Overall, the quality of included studies was moderate to low (see Supplemental Digital Content 2, available at: http://links.lww.com/JCRP/A77). The random sequence generation was defined in 4 included trials.14–17 Allocation sequence was concealed in only 2 of the 4 randomized studies15 , 17 and was unclear in 2 studies.14 , 16 The risk of bias for allocation concealment was high in the nonrandomized studies. The participants were unblinded for the intervention in all the included studies due to the nature of the intervention (exercise); however, this is unlikely to introduce a bias. The outcomes assessors were blinded in 4 studies, reflecting a low risk of detection bias. The blinding of outcome assessors is unclear in 2 studies.14 , 18 Two studies had a high dropout rate and, therefore, had high risk of attrition bias.14 , 19 All included studies reported all the clinically relevant outcomes, except for 1,17 which did not report peak oxygen uptake, thereby reflecting a high risk of reporting bias. We also found significant other biases in all included studies: small sample size14–16; lack of true control group14; self-reporting of physical activity15; differences in baseline characteristics between the 2 groups16; and change in study design from randomized to nonrandomized controlled.18 , 19
There were nonsignificant differences noted between exercise and control groups when other parameters of diastolic dysfunction E/A, E/é and DT were analyzed from baseline to follow-up. Four of the 6 studies reported both E/A and E/é outcomes.14 , 17–19 Meta-analysis using random-effects model did not show a significant difference between exercise and control groups (SMD = 0.59; 95% CI, −0.40 to 1.58, and SMD = −0.34; 95% CI, −0.99 to 0.31, respectively) (Figures 2A and 2B). Pooling across the available studies17–19 was done using fixed-effects analysis for DT and found no significant difference between the groups (SMD = 0.14; 95% CI, −0.16 to 0.44; I 2 = 39%) (Figure 2C).
Our results are similar to the studies conducted in obese patients and patients with metabolic syndrome with subclinical diastolic dysfunction which showed favorable effects of exercise intervention on é,25 , 26 but no improvement in other markers of diastolic dysfunction. It is important to note that improvement in some of the markers of diastolic dysfunction was also observed with good glycemic control in 1 study27; however, the results were not reproducible in other studies,28 , 29 suggesting that glycemic control without exercise training is insufficient in producing improvement in diastolic function.
Strain and strain-rate imaging is a new echocardiographic method for comprehensive assessment of early myocardial dysfunction30; therefore, we assessed it as our coprimary outcome and observed improvements in systolic function measured as longitudinal strain. This is consistent with studies that have shown significantly higher left ventricular longitudinal strain and strain rates in athletes than in controls.31 , 32
The mechanisms underlying the improvement in cardiac function are unclear. Some of the proposed mechanisms include decreased afterload; improved cardiac sympathovagal balance18; cardiac remodeling as seen in an athletic heart33 , 34; enhanced endothelial function; alterations in cardiac lipid deposition; receptor for advanced glycation end products; and improved myofilament calcium sensitivity.16 , 20 However, these could not be assessed in the current meta-analysis because of lack of reporting of these outcomes in the included trials.
The limitations of this study include the number of included studies and inclusion of nonrandomized trials that were initially planned as randomized, reflecting the paucity of and challenges to conduct randomized controlled trials addressing this question. The high allocation bias seen in some of the included studies reflects the difficulties in allocation of participants in the control arm. Also, there is a high dropout rate and subjectivity in assessment during the maintenance phase of the intervention. There was also suspected detection bias in 2 included studies that did not specify whether the cardiologists reading the echocardiograms were blinded. In addition, the small sample size of some included trials and high dropout rate in a few included studies resulted in wide CIs for effect estimates. This emphasizes the significance of this systematic review and meta-analysis, which pooled all the available data.
It is important to note that there was, overall, a short duration follow-up in the included studies (mean = 12 mo), thereby probably leading to lack of significant changes in other parameters of diastolic dysfunction which may be affected by longer-term remodeling with consistent exercise. Longer duration trials are also needed to assess sustainability of effects and clinical outcomes such as development of heart failure and mortality. Other potential bias in this meta-analysis is the inclusion of only published studies.
Current studies do not allow us to draw conclusions regarding the evolution and maintenance of improvements in a broader panel of indices of diastolic function. Overall, our findings suggest that exercise training in patients with T2D in the pre-clinical stage, without overt coronary artery disease or congestive heart failure, improves early diastolic dysfunction, myocardial strain, and peak
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