SSRI use was associated with higher RVSV in men and women and with greater RV mass in men only. SSRI use may have been associated with larger RVESV in both sexes and was more strongly associated with larger RVEDV in men than in women. There was no association between SSRI use and RVEF. To our knowledge, this is the only study of SSRI use and RV morphology in humans.
Increased stroke volume and end-diastolic volume without a change in ejection fraction is seen in the LV in athletes, and even in the RV in MESA participants who report higher levels of exercise 
. This suggests that the SSRI-associated changes may be adaptive. Animal models suggest that RV adaptation to exercise may not only outstrip LV changes, but that RV eccentric hypertrophy leads to an increase in capillary networks and oxygen transport, implying a compensatory response 
. While ventricular response to pressure loading has been well-described in the LV, in pulmonary vascular disease the spectrum of RV changes (from adaptive to maladaptive) is less well understood 
. In animals with moderate PH, exercise results in enhanced capillarization (implying compensation) whereas in those with progressive disease increased RV diameter and wall stress develops (implying maladaptation), albeit with a similar degree of hypertrophy in both moderate and progressive PH 
. Several small observational and a single randomized trial have examined changes in RV morphology with therapy in PAH patients at advanced stages of disease (i.e., predominantly World Health Organization functional class II/III) and shown decrements in RV mass and volumes with improved systolic function 
. While we postulate that the SSRI-related associations with RV mass and volumes seen here may be adaptive in health or in subclinical disease, the clinical impact of SSRI-related changes in patients with advanced pulmonary vascular disease is not known.
In our study, the association between SSRI use and greater RV mass (in men only) persisted after adjustment for LV mass, implying that 5-HTT inhibition may not only uniquely impact the RV but that these effects may vary by sex. Endurance training and subsequent ventricular hypertrophy have been correlated with increased aerobic capacity in athletes, and interestingly men may have a more pronounced response as compared to women 
. In experimental PH, 5-HTT inhibition leads to reductions in pulmonary artery pressure and subsequent decreases in RV mass 
. However, our observations suggest that in normal individuals presumably without significant pulmonary vascular disease, SSRI use is associated with increased RV mass. Although not feasible in a disease-free cohort of over 4000 individuals, hemodynamic data from right heart catheterization could have elucidated the association between SSRI use and pulmonary vascular function.
We have recently shown that serum sex hormone levels are associated with RV morphology in a sex-specific manner 
. While sex hormones do not appear to confound the associations seen here, sex is known to play a role in serotonin-stimulated platelet aggregation and kinetics and 5-HTT is differentially regulated in men and women 
. Additionally, RV structure and function vary by sex in both health and disease, with men having greater RV mass and volumes but lower RVEF than women, suggesting SSRIs may differentially impact morphology depending on sex 
. While adjustment for sex hormone levels did not change effect estimates in our study, it is certainly possible that hormones may underpin different morphologic changes in men and women.
Animal studies of acute and chronic left heart failure have implicated serotonin as an important regulator of cardiac hypertrophy 
. In young animals, knock-out of serotonin receptors results in dilated cardiomyopathy, suggesting an important role of serotonin in the developing heart. Receptor overexpression in adult animals, however, leads to maladaptive hypertrophy 
. Epidemiologic studies suggest that the use of SSRIs in patients with ischemic heart disease may be beneficial 
. In a randomized clinical trial of SSRIs to treat patients with major depressive disorder and acute coronary syndrome, SSRI use did not affect LV ejection fraction, but did lower risk of adverse cardiovascular events, possibly by inhibiting platelet activation and preserving endothelial function 
. A follow-up clinical trial of sertraline in depressed patients with congestive heart failure (CHF) showed no difference in composite cardiovascular events between intervention and control arms 
. A larger trial of escitalopram in CHF is on-going and includes sub-studies to investigate escitalopram's effects on platelet function and endothelial vasoreactivity 
The impact of serotonin and its pathways on RV structure and function has not been extensively studied. In animals, serotonin causes protein oxidation in the RV (but not in the LV) and treatment with SSRIs prevents RV hypertrophy and lowers RV weight in PH models 
. Treatment with SSRIs suppresses PA-SMC proliferation but also increases pulmonary arterial cellular apoptosis, which may or may not be beneficial in the RV 
. While serotonin released from pulmonary endothelial cells stimulates growth of PA-SMCs, it is unknown how cardiac endothelial function and myocytes might be affected by these paracrine effects 
. Finally, it is difficult to reconcile the potential benefit of SSRIs in PAH with the observational evidence that maternal SSRI use may increase the risk of persistent pulmonary hypertension of the newborn in infants 
Our study has several limitations. While the effect sizes seem small (ranging from 3.2% to 5.5%), they are comparable to those seen in the LV related to active smoking and diabetes mellitus and in the RV related to physical activity (e.g., a 7% increase in RVEDV and a 5% increase in RV mass with higher levels of physical activity), but more subtle than the associations we have shown in the RV related to obesity 
. A few small studies have shown similar magnitudes of effect on RV tissue Doppler imaging 
. In severe PAH, long-term intravenous epoprostenol improves RVSV by approximately 12% 
. In a normal individual, similar or smaller differences (in absolute or relative terms) may therefore have important physiologic effects. As our study is observational, no conclusions can be drawn about a causal role of SSRI use in RV morphology. Confounding by indication is possible, although it is unlikely that SSRIs were differentially prescribed based on subclinical differences in RV structure and function. Certain covariates may have influenced both SSRI use and RV measures, leading to unmeasured or residual confounding. While recall bias could be present, the medication inventory method utilized has been validated and medication use was assessed before the RV data were available, making differential recall based on RV morphology unlikely 
. Unfortunately, duration of SSRI use was not assessed but would have allowed for further quantification of the observed associations. Some participants could have been on long-term SSRIs, while others for only a short period of time (a minimum of two weeks). However, such misclassification would likely bias to the null (e.g., a participant taking an SSRI for a few months before the baseline study visit would be unlikely to experience RV effects, yet would still be classified as “exposed”).
We have shown that SSRI use is associated with higher RVSV, larger RVEDV and greater RV mass (in men) in cardiovascular disease-free participants. Studies of SSRIs in patients with or at risk for pulmonary vascular disease should include specific assessments of RV effects and sex may prove important in modifying this relationship.