Determinants of left ventricular diastolic dysfunction in hemodialysis patients

prevalence of


Introduction
Left ventricular diastolic dysfunction (LVDD) is frequent in Chronic kidney disease (CKD) patients (1), particularly in those on hemodialysis (2). Multiple cardiac/myocardial anomalies acknowledged to exist in CKD patients may explain it (3), including (a) left ventricular hypertrophy (LVH) (4), which is an early occurrence during the course of CKD (5), has a high prevalence in CKD patients and increases death risk (1); (b) myocardial fibrosis as a consequence of both traditional and CKD-associated risk factors (6); (c) wall thickening of the intramyocardial arterioles (7).

Objectives
This study aimed at uncovering the clinically relevant correlates (which might include putative determinants) of LVDD in hemodialysis patients, with the perspective that they might constitute in the future the basis for prevention programs or interventions.

Patients and Methods
The present study is an observational study performed on 51 patients (30 males, 21 females, age 59.76 ± 13.24 years) on hemodialysis treatment (for 2-84 months, with an average ± standard deviation of 40.76 ± 21.64 months, with an ultrafiltration of 1.95 ± 0.93 L) in the hemodialysis department of the university emergency hospital, Bucharest, Romania.
The diagnosis of LVDD was made according to the current European and American guidelines (17) as they are readily applicable in clinical practice, well correlated with invasive measurements, and reliable in predicted outcome (18).
The imaging atherosclerosis markers (IAMs) employed in our study were; 1. valvular calcifications (both aortic and mitral), estimated by transthoracic cardiac ultrasound, and 2. arterial atherosclerosis burden reflected by: (a) atheroma plaques (both carotid and femoral) and common carotid intima-media thickness, evaluated by vascular ultrasound, and (b) aortic calcification score as defined by Kauppila et al (19), calculated on lateral lumbar films (in which the spine was visible from eleventh thoracic to the second sacral vertebra).
Certified, experienced sonographers and radiologists blinded to the results of lab tests performed the imaging examinations.
In each patient, two radiologists, each blinded to the assessment of the other, calculated the aortic calcification score. The value included in the statistical analysis was the average of the two independent estimations.
The nutrition status was assessed by means of anthropometric (body mass index), biochemical (serum levels of albumin, cholesterol, and triglycerides, and diet related (normalized protein catabolic rate) parameters.

Statistical analysis
The correlations between two categorical parameters (such as LVDD and degenerative aortic stenosis) were assessed by means of Fisher's exact test. Chi-square test was also applied in the cases were none of the expected values was less than 5 (20). The correlations between one categorical parameter and one numerical parameter were assessed by Mann-Whitney test. Regression analysis was employed to assess the correlation between two numerical parameters, estimating the strength of the correlation by means of the correlation coefficient and the statistical significance of the correlation by means of t-statistic. R language and environment for statistical computing and graphics (version 4.1.2) was used to perform the statistical computations. A P value equal to or less than 0.05 was considered as indicator of statistical significance.

Results
There were 32 patients with and 19 without LVDD. Table  1 is a summary of the demographic, biochemical, and imagistic features of our patients.

Associations between LVDD and inflammation-and oxidative stress-related parameters
Left ventricular diastolic dysfunction appears to have positive statistically significant correlations with serum CRP level (but not with others inflammation markers, such as fibrinogen, IL-6 and TNF-α) and with serum total antioxidant capacity ( Figure 1 and Table 2). An intriguing negative statistically significant correlation was also found between LVDD and cortisol level ( Table 2).

Associations between LVDD and demographic and metabolic parameters
There was no association between LVDD and age, but a tendency to association with male gender was obvious,

Associations between LVDD and imaging atherosclerosis markers
Mann-Whitney U test uncovered a correlation between LVDD and arterial atherosclerosis burden as reflected by the number of femoral plaques and the aortic calcification score (Table 3 and Figure 1). Fisher's exact test revealed associations between LVDD and most of the imaging atherosclerosis markers (but for aortic valve calcifications and carotid plaques) ( Table 3). There was no association between LVDD and aortic or mitral valve regurgitation or pulmonary hypertension.

Mean ± SD Median (q1-q3) Mean ± SD Median (q1 -q3)
The most obvious putative confounder is degenerative aortic stenosis which by itself engenders LVDD (via the LVH it induces (21)) and is expected to be correlated with degenerative changes in other cardiac and arterial structures as CKD induces widespread valvular and arterial calcifications (22). All our patients with aortic valve stenosis also had LVDD. Therefore, the statistical computations needed to be repeated after eliminating this possible confounder, i.e. after eliminating the seven patients with aortic stenosis. Among the 44 remaining patients, 25 have LVDD and 19 have not. The only associations that remained statistically significant were those of LVDD with serum total antioxidant capacity, cortisol level, and aortic calcification score ( Table 4). The tendency to association also with CRP is clear (compare the medians and third quartiles), but it narrowly fails to reach statistical significance, probably due to the smallness of the sample.
None of the associations between LVDD and IAMs (presence of femoral plaques, of aortic annulus calcifications, and of mitral valve calcifications) remained statistically significant after removing the seven patients with aortic stenosis.

Discussion
Although multiple mechanisms have been identified explaining myocardial hypertrophy and fibrosis underlying LVDD in hemodialysis patients (5), the biochemical and imaging associations relevant for clinical practice have been less explored. Our study, aimed at contributing to this under researched area, revealed some data concordant with what is already known, but also some differences. The statistical analysis of our data indicated that in hemodialysis patients there is an association between LVDD and inflammation, as reflected by CRP, which is in agreement with the association between LVDD and highsensitivity CRP (hs-CRP) in CKD patients demonstrated by other researchers (1), and is at least partially explained by the correlation between LVH and CRP in pre-dialysis patients (9) and in patients on hemodialysis (10) and with hs-CRP in hemodialysis patients (23), hs-CRP being an independent predictor for LVH in CKD (11). However, we found no correlation between LVDD and other inflammatory markers, such as IL-6 and TNF-α (in agreement with previous studies on CKD patients   (1)), although other researchers demonstrated that LVH is associated with TNF-α in CKD patients (11) and in hemodialysis patients (23) and with IL-6 in CKD patients (1) and in hemodialysis patients (23).
The association of LVDD with oxidative stress demonstrated by our study is concordant with the findings of other researchers linking diastolic function to overproduction of ROS due to the involvement of oxidative stress in promoting cardiac remodeling (5) in CKD patients.
Our study failed to demonstrate a relation between LVDD and anemia, although there are studies suggesting that in CKD patients anemia is correlated with cardiac hypertrophy (24) and with left ventricular dilatation and heart failure (25).
We did not find an association between LVDD and disorders of bone and mineral metabolism, although other studies demonstrated that in hemodialysis patients LVDD is correlated with serum phosphorus level and calcium × phosphate product (13), while LVH is associated with serum PTH (13), phosphorus, and calcium level (13), and with vitamin D deficiency (16). Interestingly, in uremic rats cardiac fibrosis is associated with high serum parathormone level (15) and with hyperphosphatemia (14).

Conclusion
LVDD is positively correlated with inflammation and oxidative stress markers and with the severity of aortic calcification. The association of LVDD with valvular and peripheral arterial calcifications / atherosclerosis is largely mediated by its association with degenerative aortic stenosis. The purpose of designing therapeutic strategies is to prevent or slow the course of LVDD, thereby influencing the cardiovascular and general outcomes of these patients.

Limitations of the study
The most important limitations of this study are; 1. The relatively low number of enrolled patients. 2. The time interval the imaging investigation lagged behind the performance of laboratory tests; however, this delay was unavoidable given the ultrasound examination, as a human-dependent investigation, is inherently more labor-and time-intensive than laboratory tests, which are machine-dependent. 3. The putative confounders, among which degenerative aortic stenosis was probably the most important; the elimination of this confounding factor resulted in an even smaller sample of patients on which to base our conclusions. Studies on larger samples are necessary to identify the biochemical correlates/markers/ determinants of LVDD in hemodialysis patients.