Introduction
Heart failure (HF) with preserved ejection fraction (HFpEF), defined as a state of diastolic dysfunction and myocardial stiffness with a left ventricular ejection fraction (LVEF) exceeding 50%, is a complex clinical condition and is the most prominent form of HF among the elderly [
1]. Despite the substantial increase in HFpEF at a rate of 1% a year, there is a critical paucity of rational therapeutic interventions, suggesting that the increasing burden for HF/HFpEF will likely continue to increase globally [
1,
2]. This lack of progress may be because HF/HFpEF is heterogeneous, and existing preclinical animal models may not fully capture the complexity of the cellular remodeling processes involved in HF [
2]. Therefore, there is an unmet clinical need to improve our current understanding of the underlying mechanisms of HF.
There is increasing evidence in the extant literature that HF/HFpEF mortality in patients occurs in 53% to 74% of all HFpEF cases in the first 5 years of diagnosis [
1]. Randomized clinical trials of HFpEF patients have shown an increased risk of sudden cardiac death (SCD) in patients [
3]. However, the underlying mechanisms involved are unknown. The major drivers of SCD are known to be lethal cardiac arrhythmias. While ventricular arrhythmias (VAs) are the most common cause of SCD in HF with reduced ejection fraction (HFrEF), their role and incidence in HFpEF need further investigation [
4]. Ventricular arrhythmias predispose HF patients to an increased number of hospitalizations, in-hospital cardiac arrest, and overall higher rates of morbidity [
5]. Clinical studies, despite involving a relatively small patient population, have observed a high prevalence of non-sustained ventricular tachycardia (NSVT) in HFpEF patients [
6,
7], accompanied by a probability of SCD that is 2.3 times higher [
6]. Although the concurrent occurrence of VA fails to surpass that of HFrEF in a pooled analysis of large clinical HFpEF trials, its presence remains significantly linked to poor overall prognosis and higher overall mortality rates [
8].
The putative mechanisms governing the development of VA in HFpEF include deteriorated conduction velocity and re-entry circuits stemming from hypertrophic and fibrotic ventricles, delayed repolarization, and altered excitation–contraction coupling [
9]. Major cardiac currents play pivotal roles in maintaining the integrity of the electrical activity of the heart. This electrical activity can be defined by the spatiotemporal patterns of action potential phenotypes, as well as cardiac refractoriness [
10].
Ion channel dysfunction remains one of the crucial factors in VT initiation. The normal ventricular cardiac action potential (AP) is defined as follows: Phase 0, due to a large inward sodium current (
INa), followed by currents due to voltage-gated L-type calcium (Ca) (
ICa,L) and the Na-Ca exchanger (
INCX) channels [
11]. Repolarization is controlled by the delayed rectifier current (
IK), which comprises rapid (
IKr) and slow (
IKs) components. The resting membrane potential is controlled by the inward rectifier
K current (
IK1) [
12]. Thus, decreases in outward currents [
13,
14] or increases in depolarizing mechanisms [
15] delay repolarization, resulting in the prolongation of the heart-rate-corrected QT interval (QT
c), which predisposes patients to fatal VT, such as torsades de pointes (TdP) [
16] and SCD [
17,
18].
IKr remains the dominant channel of clinical cardiotoxicity; the FDA and European Medicines Agency require screening against human ether-a-go-go-related gene (hERG) for all new drugs being evaluated [
19,
20]. Therefore, decreases in
IKr prolong the ventricular action potential duration (APD) [
14,
21,
22,
23] and predispose patients to an elevated risk for early afterdepolarizations (EADs) [
24,
25], a prolonged QT
c interval, and TdP [
26]. In addition, impaired function of
IKs,
INa (peak and late), and
ICa currents contributes to arrhythmia risk [
27,
28,
29,
30], highlighting the importance of multi-ion-channel analyses, which may inform the rational development of safer approaches (with reduced cardiotoxic effects) to antiarrhythmic monotherapy and polytherapy for patients.
Growing evidence suggests that obesity and associated pathologies (metabolic syndrome and insulin resistance) are important contributors to the development of HFpEF in patients [
31]. Furthermore, 24.3% of obese patients have a prolonged QT
c interval compared with patients with normal weight [
32,
33]. Preclinical studies have shown that the downregulation of K currents and delayed repolarization have imperative roles in the increased susceptibility to VA and, subsequently, SCD in rats fed with a high-salt diet who developed HFpEF [
34,
35]. In that regard, pathological changes in ionic currents or channelopathies may prominently contribute to an increased risk of VA/SCD in obese/HFpEF patients. Therefore, it would be interesting to discern the impact of a functional interplay between obesity triggers and pathological ion channel functional expression (Figure), as well as how they affect disease outcomes in patients. In this regard, an improved understanding of the cellular proarrhythmic mechanisms of remodeled ion channels may be a key component for the rational development of safer and more effective interventions in obese patients with HF and, particularly, HFpEF.
Obesity moderates diastolic dysfunction by triggering core pathophysiological factors of HFpEF, such as oxidative stress and inflammation [
36,
37]. Obesity and metabolic syndrome bring about a state of metabolic inflammation where damaged hypertrophic, hyperplastic, and hypoxic adipocytes provoke the accentuated production and release of inflammatory cytokines and adipokines and promote macrophage polarization towards the M1 pro-inflammatory phenotype [
36,
37]. It should be noted that although increased levels of cytokines may be initially cardioprotective, they become detrimental as inflammation persists [
36].
Obesity has been related to VA development through heightened levels of free fatty acids (FFAs), inducing dysregulation in ventricular repolarization and resulting in a prolonged Q-T interval [
38]. Guinea pig models fed with a high-fat diet (HFD) serve as an inflammatory preclinical model and have shown increased susceptibility to VA [
39]. HFD-fed preclinical models have been extensively used to study the effects of obesity on ion channels and currents. Dysregulations in Na, Ca, and K currents in the context of obesity and high FFAs have been linked to altered cardiac excitability, long QT intervals, and VA, particularly in response to an enhanced sympathetic trigger, in mice and guinea pigs [
39,
40,
41]. Moreover, epicardial adipose tissue (EAT) has recently been identified as a possible promoter of VA in addition to its already established involvement in atrial arrhythmias [
42]. Although advances have been made in identifying obesity-related VA-inducing factors, much remains to be discovered regarding the precise mechanism of how major cardiac ion channels are modulated in metabolically disrupted HFpEF. A thorough comprehension of pathways binding obesity with HFpEF and VA is crucial for filling the gap in these patients, and this will have clinical and pharmaceutical implications. This review aims to provide an overview of factors linking HFpEF, obesity, and ventricular arrhythmias by exploring the underlying mechanisms of disturbances in electrical currents and channelopathies (
Table 1). Lastly, we further summarize the role of ventricular assistance devices in HFpEF.
For the purpose of this review, search engines that included the PubMed Central and Google Scholar databases were used to search for studies published in the English language. Our searches were not limited by date restrictions, were free texts, and included the following keywords: “heart failure”, “heart failure with preserved ejection fraction”, “diastolic dysfunction”, “sudden cardiac death”, “obesity”, “lipid mediators”, “leukotrienes”, “ventricular arrhythmias”, “dyslipidemia”, “cardiac calcium channel”, “cardiac potassium channel”, “cardiac sodium channel”, “Ca handling proteins”, “SERCA2a”, “RyR2”, “phospholamban”, “pro-inflammatory cytokines”, “interleukin signaling”, “leukotrienes B4 signaling”, “cBIN1”, and “LVAD”.
Mechanical Circulatory Support Devices in Hfpef
Despite the advances in precision medicine and the early diagnosis and treatment of heart failure, many patients proceed to the late stages, where mechanical support is needed, and this is more pronounced in patients with HFpEF [
217,
218]. Left ventricular assistance devices (LVAD) were initially proposed as a bridging therapy for patients waiting for cardiac transplantation, but after the success of the landmark REMATCH trial, LVADs became FDA-approved as a definite therapy in patients with severe heart failure [
217,
219]. Currently, LVADs are viable therapeutic options in HFrEF patients, and most studies evaluating LVADs are in the HFrEF population.
Surprisingly, the prevalence of VA in patients undergoing LVAD surgery, particularly in the first month after the implantation of a device, is considerable and increases early mortality rates significantly [
220]. The probable mechanism behind the incidence of VA is the alterations caused by the mechanical unloading of the left ventricle [
221]. Ito et al. performed a heterotopic cardiac transplantation to the abdominal aorta in preclinical rat models to assess the impact of severe unloading on cardiac muscle function [
221]. The results indicated that the contractile reserve and strength were significantly reduced after 5 weeks post-unloading, and this was accompanied by a significant delay in Ca transient decay [
221]. Western blot analysis further demonstrated that the prolonged Ca transient decay was likely due to elevated PLB and reduced SERCA2a concentrations [
221], underscoring the role of SR Ca release in post-LVAD cardiac function. Agreeing with this are the results from confocal microscopy of paced human cardiomyocytes from patients undergoing LVAD implantation or heart transplantation despite previous LVAD surgery, which showed an increased number of Ca sparks at the time of the device’s implantation and heart transplant, both of which were well inhibited through the administration of AIP [
222]. Intriguingly, cardiomyocytes derived from patients undergoing heart transplants exhibited a more pronounced diastolic Ca release [
222]. These findings indicate that not only is SR Ca release of significant importance in cardiac function, but marked dysregulations of this mechanism are seen after LVAD transplants [
222].
Given the crucial role of Ca handling in EC coupling and pro-arrhythmogenic changes in the heart, the mentioned changes may be the reason behind the prevalence of VA after LVADs. Additionally, an increase in NCX function and a reduction in Kv4.3
Ito channels have also been reported in a subgroup of patients with LVAD and VA [
223]. However, contradicting data exist regarding this matter, with studies reporting reduced RyR2 activity [
224], increased SR Ca storage [
225], and a slight decrease in NCX proteins [
226] after LVAD implantation. Terracciano et al. demonstrated that while elevated SR Ca storage and reduced AP duration were evident in patients who recovered after concomitant LVAD implantation and medical therapies (as demonstrated by improved echocardiographic parameters), no such effect was seen in patients that did not recover after this dual-treatment approach [
227,
228]. Moreover, patients with no recovery after LVAD implantation exhibited a longer baseline QRS duration [
229]. Pre-LVAD QRS durations have also shown good predictive accuracy for post-LVAD recovery [
229]. Thus, it is also crucial to determine factors that can be used as predictive biomarkers of future VA in patients receiving LVADs.
Nevertheless, patients with HFpEF do not benefit much from LVADs in comparison with HFrEF patients [
230]. Patients with concentric heart failure, which is common in HFpEF, do not demonstrate the same outcome with LVADs due to their reduced left ventricular volume [
218]. Furthermore, LVAD implantation showed an increased susceptibility to right heart failure, as demonstrated by right atrial pressure, in patients with restricted and hypertrophic cardiomyopathies [
231]. In addition to structural changes in the heart in HFpEF, the accompanying metabolic conditions may also be the reason for LVADs not being a suitable option in HFpEF. It has been reported that obese patients undergoing LVAD surgery demonstrate dysregulation in their immune system and are more prone to post-LVAD infections [
232,
233]. Additionally, investigation of adipose tissue using an image segmentation technique for pre-LVAD computed tomography (CT) images showed that adipose tissue is strongly and positively correlated with higher mortality rates and increased incidence of infections [
234]. Likewise, a higher baseline hemoglobin A1c (HbA1c) level, a biomarker of the severity of hyperglycemia, is associated with elevated incidence of post-LVAD adverse events, including infections, cerebral hemorrhages, and thrombosis [
235].
Since the left atrium is enlarged in most cases of HFpEF, left atrial decompression may pose a potent solution for providing more efficient blood flow [
218,
236]. In vitro, prototypes of left atrial assistance devices (LAADs) have been positioned at the mitral valve for HFpEF patients [
237,
238]. With the LAAD pumping blood from the left atrium to the left ventricle, a decline in aortic pressure and an increase in cardiac output were observed, without adverse effects on the left ventricular pressure [
237,
238]. However, it is important to investigate whether left atrial unloading leads to cardiac arrhythmias as well. Still, much remains unknown about the use of LAADs in HFpEF and whether they can modulate ion channels to decrease VA in these patients.
Conclusions and Future Directions
In conclusion, since the prevalence of HFpEF is increasing, and the development of an effective treatment approach remains elusive, particular attention to this disease is warranted. Sudden cardiac death through VA poses a significant threat to HFpEF patients. An obesity-linked HFpEF phenotype is particularly common, with obesity not only being a comorbidity but also a significant risk factor for HFpEF; consequently, this prompts an examination of how obesity and metabolic inflammation may exacerbate the underlying pathophysiology of VA. Given the evident role of metabolic inflammation in HFpEF, exploring ion channel modulations in this context may provide novel insights into potential treatment approaches.
This study focuses on how cardiac ion channels and currents are influenced during lipotoxicity, inflammation, and HFpEF. It is postulated that identifying the specific currents and channels that are dysregulated in HFpEF paves the way for therapeutic advances in this field. This hypothesis is further supported by the inhibition of late
INa current by empagliflozin, AIP, and vericiguat, as well as the inhibition of NCX by ranolazine, in HFpEF [
57,
59,
116]. The data are, however, still limited in this regard. It would be beneficial to investigate the utilization of these medications in animal models that more accurately mimic the expression of ion channels in humans. As we have discussed, mice differ from humans in most K currents, including
IKr [
127]. This proposition is highlighted by pharmaceutical guidelines deeming hERG cardiotoxicity screening to be essential for new drugs [
239].
Moreover, it is crucial to investigate cardiac currents and channels in the context of metabolic inflammation, leading to our discussion on IL-6 and LTB4. As demonstrated in this study, LTB4 is involved in insulin resistance, a phenomenon that is crucial in the formation of diabetes, which may also drive arrhythmogenic changes in diabetic patients and eventually lead to HF. Diabetes and obesity compose an inflammatory state leading to heightened secretion of cytokines such as IL-6 and eventually the formation of HFpEF. Thus, it could be intriguing to know the following: (1) how LTB4 and IL-6 trans-signaling would affect cardiomyocytes and cardiac channels; (2) if the administration of an LTB4 inhibitor would reverse cardiac remodeling in obese and diabetic patients; (3) the differential expression of LTB4 and IL-6 in various adipose tissues and macrophages; (4) whether LTB4 could potentially influence myocardial fibrosis and instigate reentry circuits and fatal arrhythmias.
To advance our comprehension of these molecular mechanisms, there is an urgent need for preclinical models that can bridge existing gaps in the extant literature. If successful, these studies have the potential to make HFpEF more manageable for both clinicians and patients dealing with this condition.
Table 1.
Altered functional expression of ion channels in HFpEF and/or obese animal models.
Table 1.
Altered functional expression of ion channels in HFpEF and/or obese animal models.
Current |
Gene |
mRNA |
Protein |
Current Density |
Animal Model |
HFpEF/Obese |
Cardiac Tissue |
QTC
|
Drug Tx (effect) |
Ref. |
late INa
|
SCN5A |
NR |
NR |
↑ |
Mouse (C57BL/6J) |
+/+ |
Ventricle |
NR |
Pre-incubation with Empagliflozin (↓ current density) |
[57] |
|
|
NR |
NR |
↔ |
Rat (SD) |
-/+ |
Ventricle |
↔ (↑QRS) |
NR |
[79] |
|
|
NR |
NR |
↑ (male˃ female) |
Mouse (db/db+Aldo) |
+/+ |
Ventricle |
NR |
Empagliflozin (↓ APD prolongation, male + female) AIP (↓ APD prolongation, male + female) Vericiguat (↓ APD prolongation, only female) |
[116] |
Peak INa
|
SCN5A |
NR |
NR |
↔ |
Rat (SD) |
-/+ |
Ventricle |
↔ (↑QRS) |
NR |
[79] |
|
|
↔ |
NR |
↑* |
Rat (WR) |
-/+ |
Ventricle |
NR |
NR |
[106] |
ICa,L |
CACNA1c |
↔ |
↑ |
↑ |
Rat (Dahl/SS) |
+/- |
Ventricle |
NR |
NR |
[86] |
|
|
↑ |
NR |
↑* |
Rat (WR) |
-/+ |
Ventricle |
NR |
NR |
[106] |
|
|
NR |
↔ |
↑ |
Rat (WR) |
+/- |
Ventricle |
|
NR |
[88] |
|
|
NR |
NR |
↑ |
Rat (HHR) |
+/- |
Ventricle |
↔ (↑QRS) |
NR |
[98] |
|
|
NR |
↔ |
NR |
Rat (WR) |
-/+ |
Ventricle |
NR |
NR |
[99] |
|
|
↓ |
NR |
NR |
Rat (WR, 15 weeks) |
-/+ |
Ventricle |
NR |
NR |
[102] |
|
|
↑ |
NR |
NR |
Rat (WR, 30 weeks) |
-/+ |
Ventricle |
NR |
NR |
[102] |
|
|
↔ |
NR |
NR |
Rat (WR, 45 weeks) |
-/+ |
Ventricle |
NR |
NR |
[102] |
|
|
NR |
↔ |
NR |
Rat (WR) |
-/+ |
Ventricle |
NR |
NR |
[105] |
|
|
NR |
↔ |
NR |
Mouse (db/db) |
+/- |
Ventricle |
NR |
cBIN1 |
[213] |
|
|
↔ |
NR |
↑ |
Rat (Dahl/SS) |
+/- |
Ventricle |
↑ |
NR |
[34] |
|
|
NR |
NR |
↓ (only male) |
Mouse (db/db+Aldo) |
+/+ |
Ventricle |
NR |
Empagliflozin (↓ APD prolongation, male + female) AIP (↓ APD prolongation, male + female) Vericiguat (↓ APD prolongation, only female) |
[116] |
Ito |
KCND2/3, KCNA4 |
NR |
NR |
↔ |
Rat (WR) |
+/- |
Ventricle |
NR |
NR |
[87] |
|
|
↔ |
NR |
↑* |
Rat (WR) |
-/+ |
Ventricle |
NR |
NR |
[106] |
|
|
NR |
NR |
↓ (male + female) |
Mouse (db/db+Aldo) |
+/+ |
Ventricle |
NR |
Empagliflozin (↓ APD prolongation, male + female) AIP (↓ APD prolongation, male + female) Vericiguat (↓ APD prolongation, only female) |
[116] |
|
|
NR |
NR |
↑ |
Mouse (C57BL6) |
-/+ |
Ventricle |
NR |
NR |
[126] |
|
KCND2 |
↔ |
↔ |
↓ |
Rat (Dahl/SS) |
+/- |
Ventricle |
↑ |
NR |
[34] |
|
KCND3 |
↓ |
↓ |
↓ |
Rat (Dahl/SS) |
+/- |
Ventricle |
↑ |
NR |
[34] |
|
KCNA4 |
↔ |
↔ |
↓ |
Rat (Dahl/SS) |
+/- |
Ventricle |
↑ |
NR |
[34] |
IKr
|
hERG |
↔ |
↔ |
↓ |
Rat (Dahl/SS) |
+/- |
Ventricle |
↑ |
NR |
[34] |
|
|
↓ |
NR |
NR |
Rat (WR) |
-/+ |
Ventricle |
NR |
NR |
[106] |
|
|
NR |
↓ |
↓ |
Guinea pig (HFD) |
-/+ |
Ventricle |
↑ |
NR |
[39] |
IKs |
KCNQ1, KCNE1 |
↓ |
NR |
↓ |
Guinea pig (HFD) |
-/+ |
Ventricle |
↑ |
NR |
[39] |
IK1 |
KCNJ12/14/4 |
↔ |
NR |
↓ |
Rat (WR) |
+/- |
Ventricle |
NR |
NR |
[87] |
|
|
↔ |
↔ |
NR |
Rat (Dahl/SS) |
+/- |
Ventricle |
↑ |
NR |
[34] |
|
|
↑ |
NR |
↑* |
Rat (WR) |
-/+ |
Ventricle |
NR |
NR |
[106] |
|
|
NR |
NR |
↓ (male + female) |
Mouse (db/db+Aldo) |
+/+ |
Ventricle |
NR |
Empagliflozin (↓ APD prolongation, male + female) AIP (↓ APD prolongation, male + female) Vericiguat (↓ APD prolongation, only female) |
[116] |
Table 2.
Altered functional expression of cardiac Ca-handling proteins in HFpEF and/or obese animal models.
Table 2.
Altered functional expression of cardiac Ca-handling proteins in HFpEF and/or obese animal models.
Ca handling protein |
mRNA |
Protein |
Animal Model |
HFpEF/Obese |
Cardiac Tissue |
Drug Tx (effect) |
Ref. |
SERCA2a |
↑ |
NR |
Rat (WR) |
-/+ |
Ventricle |
NR |
[106] |
|
↓ |
↓ |
Rat (Dahl/SS) |
+/- |
Ventricle |
Intraperitoneal Ranolazine (↑ expression) |
[59] |
|
NR |
↔ |
Rat (WR) |
+/- |
Ventricle |
NR |
[87] |
|
NR |
↓ |
Rat (WR) |
+/- |
Ventricle |
NR |
[88] |
|
NR |
↓ |
Rat (HHR) |
+/- |
Ventricle |
NR |
[98] |
|
NR |
↔ |
Rat (WR) |
-/+ |
Ventricle |
NR |
[99] |
|
↓ |
NR |
Rat (WR, 15 weeks) |
-/+ |
Ventricle |
NR |
[102] |
|
↑ |
NR |
Rat (WR, 30 weeks) |
-/+ |
Ventricle |
NR |
[102] |
|
↓ |
NR |
Rat (WR, 45 weeks) |
-/+ |
Ventricle |
NR |
[102] |
|
NR |
↔ |
Rat (WR) |
-/+ |
Ventricle |
NR |
[105] |
|
↑ |
NR |
Rat (WR) |
-/+ |
Ventricle |
NR |
[101] |
|
NR |
↔ |
Rat (ZSF1) |
+/+ |
Ventricle |
NR |
[100] |
|
NR |
↔ |
Mouse (C57BL/6J) |
*+/+ |
NR |
NR |
[104] |
|
NR |
↓ |
Mouse (db/db) |
+/- |
Ventricle |
cBIN1 (↑expression) |
[213] |
|
NR |
↓ |
Rat (Dahl/SS) |
+/- |
Ventricle |
NR |
[90] |
|
NR |
↓ |
Rat (ZSF1) |
+/+ |
Ventricle |
NR |
[90] |
RyR2 |
↑ |
NR |
Rat (WR) |
-/+ |
Ventricle |
NR |
[106] |
|
NR |
↔ |
Rat (WR) |
+/- |
Ventricle |
NR |
[87] |
|
NR |
NR |
Rat (SD) |
+/- |
Ventricle |
Dantrolene (↑RyR2 inhibition) |
[89] |
|
↔ |
NR |
Rat (WR, 15 weeks) |
-/+ |
Ventricle |
NR |
[102] |
|
↑ |
NR |
Rat (WR, 30 weeks) |
-/+ |
Ventricle |
NR |
[102] |
|
↔ |
NR |
Rat (WR, 45 weeks) |
-/+ |
Ventricle |
NR |
[102] |
|
↑ |
NR |
Rat (WR) |
-/+ |
Ventricle |
NR |
[101] |
|
NR |
↔ |
Mouse (db/db) |
+/- |
Ventricle |
cBIN1 |
[213] |
|
|
|
|
|
|
|
|
NCX |
↑ |
NR |
Rat (WR) |
-/+ |
Ventricle |
NR |
[106] |
|
↑ |
↑ |
Rat (Dahl/SS) |
+/- |
Ventricle |
Intraperitoneal Ranolazine (↓ expression) |
[59] |
|
NR |
↔ |
Rat (WR) |
+/- |
Ventricle |
NR |
[87] |
|
NR |
↔ |
Rat (WR) |
+/- |
Ventricle |
NR |
[88] |
|
|
↔ |
Rat (WR) |
+/- |
|
|
[98] |
|
↓ |
|
Rat (WR, 15 weeks) |
-/+ |
Ventricle |
NR |
[102] |
|
↑ |
NR |
Rat (WR, 30 weeks) |
-/+ |
Ventricle |
NR |
[102] |
|
↓ |
NR |
Rat (WR, 45 weeks) |
-/+ |
Ventricle |
NR |
[102] |
|
NR |
↔ |
Rat (Dahl/SS) |
+/- |
Ventricle |
NR |
[90] |
|
NR |
↓ |
Rat (ZSF1) |
+/+ |
Ventricle |
NR |
[90] |
PLB |
NR |
↔ |
Rat (WR) |
+/- |
Ventricle |
NR |
[87] |
|
NR |
↔ |
Rat (WR) |
+/- |
Ventricle |
NR |
[88] |
|
NR |
↓ |
Rat (HHR) |
+/- |
Ventricle |
NR |
[98] |
|
NR |
↔ |
Rat (WR) |
-/+ |
Ventricle |
NR |
[99] |
|
↓ |
NR |
Rat (WR, 15 weeks) |
-/+ |
Ventricle |
NR |
[102] |
|
↑ |
NR |
Rat (WR, 30 weeks) |
-/+ |
Ventricle |
NR |
[102] |
|
↔ |
NR |
Rat (WR, 45 weeks) |
-/+ |
Ventricle |
NR |
[102] |
|
NR |
↓ |
Rat (WR) |
-/+ |
Ventricle |
NR |
[105] |
|
↑ |
NR |
Rat (WR) |
-/+ |
Ventricle |
NR |
[101] |
|
NR |
↑ |
Rat (ZSF1) |
+/+ |
Ventricle |
NR |
[100] |
|
NR |
↔ |
Rat (Dahl/SS) |
+/- |
Ventricle |
NR |
[90] |
|
NR |
↔ |
Rat (ZSF1) |
+/+ |
Ventricle |
NR |
[90] |