Heart Vessels DOI 10.1007/s00380-014-0521-8

ORIGINAL ARTICLE

The protective effect of heat shock protein 70 (Hsp70) in atrial fibrillation in various cardiomyopathy conditions Too Jae Min • Won-Min Jo • Seung Yong Shin Hong Euy Lim



Received: 1 October 2013 / Accepted: 1 May 2014 Ó Springer Japan 2014

Abstract Heat shock proteins (Hsp) protect myocardial cells from acute stress such as atrial fibrillation (AF) and also from the chronic stress. It is not understood that Hsp70 can prevent AF under cardiomyopathy (CM) conditions. Therefore, we hypothesized that Hsp70 might beneficially influence on the occurrence of AF in CM conditions. We purposed to investigate the correlation between Hsp70 and the AF inducibility in various CM conditions that are unclear. We constructed four different animal models using Sprague–Dawley rats: an ischemic CM group (n = 12), a non-ischemic dilated CM group (n = 12), a pressure-overload hypertrophic CM group (n = 12), and a sham group (CON, n = 12). After 4–6 weeks of intervention animals, AF was induced acutely prior to hemodynamic studies. Hemodynamic data using the Langendorff technique and histologic evaluation were conducted sequentially in all animal groups.

Afterwards, levels of Hsp70 were measured from atrial tissues by real-time polymerase chain reaction study. The hemodynamic data and histologic studies proved that each animal model was suitable to this study protocol. All CM groups showed that Hsp70 was elevated significantly compared to the control groups (P \ 0.005). Among these CM groups, the TAC group revealed lower Hsp70 levels and higher induction rates of atrial fibrillation than the other groups (P \ 0.005). The level of Hsp70 was elevated in all the CM models and it was negatively correlated with AF induction rate in sham group. However, we could not find correlation between Hsp70 and AF among the CM models. Keywords Heat shock protein 70  Atrial fibrillation  Cardiomyopathy

Introduction T. J. Min Department of Anesthesiology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, South Korea W.-M. Jo (&) Department of Thoracic and Cardiovascular Surgery, Korea University Ansan Hospital, Korea University College of Medicine, Gojan-1-dong, Ansan, Gyonggi-do 425-707, South Korea e-mail: [email protected]; [email protected] S. Y. Shin Division of Cardiology, Heart Research Institute, College of Medicine, Chung-Ang University, Seoul, South Korea H. E. Lim Division of Cardiology, Cardiovascular Center, Korea University Guro Hospital, Korea University College of Medicine, Ansan, South Korea

Heat shock proteins (Hsps), originally identified as heatinducible gene products, are molecular chaperones that protect cells from various conditions of stress. Hsps are traditionally classified into two groups: the high-molecularweight Hsps and the small Hsp family. The Hsp90, Hsp70, and Hsp60 families belong to the first group [1], and are ATP-dependent chaperones. They stabilize proteins either in an ATP- or ADP-binding conformation, thereby maintaining proteins in their correctly folded state, especially in stressful situations like ischemia. In contrast to the highmolecular-weight Hsps, small Hsps are ATP-independent. Their functions appear to be controlled by their phosphorylation status. Hsp70 plays an important intracellular role in facilitating protein transport, preventing protein aggregation during folding, and protecting newly

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synthesized polypeptide chains from misfolding and protein denaturation [2]. It is widely accepted that induction of the heat shock response provides cytoprotective effects that may be beneficial in a variety of acute diseases. In major cardiac disorders, Hsps may protect against tissue injury, repair injured proteins, and promote the healing of damaged tissue [3, 4]. Moreover, Hsp70 also holds great promise as a potential therapeutic index in many ischemic diseases [5, 6]. Decker et al. [7] proved that the stress-inducible protein Hsp70 binds and protects the microtubule network from variable conditions of stress, limiting myofibril disruption after ischemic stress to the myocardium. And Amanvermez et al. [8] found that Hsp70 levels are higher in acute coronary syndromes than that in control subjects. In addition, there have been many articles about Hsp and AF. Several studies investigated the role of various Hsps in clinical atrial fibrillation (AF) by determining levels of expression of Hsps in the atrial tissue of patients with paroxysmal and/or persistent AF [9–11]. Mandal et al. [12] also reported that intracellular levels of Hsp70 in the right atrium correlate negatively with postoperative atrial fibrillation in patients who have undergone cardiac surgery. Wei et al. [13] revealed that Hsp70 might be used as a biomarker for the presence of heart failure from different forms of cardiomyopathy (CM); however, the role of Hsps in AF in cardiac diseases like CM has not yet been determined. Therefore, we hypothesized that the myocardium in cardiomyopathies, with its altered conformations, would have a lower voltage threshold for inducing atrial fibrillation than normal myocardium. The role of Hsps in the inducibility of atrial fibrillation might be different in different cardiomyopathies though.

Methods Study animals A total of 48 Sprague–Dawley male rats (6- to 8-week old, 200–300 g) were housed at 20 ± 2 °C and 55 ± 20 % humidity with 12-h light/dark cycles and free access to food and water in the Animal Care Facility at the Ansan Hospital, Korea University, Korea. This study was approved by the Committee of Animal Care of Korea University and conforms to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996). Experimental design We divided the experimental animal model, the Sprague– Dawley rats, into four groups: an ischemic cardiomyopathy

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group (ICMP, n = 12), a non-ischemic dilated cardiomyopathy group (DOX, n = 12), a pressure-overload hypertrophic cardiomyopathy group (TAC, n = 12), and a sham group (CON, n = 12). After 4–6 weeks of breeding the rats, atrial fibrillation was induced acutely prior to performing hemodynamic studies. Atrial fibrillation induction was performed with an esophageal nerve stimulator in whole animal models. Afterwards, hemodynamic studies using the Langendorff technique and histologic evaluation were conducted in all animal groups sequentially to confirm the appropriate of animal models. Lastly, Hsp70 levels were measured from left atrial tissues using real-time polymerase chain reaction (PCR) technique (Fig. 1). Construction of various CM models The CM models that we desired to study were ischemic cardiomyopathy (ICMP), doxorubicin-induced non-ischemic dilated cardiomyopathy model (DOX), and pressureoverload hypertrophic CM model by transverse aortic constriction (TAC). These experimental models were constructed according to the methods of our previous study [14]. Atrial fibrillation induction study Anesthesia was induced with 3–5 % sevoflurane in an animal anesthetic chamber and maintained with 1.5–2 % sevoflurane by continuous mask positive ventilation throughout the study. The continuous monitoring of surface limb-lead electrocardiographs (ECG) was recorded with filtering within the range of 0.1–100 Hz via a polygraph system and analyzed automatically (MacLab, GE, Horton, USA/Pruka, GE, Horton, USA). A 6-F decapolar electrode catheter with an inter-electrode distance of 2 mm was inserted into the esophagus. Burst atrial pacing (frequency, 40 Hz; current, 30 mA; pulse width, 2 ms; duration, 30 s) was then conducted to induce AF using an electrical stimulator (Grass s-88, Quincy, MA, USA). AF was induced 5 times at intervals of 10 min, after which its inducibility and duration were assessed (Fig. 2). Hemodynamic studies for cardiac performance The hemodynamic study was performed using the Langendorff technique (size 3, type 830, Hugo Sachs Elektronik, March-Hugstetten, Germany). After 15 min of stabilization, data were collected for 2 h. The peak positive derivatives [dP/dt (max)], heart rates, the peak left ventricular pressure (peak LVP), and coronary flow were measured. Coronary blood flow was also determined by collecting the coronary effluent from the hearts. These hemodynamic studies were conducted to confirm the appropriateness of

Heart Vessels Fig. 1 Experimental designs. a Overall experimental design. b The continuous monitoring of surface limb-lead electrocardiographs was conducted during atrial fibrillation induction study. ICMP ischemic cardiomyopathy rat group, DOX doxorubicin treated non-ischemic dilated cardiomyopathy rat group, TAC hypertrophic cardiomyopathy rat group by transverse aortic constriction, SHAM Shamoperated group

the CM models. The methods were same as those in our previous report [14]. Real-time PCR RNA was prepared using a RNeasyÒ RNA isolation mini kit (Qiagen, Hilden, Germany). Reverse-transcription polymerase chain reaction (RT-PCR) was performed using a one-step RT-PCR kit from Roche. The RT-PCR experiments were performed with primers for the respective target enzyme: 50 -AGT-GGT-GGG-GGA-GAC-ATA-GC-

30 (sense), (antisense); 30 -GTG-TGG-GCC-TTT-GTG-TTTTG-50 . The conditions were as follows for Hsp70: 1 cycle at 95 °C for 10 min; 50 (for quantitative real-time PCR or qRT-PCR) cycles at 95 °C for 15 s, 55 °C for 5 s, and 72 °C for 6 s; 1 cycle at 65 °C for 15 s; and a final extension cycle at 40 °C for 30 s. The specificity of the qRT-PCR amplification was verified by melting curve analysis (from 50 to 90 °C) using SYBR Premix Ex Taq (Roche Diagnostic, Mannheim, Germany). The relative gene expression levels were calculated as ratios using bactin for normalization.

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Chi square test and comparisons among groups were carried out using the one-way ANOVA test. The correlation between Hsp70 levels and AF induction rates was analyzed using simple regression analysis. Differences were considered significant at P \ 0.05. Results The hemodynamic parameters revealed that these experimental CM models are adequate in our present study to confirm that Hsp exerts a myocardial protective effect in various rat CM models. It should be mentioned that these hemodynamic parameters have been used to prove drug efficacy in the Langendorff technique [15]. Hemodynamic data (Table 1) dP/dt (max)

Fig. 2 Atrial fibrillation induction rate and expression of Hsp70. Hsp70 and AF inducibility were elevated in CMP groups than Sham group. In CM groups, DOX group showed most high Hsp70 level and also most low atrial fibrillation induction rate. a Atrial induction rate. *Statistical significance for AF inducibility; TAC, ICMP, DOX vs. Sham group.  The DOX group showed lower AF induction rate, compared to the other CM groups. (v2 test: P \ 0.05, Fisher’s Exact test : P \ 0.05). b Expression of Hsp70. *Statistical significance for expression of Hsp70: DOX, ICMP, TAC vs. Sham.  DOX group showed higher Hsp70 level, compared to the other CM groups. (Oneway ANOVA: P \ 0.001)

In the sham group, the dP/dt (max) was significantly different from the other groups (sham, 2561 ± 255.5 mmHg/s; TAC 2105 ± 157.2 mmHg/s; DOX2015.1 ± 92.9 mmHg/s; ICMP 2249 ± 142.9 mmHg/s; P \ 0.05). The dP/dt (max) was also significantly decreased in the DOX and TAC groups compared to the ICMP groups. Peak left ventricular pressure The peak left ventricular pressure of the DOX group was significantly lower than that of the other models (123 ± 7.1 mmHg; P \ 0.001). Otherwise, there were no significant differences among the sham, ICMP, and TAC groups.

Statistical analysis Coronary flow The power of this study was 99 % for a dP/dt (max) as recorded in a previous study [14] with an alpha equal to 0.05. We used SPSS 19.0 (SPSS, Chicago, IL, USA) for the statistical analysis. All data are presented as mean ± standard error of the mean. Induction rates of AF were compared by

Coronary flow of the DOX group was significantly lower than that of the others (762.5 ± 70.6 mL/h; P \ 0.001). Otherwise, there were no significant differences among the sham, ICMP, and TAC groups.

Table 1 Hemodynamic data (mean ± standard deviation)

(dP/dt) max* (mmHg/s) Peak ventricular pressure* (mmHg)

SHAM (n = 12)

ICMP (n = 12)

DOC (n = 12)

TAC (n = 12)

2561.00 ± 255.49 140.80 ± 7.21

2249.00 ± 142.88 135.50 ± 5.99

2015.10 ± 92.90 123.00 ± 7.15

2105.90 ± 157.24 136.30 ± 10.05

Coronary blood flow* (mL/min)

916.50 ± 59.96

903.50 ± 58.88

762.50 ± 70.56

866.67 ± 63.93

Heart rate* (frequency/min)

240.70 ± 9.73

226.50 ± 11.80

220.50 ± 9.69

213.90 ± 15.82

ICMP ischemic cardiomyopathy rat group, DOX doxorubicin treated non-ischemic dilated cardiomyopathy rat group, TAC hypertrophic cardiomyopathy rat group by transverse aortic constriction, SHAM Sham-operated group * There are significant statistical differences among each groups (one-way ANOVA, P \ 0.001). Therefore, these data proved that each animal model was suitable to its purpose

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Correlation of hemodynamic data and Hsp70 We could see that hemodynamic data were significantly distressed in the CM groups than the sham group and in CM groups; the DOX group showed lower peak ventricular pressure, coronary flow than the other CM groups. However, we could not find any significant correlation between HSP 70 level and hemodynamic data among the CM groups. Atrial fibrillation induction rate/Hsp70 level Induction of atrial fibrillation shows significant value in this study (P = 0.007). In CM groups, atrial fibrillation was more easily induced in the TAC and ICMP CM models than in the DOX CM group (Fig. 2a). Hsp70 levels were highly detected in the DOX CM model, compared to the TAC and ICMP CM models. And Hsp70 levels were

Fig. 3 The correlation analysis between atrial fibrillation induction rate and expressed level of Hsp70. a The correlation analysis between AF induction rate and Hsp70 in overall groups. In overall groups, AF induction rates were not correlated with Hsp70 level statistically. (Single regression analysis; b = -0.015, F = 0.010, adjusted R2 = -0.024, P [ 0.05.) b The correlation analysis between AF induction rate and Hsp70 in the sham group. In the sham group, AF induction rates were negatively correlated with Hsp70 level statistically. (Single regression analysis; b = -0.773, F = 11.894, adjusted R2 = 0.548, P \ 0.01.) c The correlation analysis between AF

higher overall in the CM models compared to the sham group (Fig. 2b). The correlation of AF induction rate/Hsp70 levels (Fig. 3) The AF induction rate/Hsp70 levels in all groups were estimated using simple regression analysis. Although the atrial fibrillation induction rate was negatively correlated with Hsp70 levels in the sham group, it was not correlated statistically with Hsp70 levels in all the CM groups as well as the overall groups. Limitation We could not find any correlation between AF induction rates and Hsp70 levels among CM models because our

induction rate and Hsp70 in various c CM groups. (1) ICMP group. In the ICMP group, AF induction rates were not correlated with Hsp70 level statistically. (Single regression analysis; b = -0.536, F = 3.228, adjusted R2 = 0.198, P [ 0.05). (2) DOX group. In the DOX group, AF induction rates were not correlated with Hsp70 level statistically. (Single regression analysis; b = 0.205, F = 0.438, adjusted R2 = -0.054, P [ 0.05). (3) TAC group. In the TAC group, AF induction rates were not correlated with Hsp70 level statistically. (Single regression analysis; b = -0.294, F = 0.944, adjusted R2 = -0.005, P [ 0.05)

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animal model could not be standardized bias in the AF inducibility under various CM conditions, and it was difficult to apply co-morbidities such as hypertension, diabetes to our animal model. Also, our study model was limited to study persistent AF because atrial fibrillation was induced paroxysmally by electrical stimulation.

Discussion AF, the most common sustained clinical tachyarrhythmia, is a significant risk factor for cardiovascular morbidity and mortality [16–18]. It results from electrophysiological disturbances that are associated with molecular changes in the cardiomyocytes that are caused by various severe stresses. These changes may or may not arise from genetic mutations. However, the mechanisms behind atrial fibrillation are not fully understood [19, 20], even in CM. Since the initial discovery of heat shock proteins, we have learned a lot about their role and variable expression. That said, we are still trying to understand the mechanisms behind heat shock protein expression under certain circumstances, such as cardiovascular ischemia, neurodegenerative diseases, and acute hypoxic injury. There are several reports about the protective effects of Hsp70 in the situations of cardiac diseases. Yellon et al. [21] revealed that higher levels of Hsp70 in the myocardium increased the resistance of the heart to ischemia and offered an endogenous route to myocardial protection in animal models. Similar cardioprotective effects of Hsp70 have been shown in human studies [22] as well. The mechanism behind these effects was demonstrated by Ficker et al. [23]: high levels of Hsp70 allow the maturation of the cardiac potassium channel hERG, even in the face of ischemia. Therefore, the cardiac potassium channel hERG is preserved in myocardial cells during ischemia, allowing better electrophysiological recovery and a decreased risk of arrhythmias in the reperfusion period. This theory can be applied to the positive effect of Hsp70 on the occurrence and recovery of AF. Recently, Wei et al. [13] reported on the role of Hsp70 in patients with chronic heart failure. Through Wei et al.’s study, it was proved that Hsp70 levels were highly elevated in various heart failure conditions, such as arrhythmogenic right ventricular CM, ischemic CM, and dilated CM, as compared to patients without CM. Actually, we hypothesized that the cardioprotective effects of Hsp70 on the occurrence of AF might be applied to the CM conditions in any shape. Our three study models [ischemic cardiomyopathy (ICMP), non-ischemic dilated cardiomyopathy (DOX), and hypertrophic cardiomyopathy model (TAC)] look similar and have the common features

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of chronic and irreversible cardiac disease. However, these models each have different pathogeneses and conformational changes of the myocardium. Therefore, we also preconceived that the results of our study can be differ from each group. Ogawa et al. [24] also demonstrated that chronic stressful conditions such as oxidative stress, inflammation, cardiovascular disorders and pulmonary fibrosis are directly correlated with Hsp70 concentration in the bloodstream. It suggested that Hsp70 might be a good biomarker for the physiologic disorders of myocardium. It has further been suggested that the elevation of Hsp70 levels could be an important immune-inflammatory response against physiologic disorders or disease. We agree with them completely that Hsp70 can be a useful biomarker for acute and chronic stressful conditions including cardiac disease. Our study can contribute to their insistence in some degree. Several studies have reported a protective role of Hsp70 in suppressing subsequent activation of the NF-jB pathway in states of both acute and chronic stress such as Alzheimer’s disease, Parkinson’s disease, heavy exercise, and postoperative cardiac surgery [12, 25–28]. In previous studies, patients with higher Hsp70 levels in the bloodstream showed better outcomes, such as a lower hospital treatment period [29], lower rates of postoperative AF [12], and smaller areas of infarction in the brain and preserved cognitive function after ischemia [27]. We proved that the statistically significant elevation of Hsp70 expression in all the CM groups was compared to the sham group through this study, to a greater or lesser extent (Fig. 2b), and AF induction rates in the CM groups were significantly increased compared to the sham group. Moreover, the levels of Hsp70 were negatively correlated with atrial fibrillation induction rates in the sham group, that is acute stressful condition (P = 0.009) (Fig. 3b). However, there was no significant correlation between Hsp70 and AF inducibility among the various CM groups (Fig. 3c). The causes of AF in CM are variable and can involve atrial fibrosis, the proliferation of myofibroblasts, the down-regulation of gap junctions, and electrophysiological remodeling of the conduction systems [19, 30, 31]. We believe that we may not have been able to find any correlation between AF induction rates and Hsp70 levels among CM models due to our inability to correct for the various mechanisms behind AF in the CM models and standardize the disease status of each CM model. Although this study is incomplete with limitations, we are convinced that it would be helpful to understand the protective effects and mechanism behind Hsp in the AF of various cardiac diseases and also may contribute to the advancement of treatment for these cardiac diseases.

Heart Vessels Acknowledgments This work was supported by Grants of the Korea University College of Medicine (K1032251). Conflict of interest of interest.

The authors declare that they have no conflict

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The protective effect of heat shock protein 70 (Hsp70) in atrial fibrillation in various cardiomyopathy conditions.

Heat shock proteins (Hsp) protect myocardial cells from acute stress such as atrial fibrillation (AF) and also from the chronic stress. It is not unde...
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