In the present study, we demonstrated a better diastolic cardiac function in response to a decrease in d[Ca] from 1.75 to 1.25 mmol/L in patients on PD. This result was independent of the serum calcium concentration, which did not change. The improvement of diastolic echocardiographic parameters may be related to a new set point of calcium myocardium homeostasis in these patients. We can speculate that improvement of left ventricular relaxation mediated by low d[Ca] might detain the development of heart failure in dialytic patients.
Sidney Ringer discovered in the 1880s that Ca is essential for the heart’s contraction, and many roles of Ca in the cell continue to astonish us. Maintaining serum Ca at physiological levels is especially important for several biological processes, including vascular tone, muscle contractility, and stimulus conduction activity in the nervous system. The myocardium uses Ca in a positive feedback loop to trigger contraction. Indeed, Ca is a crucial element in cardiac systolic and diastolic function [6] and hypercalcemia impairs especially myocardium relaxation [16]. Therefore, there might be a link between high Ca concentration, worse ventricular relaxation, DD, and the development of clinical manifestation of heart failure with preserved LVEF.
The prevalence of DD is becoming more frequent than systolic dysfunction [26]. According to a recent systematic review, DD affects approximately 36% of the population older than 60 years [27]. Importantly, not all patients with DD develop clinical heart failure. Diastolic heart failure occurs more often in heart failure with an LV ejection fraction of more than 50% [28]. DD is associated with a 3.53-fold higher risk of combined events of MACE and death and a 3.13-fold increased risk of death [26]. Patients with CKD have a high burden of cardiovascular risk factors closely related to accelerated atherosclerosis, left ventricular dilatation with hypertrophy, systolic dysfunction, and high left ventricular filling pressure [29]. In line with these findings, most of our patients were hypertensive and had LVH and, although EF was normal in 63.15%, DD was found in 78.9% of cases.
Pathophysiological changes that lead to DD have a deleterious impact on cardiac function. Hypertension, obesity, hypercholesterolemia, and diabetes are associated with systemic inflammation, myocardial oxidative stress, and coronary microvascular dysfunction, common risk factors for cardiovascular disease, contributing to myocardial stiffening and left ventricular DD [30]. As explained by Ogawa and Nitta [31], the central mechanism of left ventricular DD is LVH with myocardial interstitial fibrosis, which induces myocardial stiffness and impairs heart function during diastole. In patients with CKD, congestive heart failure is caused by LVH due to arterial hypertension and chronic anemia. Left ventricular DD causes an increase in left ventricular filling pressure, which may lead to pulmonary congestion. The severity of CKD is the most independent predictor of elevated left ventricular filling pressure and might be responsible for systolic and diastolic dysfunction in patients with CKD not on dialysis [32]. The prevalence and severity of LVH increase as the CKD progresses, according to Levin et al.[33]. Structural changes combined with anemia and hyperparathyroidism promote maladaptive LVH, leading to systolic and DD [34].
Echocardiography, a non-invasive technique, allows the assessment of multiple indices of diastolic function, with good concordance with invasive hemodynamic monitoring [29, 35]. However, no single echocardiographic parameter is considered sufficiently accurate and reproducible to establish the diagnosis of DD [36]. DD is difficult to characterize, and refers to abnormal mechanical properties of the myocardium, including abnormal LV diastolic distensibility, impaired filling, and slow or delayed relaxation, regardless of whether the EF is normal or depressed and regardless the presence of symptoms [37]. Since DD implies that the myofibrils do not rapidly or entirely return to their resting length, the ventricle cannot accept blood at low pressures [34]. In this situation, the ventricular filling is slow or inadequate unless there is an increase in the atrial pressure [38]. Consequently, there is an increased dependence on filling through the atrial contraction and higher atrial pressures to maintain filling or cardiac output [38]. These parameters were improved in our patients after a reduction in the d[Ca], suggesting that lower d[Ca] improved diastolic function in patients on PD. During diastole, the left ventricle, the left atrium, and the pulmonary veins form a common chamber continuous with the pulmonary capillary bed [39]. In late diastole, the ventricle is most compliant and easily distensible, offering minimal resistance to ventricular filling over a normal volume range [39]. The active phase is myocyte dependent and relies on the rapid decline in [Ca2+] at the beginning of diastole, leading to dissociation of the thick and thin filaments. In the subsequent passive phases of diastole, the pressure gradient distends the ventricle [40].
The importance of d[Ca] in patients on dialysis and its correlation with cardiac function has been gaining ground in recent years. Most studies, however, included patients on hemodialysis. Usually, patients on PD dialyze against high d[Ca], 1.75mmol/L [6, 38, 39]. The influence of d[Ca] in cardiovascular risk as well as in systolic and diastolic function in patients on PD has been demonstrated. Liang et al. have shown that low d[Ca] is associated with a reduced number of newly occurring cardiovascular events [40]. Wang et al. have suggested that d[Ca] was associated with a better cardiac function [41]. Standard 1.75 mmol/L D[Ca] impaired left ventricular cardiac function in patients on PD [18]. Kim et al. have also found that low d[Ca] improved arterial stiffness parameters in patients on PD [42]. Whether long-term low d[Ca] could improve cardiac function has not been fully addressed. Tuncer et al. have shown an improvement of LV relaxation by reducing d[Ca] from 1.75 mmol/L to 1.25 mmol/L for only a month in patients on continuous ambulatory PD [18].
Our results need to be interpreted considering some limitations: it was a single-center study that included a small number of patients, with a short follow-up. Although the precise prevalence rate of diastolic heart failure in PD patients is unknown, a higher prevalence of left ventricular diastolic heart failure in patients with CKD than in the general population is expected in light of the occurrence of inflammation, fluid overload, hypertension, renin-angiotensin-aldosterone system activation, and LVH [43]. Strengths of our study rely upon having included patients on automatic PD, the most applied technique nowadays, echocardiography was performed by the same expert observer, and the same researcher followed all patients during the study.