The results of this meta-analysis demonstrated a pooled RR estimate of 0.72 (0.57 to 0.91, p = 0.005), indicating 28% lower mortality in groups with treatment-induced reductions in LVM relative to control over periods of ≥ 12 months. It is further notable that the pooled RR for studies with > 12 months (median 24 months) follow-up showed 48% lower cumulative mortality (RR 0.52, 95% CI 0.36 to 0.76). No significant heterogeneity was observed overall. None of the 3 main subgroups of intervention type showed statistically significant results individually, but the directionality of the association was the same for each intervention type, and no statistically significant heterogeneity was noted across intervention types. Studies of subjects with ESRD showed a statistically significant reduction in mortality with treatment-induced reduction in LVM, whereas studies in subjects without ESRD did not show a significant effect, although results were similar and there was no statistically heterogeneity.
Authors of a previous meta-regression analysis concluded that there was no compelling relationship between changes in LVM and mortality . However, many of the studies included in that analysis were limited by short duration of follow-up and minimal differences between treatment arms for changes in LVM, with some of the interventions producing an increase in LVM. The present analysis avoided those limitations by examining only studies that showed some degree of relative LVM reduction in studies of ≥ 12 months duration. However, the various interventions investigated in the included studies did not always produce reductions in LVM. Furthermore, in clinical practice, several interventions are often used simultaneously, which will result in a combined effect on LVM. The results from this meta-analysis suggest that a reduction in LVM should be considered a favorable clinical result, although prospective trials are needed to assess the use of LVM as a surrogate marker.
The results from the LIFE study demonstrated that reversion from LVH to normal LVMI induced by antihypertensive therapy did not produce material reductions in adverse outcomes for several months . Each SD reduction in LVMI was associated with a reduction of 26% (95% CI 7–41%, p = 0.008) in all-cause mortality and a reduction of 34% (95% CI 10–51%, p = 0.009) in cardiovascular mortality over the full study period in models adjusted for several covariates. Based on results from the LIFE study, the median reduction of 0.33 SD in the present meta-analysis would have been predicted to produce a ~ 10% reduction in all-cause mortality. The larger mortality reductions observed of 28% in studies with ≥ 12 months of follow-up, and 48% in studies with > 12 months of follow-up, might be attributable to markedly higher average mortality risk in the studies included in the analysis: 6.7% cumulative mortality in the control conditions over a median follow-up period of 1 year, compared to approximately 1.4% per year over a median follow-up period of 4.8 years in LIFE .
In patients with CKD, total mortality is increased due to several types of events, but CVD mortality accounts for a large proportion of deaths, exceeding 50% in those with end-stage disease [17–20]. In prior studies, such as LIFE, there was a strong concordance between the effects of treatment-induced changes in LVM and results for total and cardiovascular mortality [6, 10, 83]. In the present investigation, the result for cardiovascular mortality was not statistically significant in the main analysis that included studies of at least 12 months of follow-up, but the pattern and point estimates were similar to those for the analysis of all-cause mortality, suggesting that the lack of statistical significance may have been due to insufficient statistical power.
CKD and CVD share several risk factors, such as hypertension, vascular stiffness, and endothelial dysfunction . LVH is highly prevalent in CKD patients and is associated with risk of mortality and unfavorable prognosis [7, 85, 86]. In addition, CKD patients show progressively increasing LVM with decreased renal function . Increased CVD mortality in CKD results from higher incidence of atherosclerotic and non-atherosclerotic (particularly arrhythmic) cardiovascular events [19, 20, 87–89]. LVM regression has been associated with reductions in both types of events .
LVM regression is typically associated with decreased myocardial fibrosis, which is clinically relevant because the degree of fibrosis is a strong predictor of ventricular arrhythmia risk . The pathophysiologic mechanisms leading to LVH in CKD patients include additive and synergistic effects of afterload and preload factors . Afterload factors, such as increased systemic arterial resistance and arterial blood pressure, and reduced large vessel compliance, lead to myocardial cell thickening and left ventricular remodeling, along with activation of the intracardiac renin-angiotensin system, which promotes cardiac fibrosis. Preload factors, including intravascular volume expansion, secondary anemia, and arteriovenous fistulas, also result in myocardial cell lengthening and left ventricular remodeling . The hypertrophy of the myocardium activates cellular apoptosis and increases extracellular matrix production resulting in fibrosis . Fibrosis impairs the contractility of the myocardium and causes systolic and diastolic dysfunction, potentially leading to congestive heart failure and disturbances in cardiac electrophysiology.
The present analysis was limited by the fact that patient-level data were not available, therefore only summary data could be included and the number of subjects in each type of intervention was relatively small. Because a relatively small number of studies reported cardiovascular mortality, the analysis had low statistical power for detection of an effect for this outcome. Nevertheless, the results are supportive of the conclusion that LVM regression produced by several types of interventions in patients with CKD is predictive of lower risk for all-cause mortality, which may be attributable, at least in part, to reduced cardiovascular mortality. The finding of lower all-cause mortality with LVM regression was robust in several subgroup and sensitivity analyses.