth (24%) of RA patients exhibit subclinical LVSD; 2) these patients face a fourfold increased risk of MACE; 3) subclinical LVSD independently predicts MACE in the mid- and long-term follow-up.

In 2021, Ferreira et al. investigated the prevalence, clinical risk factors, and proteomic biomarkers associated with HF development in this same cohort of RA patients, concluding that classical CV risk factors, RA duration, and age are associated with HF risk [8]. Additionally, the proteomic profile provided insights into some of the mechanistic pathways for HF development in these patients [8]. The reported incidence of CV events (composite of CV death and CV hospitalization) during the follow-up period was 10% [8]. HF development was associated, as expected, with a higher risk of CV events (HR 2.37; 95% CI 1.07–5.30; p = 0.034) during a median follow-up of four years [8].

Also in 2021, Rodrigues et al. studied the prevalence of ventricular systolic (evaluated by LV EF) and diastolic dysfunction, aiming to identify the predictors of ventricular dysfunction in RA patients, as well as analyzing its associations with surrogate prognostic markers [3]. The study concluded that RA patients without overt cardiac disease had a prevalence of systolic and diastolic dysfunction of 4% and 13%, respectively, with age being associated with a higher prevalence of ventricular dysfunction [3]. Notably, this study compared RA patients with a cohort from the general population of the same city, revealing a higher prevalence of diastolic dysfunction among RA patients (13% vs 1.4%; p < 0.001) [3].

The present study expands the knowledge about this reasonably large RA cohort, particularly by adding information about subclinical LVSD using LV GLS as an early sign of LVSD, thereby increasing the sensitivity of its detection. Furthermore, the longer follow-up period allowed by the time span between these analyses permitted the observation of a larger number of CV events, offering a more detailed description of the natural history of CV disease in RA patients.

Our study’s findings align with earlier reports on reduced LV strain in RA patients without overt cardiac disease [1, 4,5,6, 17]. The hypothesis that impaired ventricular strain serves as an early and subclinical marker for CV disease has been gaining support. Previous studies have noted decreased global LV strain in RA patients compared to normal individuals [9, 12, 18]. For instance, Cioffi et al. demonstrated that a low LV GLS was detected in 24% of RA patients and in only 5% of matched control individuals [9, 18]. However, most of these studies involved a smaller or comparable number of patients and did not investigate the prognostic role of subclinical LVSD through long-term follow-up.

Our larger-scale research with an extended follow-up period strengthens the evidence that LV strain measurement can serve as a sensitive indicator of early myocardial dysfunction in RA. In our study, nearly one-fourth of RA patients exhibited subclinical LVSD, with one-tenth showing abnormal LV GLS. Although the prevalence of abnormal GLS in our cohort was lower than reported in some previous RA studies, such as the 24% prevalence reported by Cioffi et al. [18], our findings reveal a higher proportion of abnormal LV GLS (10%) compared to that observed in a normal matched control group (5%) [18]. The lower proportion of abnormal GLS cases observed in our study could be attributed to more stringent exclusion criteria, particularly excluding patients with severe comorbidities, as well as the exclusion of individuals with reduced LV EF. Still, the prevalence of LVSD as assessed by GLS impairment was nearly twofold higher than that detected in patients used as matched control representing the general health population [18]. These findings underscore the presence of subclinical disease in RA patients despite a normal LV EF and highlight the efficacy of myocardial strain imaging in its detection [1, 12].

Over a median follow-up of 6.1 years, MACE events were observed in 8% of all RA patients and in 21% of those with subclinical LVSD. The yearly all-cause mortality was approximately 1.1%, which is lower than the mortality rates reported in other studies [10, 19]. This could be attributed to our study's exclusion criteria, which excluded critically ill patients with RA, those with an expected survival of less than 6 months, active neoplasm, or previously known heart disease. Notably, subclinical LVSD was independently associated with a fourfold higher risk of MACE, a fivefold higher risk of 3P-MACE, and a threefold higher risk of HF hospitalization or CV death compared to patients with normal LV GLS. Concerning other secondary outcomes, no significant differences were observed in all-cause mortality and distance in 6MWT after adjusting for potential confounding factors.

The notably increased incidence of MACE among patients with reduced LV GLS, compared to those with normal strain, within this highly selected cohort emphasizes the prognostic significance of this imaging marker in identifying patients at heightened risk. Additionally, the comparison between LV GLS and LV EF as predictors of MACE indicated that LV GLS outperformed LV EF in terms of sensitivity and specificity. The ROC analysis highlighted a LV GLS threshold of > − 18.5% as optimal for identifying RA patients at elevated risk of MACE, with a sensitivity 78% and a specificity of 74%. This analysis further demonstrated that LV GLS remained a more accurate predictor of MACE compared to all other variables.

Identifying predictors of subclinical LVSD is crucial for effective screening. In our analysis, patients with reduced LV GLS were older, exhibited higher prevalence of dyslipidemia and chronic kidney disease, higher body mass index, heart rate, and hsTnT levels. After adjusting for potential confounding factors, obesity, lower eGFR, higher heart rate, and elevated hsTnT emerged as multivariate predictors of subclinical LVSD. This indicates potential screening benefits for obese and chronic kidney disease patients. Concerning heart rate, we observed a positive linear correlation with subclinical LVSD, with an adjusted OR of 1.72 per each 10 bpm increase, aligning with previous research [20]. However, the therapeutic implications of this finding require further exploration in clinical trials, since the benefit of beta-blockers in HF with preserved EF remains uncertain [21, 22]. Regarding hsTnT, we observed an association between elevated hsTnT levels (> 14 ng/L) and subclinical LVSD, with an adjusted OR of 4.36. In contrast, no similar association was found with NT-proBNP, suggesting hsTnT’s potential as a more sensitive and earlier biomarker of cardiac dysfunction in RA.

Our cohort exhibited a substantial prevalence of traditional CV risk factors, including diabetes, dyslipidemia, and hypertension, especially in the subclinical LSVD group. However, the prevalence of diabetes in our cohort was comparable to that of the general Portuguese population, which was estimated to be 11.7% in 2010 and has since increased to 13%, according to the International Diabetes Federation [23, 24]. The association between RA and an increased risk of CV disease is well-established, with RA patients experiencing an estimated 1.5 times higher risk [25, 26]. This risk burden is multifactorial, stemming from the higher prevalence of traditional risk factors as well as chronic inflammation [27]. Inflammation has a direct effect on endothelial cells and atherosclerotic disease progression, independently contributing to CV disease [28, 29]. The cumulative effect of these classical risk factors and chronic inflammation is likely significant in this subgroup. Nevertheless, our study demonstrated that subclinical LVSD remained independently associated with a higher risk of MACE.

Compared to the general population, the annualized event rates for MACE and all-cause mortality were higher in our study cohort. A study by Yusuf et al. found that in a broadly comparable population in high-income countries, the incidences of MACE and all-cause mortality were lower than in our population (4 vs 14 and 2 vs 12 events per 1000 person-years, respectively) [30]. When compared to a diabetic population in a large population-based study, our cohort showed a comparable MACE risk (14 events per 1000 person-years) [31]. Regarding chronic kidney disease, the MACE risk in our RA population was lower compared to a large population-based study with mild to moderate chronic kidney disease (14 vs 36.5 events per 1000 person-years), while all-cause mortality was comparable (12 vs 11 events per 1000 person-years) [32]. However, in the later study, MACE included peripheral artery disease events, which were not captured in our study population, potentially explaining the higher event rates reported. Therefore, although RA is known to increase global CV and mortality risks, our carefully selected population likely excluded many of the higher-risk patients, resulting in an overall low-to-intermediate risk population.

Some studies have linked high disease activity to CV disease in RA, irrespective of traditional risk factors [33, 34]. However, our study found no association between RA activity characteristics (e.g., RA duration, DAS28-ESR score) or inflammatory markers (e.g., ESR and CRP) and subclinical LVSD, underscoring the challenges of using these biomarkers in early cardiac disease detection.

In terms of other echocardiographic characteristics, while patients with subclinical LVSD showed a trend toward diastolic dysfunction, statistical significance was not reached. Additionally, no significant differences in MACE incidence were found between patients with various diastolic function statuses. This underscores LV GLS's potential as a sensitive tool for early myocardial dysfunction detection, independent of diastolic dysfunction.

Our findings support the hypothesis that impaired ventricular strain could serve as an early marker for CV disease, prompting further investigations into targeted interventions and management strategies. However, the integration of these results into clinical practice remains unclear. Studies by Shah et al. [35] and Minamisawa et al. [36] suggest potential benefits with spironolactone but inconclusive results with sacubitril/valsartan in improving GLS in a population with HF with preserved EF, emphasizing the need for additional research in clinical trials and specifically in RA patients.

This study has certain limitations that should be considered. First, the lack of a sex- and gender-matched healthy control group hinders direct comparisons and precludes conclusions about the specific impact of RA on subclinical LVSD. Second, while the inclusion and exclusion criteria ensure a more selective cohort and enhance the internal validity of our study, they also limit the generalizability and comparability to existing literature. Third, despite the prospective nature of the study, the observational design prevents causal inference. Fourth, although the relatively long follow-up period is a strength, providing valuable insights into the natural history of the disease and allowing for the capture of more clinical events, it also imposes limitations on the interpretation of results, particularly due to the lack of information on treatment changes over time. Additionally, the absence of systematic follow-up echocardiography data, due to resource constraints and logistical challenges, represents another limitation that future research could address. Lastly, the effectiveness of interventions targeting subclinical LVSD on clinical outcomes remains uncertain, reflecting a gap in the current knowledge for this subpopulation. Notwithstanding these limitations, the prospective design and the inclusion of a relatively large and thoroughly selected sample of RA patients make this study one of the most comprehensive descriptions of the natural history of cardiac disease in RA patients.