4. DISCUSSION
In the present study, it was shown that younger CKD patients without a
previous history of CVD (i.e. <60 years old) had worse indices
of diastolic function (E’ and E/E’), more LV hypertrophy and signs of
concentric remodeling and lower values of CFR compared to age-matched
healthy controlswith similar demographic and clinical characteristics.
In older CKD patients, a trend towards further worsening of these
indices compared to younger CKD patients was observed but this was
probably attributed to aging since all differences were lost after
adjustment for differences in age between patients. This finding may be
explained by the direct effect of aging on myocardial structure and
function and microcirculatory function, the longer exposure to CKD and
the potential relation of age to different CKD etiologies (i.e. diabetic
and/or hypertensive nephropathy may be more prevalent in older CKD
patients while various glomerulopathies may be more frequent in younger
CKD patients). The effects of dipyridamole on classic and myocardial
strain indices were similar in all studied groups.
Left ventricular diastolic dysfunction has been shown to be common in
various stages of CKD and it has been suggested that the severity of CKD
may be associated with the progression of asymptomatic LV diastolic
dysfunction to symptomatic stages of heart failure independently of
other clinical parameters [24]. In
animal-based experimental CKD models, the development of LV diastolic
dysfunction has been demonstrated to be independent of the presence of
hypertension [25]. Various measures
of LV diastolic dysfunction have been associated with increased
mortality in the general population
[26] while E/Eʹ has been shown to be
a very useful parameter in predicting prognosis of CKD patients
[27]. Enlarged left atrium has been
demonstrated early in CKD patients
[28] and has emerged as a useful
biomarker for risk stratification and risk monitoring in patients with
CKD [29,
30]. Currently, we showed that young
asymptomatic CKD patients (mean age 49 years) had worse E’ and E/E’
compared to age-matched healthy controls. On the other hand, LAVI was
similar between healthy controls and young CKD patients while it
increased in older CKD patients suggesting that longer duration of
exposure to CKD and/or aging per se are probably the main contributors
of LA enlargement.
LV hypertrophy has been previously reported to be highly prevalent in
patients with CKD even in early stages and related to both worsening GFR
and albuminuria [31] and has been
associated with cardiovascular mortality
[2]. It has been demonstrated that LVH
may be present up to 50-75% in patients with eGFR<60
mL/min/1.73 m2 [32]
while other forms of structural LV abnormalities including LV concentric
remodeling may be also common in CKD populations (ca. 20.0%)
[33]. In the present study, we showed
that increased LV mass and LV concentric remodeling are prevalent in CKD
patients (irrespectively of age) compared to healthy controls suggesting
that these findings are more closely related to CKD per se (impaired GFR
and proteinuria) and not aging. Among persons with CKD, left ventricular
mass index has been associated with incident heart failure, even after
adjustment for major cardiovascular risk factors
[34].
CFR is a useful marker non-invasive echocardiographic index of
epicardial artery stenosis of the LAD territory and coronary
microcirculation; in our study in CKD patients without clinical or
subclinical CAD, CFR is more likely to describe coronary
microcirculation function [23,
35-39]. In agreement with our findings
decreased CFR has been demonstrated in CKD patients even with mild to
moderate GFR impairment [18,
40, 41].
Impaired CFR and subsequent dysfunction of coronary microcirculation has
been related to LV diastolic dysfunction and other LV structural changes
[23,
41-43] in various CKD populations as
well as to prognosis in CKD patients
[42, 44,
45].
Chronic renal disease has been proven to be associated with early and
subclinical impairment of LV systolic function as assessed by
2D-myocardial strain indices and especially GLS
[9, 10,
14, 46].
In a single study TWIST was shown to increase in CKD patients
[46] in contrast to our findings.
Currently, there were no differences in 2DSTE-related indices between
young CKD patients and age-matched healthy controls as well as no
differences among younger and older CKD patients with similar GFR and
albuminuria values. GLS has been reported to be a predictor of adverse
cardiovascular prognosis in CKD patients following adjustment for
relevant clinical variables [47].
DIPSE has been previously shown to be effective for both the assessment
of myocardial ischemia and CFR assessment. It has also been suggested
that it could be used as a test to evaluate the systolic and diastolic
myocardial reserve in various populations
[23, 39,
48]. In our study, DIPSE produced
similar improvement in various indices of LV systolic and diastolic
function (classic and 2DSTE-related) in all three patient groups.These
findings suggest that DIPSE test may not be suitable for detecting early
myocardial abnormalities and risk stratification in relatively healthy
asymptomatic CKD patients free of established cardiovascular disease.
However, there is a need for larger longitudinal studies in order to
clarify the value of DIPSE test in CKD patients besides the evaluation
of CFR and assessment of myocardial ischemia.
Limitations . This was a single center study that included
relatively healthy patients with CKD of various etiology without severe
comorbidities and thus the results cannot be extrapolated to the general
CKD population. As mentioned in the methods’ section a significant
portion of the CKD population was excluded due to the presence of
structural heart disease or coronary artery disease. Multivariate
association analysis was not performed due to the limitation of the size
of the study groups. For the same reason medications’ usage was not
taken into account in the association analysis.
In conclusion, in this study it was demonstrated that impaired coronary
microcirculation and LV diastolic function and increased LV mass with
concentric remodeling are the principal findings early in the process of
CKD in comparison to healthy controls. These results have implications
for pathophysiological processes behind cardiorenal syndrome type 4 and
targeted cardiac assessment in patients with CKD may be of value to
identify the progression of subclinical myocardial abnormalities. Future
studies are needed to validate our findings in terms of improvement of
clinical practice but also to assess whether any therapeutic effort
aiming to delay or reverse changes in the above mentioned
echocardiographic indices may have an impact on the cardiovascular
prognosis in CKD patients.
Author Contributions : Conceptualization, L.L., K.K.N., C.S.K.,
E.D. and L.K.M.; methodology, L.L., K.K.N. and E.D.; data acquisition,
L.L., A.D., M.M., O.B. and I.T.; data analysis and interpretation, L.L.,
A.B., K.K.N. and E.D.; writing—original draft preparation, L.L.,
K.K.N., A.B., C.S.K. and E.D.; writing—review and editing, L.L.,
K.K.N., A.B., A.D., O.B., I.T., M.M., C.S.K., E.D and L.K.M.
All authors have read and agreed to the published version of the
manuscript.
Funding : This research received no external funding
Institutional Review Board Statement : The study was conducted
according to the principles of the Declaration of Helsinki and approved
by the Ethics Committees of the University Hospital of Ioannina
Informed Consent Statement : All participants provided a written
informed consent
Data Availability Statement : The data presented in this study
are available upon request from the corresponding author. The data is
not publicly available due to privacy concerns.
Conflicts of Interest : The authors declare no conflict of
interest.