Right ventricle free wall mechanics in metabolic syndrome without type-2 diabetes: effects of a 3-month lifestyle intervention program

Study population

This study formed part of the RESOLVE trial [24]. The present experiment included 39 patients with clinically diagnosed MetS [25]. Participants with incompatible diseases such as cardiopathy, type-2 diabetes and sleep apnea syndrome were excluded. Participants with pulmonary diseases were excluded by medical history analyses, spirometry and arterial blood gas analyses. Pulmonary hypertension was excluded by verifying the absence of clinical symptoms, examination of pulmonary systolic flow profile and, in patients with detectable tricuspid regurgitation, normal pulmonary artery systolic pressure gradient [26],[27]. Coronary artery disease was excluded by verifying negative results on treadmill test and myocardial ischemia from 24-hour electrocardiographic Holter recording. MetS patients were enrolled in a 3-month lifestyle intervention program. Six participants withdrew during intervention, leaving 33 individuals for final analyses. Forty aged and gender-matched controls with no cardiovascular risk factors were recruited on a consecutive basis.

Biochemical, clinical and echocardiographic investigations were performed before and after the intervention in MetS, and at baseline only for controls. Participants provided written informed consent. The study was approved by the human ethics committee from the University Hospital of Saint-Etienne, France. The study protocol was registered with the American National Institutes of Health database N°NCT00917917.

Biochemical, clinical and anthropometric assessment

Anthropometric variables, body composition, blood pressure and routine serum biological analyses plus N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured as previously described [3]. Insulin resistance was estimated from the homeostasis model assessment-insulin resistance (HOMA-IR) index [28]. Inflammatory markers included interleukin-6 (IL-6), high sensitivity C-reactive protein (hsCRP), adiponectin, active plasminogen activator inhibitor-1 (PAI-1 active) and tumor necrosis factor α (TNF-α).

Lifestyle intervention

Participants were enrolled in a 3-week residential program, before returning home to continue the intervention on their own accord. Throughout the residential program, participants received daily individualized meals, planned by dietitians. Total dietary intake during the intervention was calculated to reach a 500 kcal/day caloric deficit with protein accounting for 15 to 20% and lipids 30-35%. Participants’ physical activity requirements included endurance (aquagym, cycling or walking) and resistance training (90 min, 4 to 5 days/week). Resistance training consisted of 8 free-weight exercises, performed for 3 sets of 10 repetitions. Participants were coached individually and heart rate was monitored by Polar™ S810. Participants also attended information seminars on MetS, nutrition, cooking and exercise, to support the sustainability of their new lifestyle upon returning home. Compliance to the intervention was monitored by a weekly self-reported questionnaire and phone interview conducted by dietitians.

Echocardiography

Images were obtained by an experienced operator (GW) using a commercially available system (MyLab30, Esaote SpA, Firenze, Italy) equipped with a 3.5 MHz sector scanning electronic transducer in the left lateral decubitus position. Images at a minimum rate of 60–75 Hz were acquired in cine loops triggered to the QRS complex and saved digitally for subsequent off-line analysis with dedicated software (Mylab desk, Esaote, Italy).

Conventional, pulsed Doppler and tissue Doppler imaging echocardiography

RV and left ventricular images were obtained following the American Society of Echocardiography guidelines [29],[26]. Left ventricular dimensions were determined from M-mode echocardiogram as previously described [3]. Left ventricular ejection fraction was obtained from the modified monoplane Simpson’s method. Left ventricular mass was calculated by the Devereux formula and indexed for height (Cornell adjustment). Pulsed-wave Doppler of mitral as well as tricuspid inflow velocities, including early (E) and atrial (A) waves, were measured. Tissue Doppler imaging (TDI) measures of myocardial systolic, early diastolic and atrial velocities were assessed at the mitral annulus level (data reported are means from lateral and septal walls) and on the lateral tricuspid annulus wall. The ratio of peak early filling velocity through the mitral valve during diastole to peak early diastolic velocity of the mitral annulus was used as an index of left ventricular filling pressure [30]. The ratio of peak early filling velocity through the tricuspid valve during diastole to peak early diastolic velocity of the lateral tricuspid annulus (E/E_tri) and the right atrial area were used as surrogates of right atrial pressures [31],[32]. The isovolumic relaxation time for the RV was also derived from TDI measurements. The tricuspid annular plane systolic excursion (TAPSE) was measured from the difference between the displacement of RV base during systole and diastole. The fractional shortening, the right atrium area and the RV end-diastolic diameter at basal level were assessed in the apical four-chamber view. RV shortening fraction was obtained using the formula: (end-diastolic area – end systolic area)/end-diastolic area [9]. The pulmonary flow was recorded using a parasternal short-axis view at the level of the pulmonary artery allowing measurement of its acceleration time and estimation of mean pulmonary artery pressure [26].

Vector velocity imaging

Velocity vector imaging is a method used to quantify myocardial wall motion through the combination of speckle tracking, tissue-blood border detection and myocardial shape [33]. It is an angle-independent measurement technique validated against sonomicrometry [33] and magnetic resonance imaging [34] which has been largely used to investigate left ventricular [3] but also RV [15],[35]-[37] mechanics in health and disease. The RV free wall longitudinal myocardial function was assessed from 2-D harmonic grey scale images in the apical 4-chamber view. The imaging sector was narrowed to optimal view and the frame rate was kept higher than 60 Hz in each case. Longitudinal strains and strain rates were measured at the basal, mid and apical segments of the free wall and averaged to give global strain (GLS) and strain rates (Figure 1). Diastolic strain rate was obtained from the peak value observed during the early filling period. To adjust all vector velocity imaging data for inter-subject differences in heart rate, a specific toolbox was used to normalize time sequence as a percentage of systolic duration calculated from the timing of pulmonary valve closure. The reproducibility of strain and strain rates (intra-observer variability: 7.8 and 8.2%, respectively) has been reported elsewhere [38].

Statistical analysis

Statistical analyses were performed using SPSS 20.0 for Windows (SPSS Inc). Statistical significance was set a priori at P < 0.05. Variables are presented as mean ± standard derivation and skewed data were log-transformed. Appropriated unpaired and paired t-tests were used to evaluate the differences between MetS (at baseline and after the lifestyle intervention) and controls and the effect of the lifestyle intervention within the MetS patients, respectively. Mann–Whitney U-test and Wilcoxon test were used for abnormally distributed variables. For categorical variables, a χ2 test was used. Correlations using Pearson’s correlation coefficient or Spearman coefficient of rank correlation for abnormally distributed variables were used to identify associations between RV longitudinal myocardial deformation and clinical as well as biological parameters or their changes after the lifestyle intervention. Multiple stepwise linear regression analyses were performed to assess variables that were independently associated with RV free wall GLS. Biometric, metabolic and inflammatory biomarkers that correlated with RV free wall GLS with a P value <0.05 during the first univariate analysis were entered into the model.

Study limitations

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 [18],[20],[55] 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. [12] 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. [20] 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 [55],[56]. 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 [32]. In our study, right atrial pressures were not invasively measured through right heart catheterization due to ethical considerations. Specifically, pressures were estimated from E/E_tri and right atrial area. Although significant, the differences between the 2 groups in E/E_tri 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. [31] 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/E_tri 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/E_tri was not a significant contributor to the RV GLS. Additionally, no changes in E/E_tri 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. [12] 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.