We provide evidence for the first time of non-diabetic MetS patients exhibiting subtle RV free wall systolic and diastolic dysfunction that was significantly improved following a 3-month lifestyle intervention based on healthy dieting and increased physical activity.
Currently, a large body of evidence associates MetS with adverse effects on left ventricular myocardial function assessed using tissue deformation imaging tools . However, far less information is available on RV myocardial function and whether the latter is sparse in the settings of MetS remains largely unresolved. Most of the available studies refer to assessment of RV free wall velocities by TDI and report inconclusive results, especially for longitudinal systolic velocities -,. Our data of reduced systolic and early diastolic longitudinal velocities agree with some of these works , but not all ,. A major limitation of TDI over speckle tracking imaging is however, its lack of sensitivity (dependency on loading conditions, tethering effect, translational cardiac movement) in detecting subtle myocardial changes ,,. This is of particular concern when evaluating systolic abnormalities but also the impact of interventional strategies (see paragraph below). Additionally, due to insonation angle-dependency, TDI data are usually restricted generally to basal and sometimes mid segments of the left or right ventricle. Subsequently, only a partial understanding is permitted of the effect of MetS on regional myocardial performance. Using sensitive echocardiographic tolls such as speckle tracking imaging surpasses most of the TDI aforementioned limitations . Speckle tracking imaging is feasible and applicable to the RV and has been shown to provide extensive information about RV myocardial function in various cardiometabolic disease ,,,. In the present study, we used vector velocity imaging, a technique that has been validated for accurate assessment of myocardial deformation , to fully explore the entire RV free wall mechanics. We demonstrated subtle alterations of both systolic and diastolic linear deformations encompassing all segments of the RV free wall in MetS patients free of type 2 diabetes. These results agree with those recently published by Tadic et al.  in MetS individuals also free of diabetes.
Abdominal obesity, a key component of MetS, is consistently associated with major increases in pro-inflammatory adipocytokines, such as TNF-α, IL-6, hsCRP or PAI-1 active, as well as reduced protective cytokines, such as adiponectin, agreeing with our data -. Growing evidence suggests a pivotal role of visceral adipose tissue to the left ventricular myocardial dysfunction observed in various metabolic diseases, postulated to occur via a low-grade state of inflammation -. Whether this is also true for RV myocardial dysfunction in MetS remains largely unknown. To our knowledge, only Tadic et al.  documented from univariate and multivariate regression analysis independent associations between global RV free wall deformations and some MetS criteria including waist circumference, fasting glucose and systolic blood pressure in MetS individuals free of diabetes. The results of the present study confirm and extend these results by demonstrating significant relationships between RV GLS and abdominal obesity as well as inflammatory biomarkers. From multivariate analysis, central fat, PAI-1 active as well as adiponectin, appeared as significant contributors to RV free wall dysfunction. Central adipose tissue-induced inflammation might have precipitated the RV free wall myocardial abnormalities reported here via enhanced oxidative stress, adversely affecting coronary endothelial function as well as impairing cardiomyocyte calcium handling and increasing fibrosis -. Of note, adiponectin exerts cardiovascular protective effects via its ability to limit apoptosis, oxidative stress and inflammation in cardiomyocytes and endothelial cells . Nonetheless, the depressed RV GLS may also be explained by ventricular interdependence, and specifically, left ventricular hypertrophic remodeling, through direct mechanical interactions between the two chambers. As previously demonstrated, left ventricular hypertrophy and dilation (a remodeling classically observed in MetS  and in the present population), result in RV compression leading in turn to impaired function . Supporting this assumption, not only indexed left ventricular mass correlated with RV GLS but also appeared as one of its main contributors from stepwise multiple regression analysis.
To the best of our knowledge, no studies have examined the effect on RV myocardial function of non-pharmacological interventional strategies in MetS populations. The other major novel finding from the present study was that a 3-month lifestyle intervention comprising nutrition and exercise training was able to fully restore RV GLS to normal values of age-matched healthy controls. Of note, improvements in RV free wall function were evidenced only using sensitive tools such as vector velocity imaging, as TDI indices were not changed. RV myocardial function enhancements have also been reported with obesity following interventions involving low calorie diet . Agreeing with previous data , the lifestyle intervention favorably impacted on abdominal obesity, glucose intolerance and most biomarkers of inflammation. Despite significant relationships between RV GLS and most of MetS components at univariate analysis, no correlations were noticed between relative change data after the intervention. This could be due in part to the low magnitude of changes observed and a relatively small sample size, although patients acted as their own controls. Accumulation of ectopic fat to the heart is emerging as the key component of myocardial dysfunction in metabolic diseases ,,. Increased epicardial fat, as established in MetS  is a local source of pro- and anti-inflammatory cytokines whereas visceral abdominal fat is mainly responsible for the increased systemic inflammation ,. Although not measured in the present study, observed improvements in the present study could be attributed to diet and exercise-induced reduction in cardiac adiposity, in turn lowering local inflammation and oxidative stress. Of note, a low calorie diet program in 20 severely obese patients  decreased epicardial fat more than in other sites of adipose tissue and improvement in LV diastolic function was more strongly related with epicardial fat changes than with other adiposity indices.
Despite its key role in left ventricular filling, RV function has been insufficiently investigated in cardiometabolic diseases. With prevalence reaching alarming proportions worldwide, MetS is now considered to be the driving force for a cardiovascular disease epidemic. In this context, the present study underlines the necessity for a close clinical RV monitoring in MetS patients even when type 2 diabetes is not associated. Moreover, this study underlines the importance of central obesity and its associated inflammation as independent factors explaining RV mechanical abnormalities, highlighting the need for treatment of central fat and inflammation to decrease or prevent the deleterious impact of MetS on RV function. Finally, the present work emphasizes the importance of lifestyle changes since the RV dysfunction can be corrected even only three months after an exercise and nutrition intervention.
A first limitation of the present study is its relatively small sample size. Additionally, most of our MetS patients presented with arterial hypertension and half were on ACE-I/ARBs, which considering previous studies ,, could have confounded our results on RV free wall function. However, blood pressure did not correlate with RV GLS, nor did it emerge as an independent contributor in multivariate analysis. Additionally, there were no differences in RV free wall mechanics indices between subgroups of MetS treated or not for hypertension. Interestingly, Gökdeniz et al.  did not shown in MetS patients any contributing effect of coexisting hypertension to RV free wall longitudinal strain by speckle tracking imaging. In contrast, systolic blood pressure emerged as an independent contributor to the altered global RV free wall strains reported by Tadic et al.  in non-diabetic MetS patients. Further studies will therefore be needed to clarify the independent effect of mild to moderate hypertension, as encountered in MetS, on RV free wall mechanics. Manipulation of the renin-angiotensin-aldosterone system via ACE-I/ARBs has been shown to affect RV remodeling and possibly RV function ,. It is however, unlikely that ACE-I/ARBs influenced our results since no differences in RV GLS were observed between the subgroups of MetS patients taking or not ACE-I/ARBs medication. Right atrial pressure is an important component of RV function . In our study, right atrial pressures were not invasively measured through right heart catheterization due to ethical considerations. Specifically, pressures were estimated from E/Etri and right atrial area. Although significant, the differences between the 2 groups in E/Etri were low (3.7 ± 0.8 vs 4.2 ± 1.1, P = 0.02) and most importantly only one MetS patient out of 39 presented with a ratio greater than 6; a cut-off value proposed by Nagueh et al.  that can be considered to be a marker of RA pressures greater than 10 mmHg. Furthermore, no right atrial remodeling was observed in our MetS patients and E/Etri failed to correlate with right atrial area (r = 0.06 P = 0.62). Collectively, these results favor the absence of elevated right atrial pressures in our MetS patients. Subsequently it is unlikely that increased right atrial pressures could have accounted for their reduced RV GLS. Of note, stepwise multiple regression results indicated that E/Etri was not a significant contributor to the RV GLS. Additionally, no changes in E/Etri ratio but also right atrial area were noticed following the lifestyle intervention program while at the same time, the latter fully restored RV GLS to normal values, demonstrating that variables were not independently associated. As previously noted, cardiac adiposity was not measured and whether it is involved in the RV myocardial abnormalities reported here and whether improvement in RV function after lifestyle intervention are linked to favorable impacts on myocardial steatosis and/or epicardial fat remains to be determined. Of note, Gökdeniz et al.  recently demonstrated in MetS patients using speckle tracking imaging, that epicardial fat was independently associated with RV free wall global longitudinal strain.
In conclusion, RV myocardial systolic and diastolic abnormalities in MetS patients free of type-2 diabetes were partially accounted for by central adiposity-induced changes in pro- and anti-inflammatory cytokines as well as ventricular interdependence, through direct mechanical interactions between the RV and left ventricular chambers. A lifestyle intervention based on healthy dieting and physical activity was associated with fully restored RV free wall mechanics to healthy control level; indicating probably that cellular and sub-cellular alterations were not permanent but still modifiable throughout adequate interventional strategies. Special attention should be paid to this specific population in clinics, as earlier identification of asymptomatic patients at high risk of evolution to RV failure is of primary importance because it may facilitate timely and more effective intervention.