The association of secondary hyperparathyroidism and myocardial damages in hemodialysis end-stage renal disease patients: assessed by cardiovascular magnetic resonance native T1 mapping

Secondary hyperparathyroidism is a common complication of end-stage renal disease (ESRD) with maintenance hemodialysis, which begins in the earlier stages of chronic renal insufficiency and is shown to be deteriorated with declining renal function. Hyperphosphatemia, hypocalcemia, decreased calcium, and vitamin D receptor expression, 1,25-dihydroxyvitamin D3 deficiency, and parathyroid hormone (PTH) resistance may partly play a role in the secondary hyperparathyroidism pathogenesis [1]. Previous studies have indicated that hyperparathyroid disorders, including primary and secondary hyperparathyroidism, are risk factors for cardiovascular morbidity and mortality [2, 3]. Hagström et al. demonstrated that high PTH levels can predict nonischemic heart failure (HF), and higher plasma parathyroid levels were significantly correlated with the advanced New York Heart Association (NYHA) level [5]. Meanwhile, plasma PTH level may have a positive value in the diagnostic criteria of HF [6, 7]. Several mechanisms may contribute to HF in high PTH circumstances, such as specific vascular endothelial dysfunction promotion and atherosclerosis-induced cardiac ischemia, or direct detrimental myocardial effects such as myocyte hypertrophy and fibrosis [5]. Some prior studies have deduced the association between elevated PTH levels and myocardial damage or even HF in patients with chronic renal insufficiency by investigating the B-type natriuretic peptide level, NYHA, myocardial infarction, or HF history, or in animal models. However, no direct evidence was acquired to prove a relationship between prolonged exposure to elevated PTH and myocardial damage measured by noninvasive imaging methods such as cardiovascular magnetic resonance (CMR). Myocardial edema, diffused myocardial fibrosis, and left ventricular (LV) deformation may be key pathogenesis of ESRD-related myocardiopathy [8‐12]. Thus, novel imaging biomarkers that can reliably and precisely measure pathological cardiac changes that are strongly linked to cardiac outcomes are needed. CMR late gadolinium enhancement (LGE) is a common imaging marker for evaluating myocardial fibrosis. However, gadolinium-based CMR contrast agents may cause complication of nephrogenic systemic fibrosis in patients with ESRD [13]. Hence, gadolinium is relative contraindicated for ESRD patients [14]. CMR native T1 mapping is a novel and non-contrast technique that can quantitatively measure myocardial fibrosis or myocardial edema [14], and myocardial strain by tissue tracking can reflect LV deformation, which may provide direct evaluation tools to assess the myocardial damage in ESRD patients. Therefore, this research was to explore cardiac involvement by examining CMR native T1 mapping and myocardial strain and further investigate the relationship between uremic myocardiopathy and PTH toxicity in ESRD hemodialysis patients.

As a worldwide public health problem due to its association with multiple comorbidities, CKD is highly associated with cardiovascular events, mortality, and high medical cost burden [19]. CKD morbidity ranged from 8 to 16% in the population [20]. Projections from the Global Health Observatory suggest that the CKD mortality rate will continue to increase from 12.2 to 14 deaths per 100,000 people by the year 2030 [21]. Although several studies on various populations have reported that low eGFR and high uremic toxicity factors are associated with cardiovascular diseases, cardiovascular mortality was still about twice higher in patients with stage 3 CKD and three times higher with stage 4 CKD. Additionally, the risk of HF is approximately doubled in patients with eGFR < 60 mL/min/1.73 m² [22‐24]. Cardiovascular mortality is estimated to be significantly higher in people with an eGFR < 60 mL/min/1.73 m² [22]. Cardiovascular risks cause most of the deaths in ESRD patients with severe renal deficiency. Multiple risk factors account for cardiovascular disease in CKD patients. In patients with severe CKD, besides the traditional risk factors such as hypertension, dyslipidemia, Na⁺ overload, Ca²⁺ and serum phosphorus abnormalities, and chronic inflammation, cardiovascular disease in CKD may also be driven by specific risk factors including anemia and malnutrition, hormonal imbalances, soft tissue calcification, erythropoietin resistance, renal replacement therapy (RRT)-related electrolyte imbalance, and high PTH level. In all the risk factors, secondary hyperparathyroidism has been linked with mineral bone disorders as well as increased cardiovascular mortality, which may be critical factors for uremic cardiomyopathy. PTH influences LV function in chronic hemodialysis patients, and plasma PTH reduction is beneficial to the uremic heart [25]. PTH lowering has been focused on as a treatment target for decades, and the effect of high PTH level on ESRD has been in research for a long time [26]. Most of the previous studies focused on the association of PTH and mineral bone disease; however, few studies have mentioned that secondary hyperparathyroidism may contribute to the cardiovascular complications of CKD. Van et al. found that higher PTH concentrations may be associated with the increased risk of cardiovascular events through a meta-analysis [27]. PTH may contribute to four major cardiovascular effects, including contractile disturbance, cardiomyocyte hypertrophy, and cardiac interstitial fibrotic and vasodilator effects. Although only the animal model by parathyroidectomy and invasive pathological examination demonstrated these correlations, very little detail and direct evidence about the inner connection of increased PTH and cardiac changes by noninvasive methods in CKD patients have been previously demonstrated.

In our study, iPTH levels in ESRD patients were much higher than the normal range. Ca²⁺ and serum phosphorus abnormalities were also found in the ESRD cohort. The iPTH of 32 patients was within the normal range by routine calcitriol and hemodynamic dialysis therapy. We found that LVEF was decreased, but still preserved in ESRD patients with either targeted iPTH or increased iPTH levels. Although no myocardial strain deterioration was detected in both ESRD cohorts, on normal iPTH, native T1 of the basal and middle segments in the LV were significantly increased. The global native T1 in subjects with both targeted and increased iPTH was higher than that in normal subjects, which may lead to the assumption that myocardial tissue deterioration happens prior to myocardial deformation. Previous studies have reported LV mechanical dyssynchrony and microvascular dysfunction detected by single-photon emission computed tomography (SPECT), and regadenoson SPECT myocardial perfusion imaging also provided a significant prognostic value in ESRD patients [28‐31]. However, SPECT, especially regadenoson SPECT, has some limitations due to the utilization of vasodilators and contrast in ESRD patients with reduced clearance and longer exposure to the drug and contrast [32]. For the CMR technique, some studies have shown that native T1 assessed by CMR acquires samples from the longitudinal magnetization perturbation and extracts the real myocardial T1 without gadolinium contrast [33, 34]. Thus, native T1 mapping is currently explored as a relatively precise diagnostic modality in a wide range of heart diseases, including diffuse myocardial tissue lesions, such as ESRD patients [33]. Conversely, gadolinium increases the risk of nephrogenic systemic fibrosis making non-contrast native T1 mapping more suitable for CKD patients. Increased native T1 account for a few characterizing tissues, such as edema, inflammation, and fibrosis, affecting the interstitial space [35]. Many studies have demonstrated that native T1 has shown an important prognostic significance in discriminating disease, especially in those with diffuse myocardial damage [36]. Thus, compared with SPECT, native T1 may provide more information, for instance edema, inflammation, or fibrosis, besides the myocardial blood flow, and non-utilization of contrast is safer for ESRD patients.

CKD contributing to decreased cardiac function, cardiac hypertrophy, and increased risk of adverse cardiovascular events is referred to as chronic renocardiac syndrome. Diffuse interstitial edema, inflammation, and fibrosis always occur in CKD patients, which can manifest as increased native myocardial T1 times [37]. We found that native T1 values were higher in patients with targeted and increased iPTH, and increased iPTH values seem more serious. Interestingly, native T1 mapping detecting myocardial damage was significantly associated with and demonstrated to be significant correlates of iPTH in this study, indicating that myocardial damage does exist in ESRD patients. Moreover, secondary hyperparathyroidism may indeed contribute to uremic myocardial changes. This result was consistent with the previous results of animal experiments on the increased PTH-induced cardiac fibrosis [38, 39]. Additionally, 40 patients presented with persistently high iPTH levels, revealing that treatment with conventional hemodialysis and medications seems limited. Meanwhile, the severity of secondary hyperparathyroidism increases with the decline in renal function. iPTH levels > 50 pg/mL in patients with CKD stages 3 and 4 are associated with an escalating combined risk of death or RRT [40]. In ESRD patients with targeted iPTH, native T1 is also increased. Thus, early and dynamic detection of myocardial damage by noninvasive imaging tools and early treatment of secondary hyperparathyroidism are particularly important.

Myocardial damage was found to be increased in ESRD patients with both normal and increased iPTH levels following conventional therapy. In addition, consistently high iPTH levels may be independently associated with myocardial damage in ESRD patients.