We report the first study using tagged CMR in patients within 6 months of commencing HD, characterising abnormalities in cardiac size, geometry and strain in terms of magnitude, rate and synchronicity. The high prevalence of reduced systolic and diastolic strain (despite preserved EF), ventricular dyssynchrony, anteroseptal segmental dysfunction and reduced aortic distensibility was more evident with the detailed methods utilised. The relative lack of correlation between bioimpedance-measured volume status and LV strain was consistent with volume-independent mechanisms playing a role in the evolution of cardiac dysfunction in this setting.
These data support and extend previous CMR-based descriptions of cardiomyopathy in established HD patients. Separate reports characterised different aspects of cardiac and aortic function; however, such a comprehensive assessment in incident HD patients has rarely been reported. Mark and co-workers reported gadolinium contrast-enhanced CMR data in 134 prevalent HD or peritoneal dialysis patients selected for cardiovascular screening for potential renal transplantation. They reported a prevalence of 72 % for LV hypertrophy and 8.2 % for reduced EF, using cut-offs derived from published reference range studies. They also found heterogeneity in the distribution of focal myocardial fibrosis as determined by gadolinium-based contrast enhancement. The study was conducted prior to awareness of the association of gadolinium contrast media with nephrogenic systemic fibrosis and did not investigate strain or relationships to troponin-T. Their findings were concordant with our study, demonstrating lower EF and greater LV mass in HD patients with regional heterogeneity in strain. The differences between these prior studies and the present might be explained by differences in the populations studied and exposure to HD.
There are no prior studies of LV strain by CMR tagging in HD patients, which is currently the reference standard technique for LV deformation. This present study reports strain values for the age and sex-matched controls without kidney disease (19.5 ± 3.3 %) in keeping with reported reference ranges for circumferential strain by tagged CMR in healthy volunteers of 16–19 % [23]. Strain values by tagged CMR may not be directly comparable to studies using tissue Doppler or speckle-tracking echocardiography. In general population studies, absolute differences of 10–25 % against a tagged CMR reference measure are reported, with wider disparities in disease states.
Ventricular morphology
Hypertrophy of the LV is an established feature of cardiomyopathy in HD patients, representing a maladaptive response that allows for normal EF despite abnormal pressure or volume load. In addition to traditional atherosclerotic risk factors, multiple factors are contributory, including aortic stiffness, volume and pressure overload, hyperphosphatemia and neurohormonal activation [24]. Recent work has extended this picture with the implication of locally generated steroids and fibroblast growth factor 23, both of which are increased in HD patients [25, 26]. In particular, sodium can induce adrenal secretion of digitalis-like steroids to produce myocyte hypertrophy independent of blood pressure or volume effects, representing a novel mechanism linking dietary or dialysate sodium to LV hypertrophy in HD patients [27]. In the present study, LV concentric remodelling by mass/volume ratio was significantly increased in HD patients compared to controls, even amongst those with preserved EF or without diabetes.
Heterogeneity of systolic strain
The regional heterogeneity of PSS has not previously been described in HD patients. In studies of hypertensive cardiomyopathy, tagged CMR demonstrated the earliest effects of pressure overload by basal septal reductions in PSS and PSSR [28]. This is in contrast to infiltrative genetic disorders such as Fabry’s disease where the earliest reductions in PSS are seen in inferolateral segments [29]. The present study reports reductions in the entire septum, as well as anterolateral segments. This supports the notion that HD might be associated with a distinct cardiomyopathy, reflecting several remodelling signals, some of which are independent of pressure or volume, including recurrent HD ischemic insults [24, 30]. We observed significant correlations of PSS to LV dyssynchrony, concentric remodelling, aortic distensibility, aortic stiffness and high sensitivity troponin-T.
Diastolic function
The determinants of diastolic function in HD patients are not well described, despite an increasing appreciation of the prognostic importance of this form of ventricular relaxation defect. Using speckle tracking echocardiography, De Bie and co-workers reported univariate determinants as LV mass, concentric remodelling and PWV [31]. Losi and co-workers found a significant relationship of diastolic dysfunction in HD patients to echocardiographic-integrated backscatter (as a surrogate for myocardial fibrosis) [32]. We additionally report significant relationships to LV dyssynchrony and age.
Synchronicity and coherence of ventricular contraction
Synchronous contraction of the LV is essential to efficient cardiac output. LV dyssynchrony by tagged CMR has not previously been described in HD patients; in other settings, good reproducibility, preload independence and the ability to predict benefit from resynchronisation therapies have been demonstrated [18, 33]. El Ghannudi and co-workers reported SD-TTP of 28.5 ± 11.5 ms in control subjects and 91.3 ± 25 ms in patients with EF < 55 % due to ischemic or dilated cardiomyopathy. This compares with 39 ± 14 ms in control subjects and 56 ± 21 ms in HD patients in the present study. LV dyssynchrony was positively correlated to PSS and inversely correlated to diastolic function by PDSR (r = -0.51, p < 0.001) and EF (-0.45, p = 0.001). This study is the first to link LV dyssynchrony and diastolic dysfunction in HD patients.
Aortic distensibility
Aortic distensibility was reduced in HD patients and this pattern persisted in the subgroup of HD patients with preserved EF or without diabetes. Reported values are consistent with prior studies [34]. In the present study, the strong correlation of aortic distensibility to troponin-T (r = -0.53, p = 0.004) is novel. Troponin-T reflects the presence and severity of HD-induced ischemia [35], and is potentially aggravated by the increased risk of demand ischemia resulting from reduced aortic distensibility causing reduced diastolic coronary blood flow [36]. Given that we examined an incident population which had been exposed to HD for a mean of 98 days, it is likely that the changes we saw in HD patients occurred, at least in part, prior to commencing HD. Edwards et al. compared aortic distensibility by CMR in patients with CKD stage 3 to normal controls [37]. They derived similar values to the present study (2.2 ± 1.8 in CKD vs. 4.1 ± 1.3 mmHg−1 × 10−3 in controls) compared with 2.0 [1.3, 3.1] vs. 4.1 [3.1, 6.2] in the present study).
Volume status
Biomarkers of volume status (ECW/TBW, LV end-diastolic volume index and NT-pro-BNP) showed no significant correlations to systolic strain, diastolic strain rate, LV dyssynchrony or aortic distensibility. This might indirectly represent volume-independent influences on cardiac function in HD patients.
Limitations
Although we have examined associations, the cross-sectional design limits our ability to determine any causal relationships. In particular, a longitudinal study design would be a better design to assess the impact of HD on the natural history of cardiomyopathy. Circumferential strain is reported, but the lack of longitudinal strain is a limitation. Furthermore, we did not have a CKD or treated hypertension control group and, thus, cannot determine the extent of their relative contributions to the observed between group differences. This could be addressed by a longitudinal study design from early-stage CKD through to HD, but as most patients with CKD do not progress to end-stage kidney disease [38], such a study would be prohibitively large. An alternative longitudinal studies amongst matched groups with hypertension, CKD and incident HD. Such a study might still have residual confounding that might not entirely be removed by statistical methods.