• 2019-07
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  • If the cell and the SR


    If the cell and the SR are overloaded with Ca2+ then abnormal Ca2+ transients (Fig. 4A) and spontaneous Ca2+ waves (Fig. 4B) are expected to appear [63]. A high occurrence of Ca2+ sparks, fueling SR Ca2+ leak and cytosolic Ca2+ overload, was an unexpected early signature in our model. Late SR Ca2+ leak, occurring after an initial slowing of Ca2+ transient decay, has been proposed to be a consequence rather than a cause of diastolic dysfunction in a rat model of chronic kidney disease (CKD) with HFpEF [60]. Post-translational modifications of RyR2, such as nitrosylation and CaMKII-dependent phosphorylation, can lead to SR Ca2+ leakage [58,73,74] but they were not detected here (Fig. 5). Increased cytosolic Ca2+, in addition to maintained luminal Ca2+, is expected to increase the likelihood of spontaneous release events. Ca2+ dependent blockade of the inward rectifier current IK1 resulting from the rise in diastolic Ca2+ may contribute to the occurrence of the abnormal cellular Ca2+ events [24,75,76]. Importantly, the Ca2+ leak identified here may not only provide a pro-arrhythmogenic substrate but could also be involved in the progression of HFpEF. Beneficial effects of enhanced SR Ca2+ uptake through PLN CORM-3 may be lost when associated with SR Ca2+ leak [67]. In addition, Ca2+ sensitive signaling factors involved in cardiac hypertrophy are known to respond to sustained changes in diastolic Ca2+ concentration [77]. The current study was constrained by a number of limitations. First, the replication of human HFpEF in animal models is difficult. However, there is a need for such investigations with an emerging interest for preclinical models including rodents [20,43,78,79] [80]. A recent review reported a set of clinical criteria helping to define animal models of HFpEF [20], that we applied to this work. Various models of HFpEF exist where both advantages and disadvantages are evident [43]. In particular, the models have different etiologies and temporal progression of the disease. For example, in the comparison of Ca2+ handling in different models including human, there are both similarities and disparities underlining complexity and multimodal adaptation to different insults [18,46,60,61,65]. As highlighted by Primessnig and collaborators, “findings should be interpreted in this context and need to be validated in HFpEF of different aetiology”. A second limitation related to the study is related to neurohormonal activation. This is generally considered a characteristic of systolic HF, but may also be involved in HFpEF [81,82]. There is extensive literature establishing that the renin–angiotensin–aldosterone system (RAAS) plays a role in inducing hypertrophy during pressure overload. Diminished blood pressure distal to the constriction transiently stimulates the secretion of renin to increase blood pressure shortly (3 days) after constriction [83]. Angiotensin receptor inhibition does not reverse the effects of banding, and removal of banding does reduce hypertrophy suggesting that angiotensin does not play a major role in causing pressure overload-induced hypertrophy or in maintaining such hypertrophy [84]. Whether RAAS activation and its extent due to the constriction itself and/or related to the progression of the pathology was involved in our experimental conditions was not investigated in the current study. Third, despite a trend, we found no statistical difference in the amplitude of caffeine-evoked Ca2+ transient content between Sham and AAB (Fig. 3K) using caffeine challenge. Indo-1, which we used here, is a high-affinity Ca2+ indicator of choice for qualitative comparisons and detection of changes in diastolic Ca2+. However, it may have some limitation for the detection of differences in peak Ca2+ between groups in the caffeine experiments. Moderate-affinity dyes, such as the fluo-4 analog fluo-5F, have been preferred by some authors for the detection of variations of cytosolic Ca2+ during caffeine challenge [27,29].