Usefulness of Running Wheel for Detection of Congestive Heart Failure in Dilated Cardiomyopathy Mouse Model

Sugihara, Masami; Odagiri, Fuminori; Suzuki, Takahiko; Murayama, Takashi; Nakazato, Yuji; Unuma, Kana; Yoshida, Ken; Daida, Hiroyuki; Sakurai, Takashi; Morimoto, Sachio; Kurebayashi, Nagomi

doi:10.1371/journal.pone.0055514

Cited by 15 publications

(18 citation statements)

References 29 publications

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“…Thus far, only a few studies have revealed the effects of ARBs on DCM using animal models [23], and these studies have not assessed the effects of ARBs on electrical remodeling in inherited DCM. In the present study, we found that candesartan improved the survival rate and cardiac systolic function, and suppressed progression of cardiac dilation and fibrosis using a DCM mouse model with the ΔK210 mutation in TNNT2 , which closely recapitulates the human phenotype [12]–[14], [16]. In addition to the above effects, candesartan suppressed occurrence of ventricular arrhythmia as well as various changes in the electrical properties in DCM hearts.…”

Section: Discussionsupporting

confidence: 64%

“…In this study, treatment of DCM mice with candesartan was started at 1 month of age when their death rate was still low [13] , [16] . Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To estimate the extent of HF in DCM mice, physical activity was evaluated by measuring voluntary wheel running activity [13] , [16] . Mice at 1.5 months or later were housed with free access to a running wheel (6 cm radius; Mini Mitter Co. Inc. OR, USA) for 2 days every 10 days, and their running activities (rounds/day) were measured.…”

Section: Methodsmentioning

confidence: 99%

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Effects of Candesartan on Electrical Remodeling in the Hearts of Inherited Dilated Cardiomyopathy Model Mice

et al. 2014

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Inherited dilated cardiomyopathy (DCM) is characterized by dilatation and dysfunction of the ventricles, and often results in sudden death or heart failure (HF). Although angiotensin receptor blockers (ARBs) have been used for the treatment of HF, little is known about the effects on postulated electrical remodeling that occurs in inherited DCM. The aim of this study was to examine the effects of candesartan, one of the ARBs, on cardiac function and electrical remodeling in the hearts of inherited DCM model mice (TNNT2 ΔK210). DCM mice were treated with candesartan in drinking water for 2 months from 1 month of age. Control, non-treated DCM mice showed an enlargement of the heart with prolongation of QRS and QT intervals, and died at t1/2 of 70 days. Candesartan dramatically extended the lifespan of DCM mice, suppressed cardiac dilatation, and improved the functional parameters of the myocardium. It also greatly suppressed prolongation of QRS and QT intervals and action potential duration (APD) in the left ventricular myocardium and occurrence of ventricular arrhythmia. Expression analysis revealed that down-regulation of Kv4.2 (Ito channel protein), KChIP2 (auxiliary subunit of Kv4.2), and Kv1.5 (IKur channel protein) in DCM was partially reversed by candesartan administration. Interestingly, non-treated DCM heart had both normal-sized myocytes with moderately decreased Ito and IKur and enlarged cells with greatly reduced K+ currents (Ito, IKur IK1 and Iss). Treatment with candesartan completely abrogated the emergence of the enlarged cells but did not reverse the Ito, and IKur in normal-sized cells in DCM hearts. Our results indicate that candesartan treatment suppresses structural remodeling to prevent severe electrical remodeling in inherited DCM.

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Section: Discussionsupporting

confidence: 64%

“…In this study, treatment of DCM mice with candesartan was started at 1 month of age when their death rate was still low [13] , [16] . Fig.…”

Section: Resultsmentioning

confidence: 99%

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Effects of Candesartan on Electrical Remodeling in the Hearts of Inherited Dilated Cardiomyopathy Model Mice

et al. 2014

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“…None of the homozygous D73N (+/+) mice survived longer than one day. The phenotype of the D73N (+/−) mice resembled that of homozygous knock-in mice harboring the DCM-linked ΔK210 mutation in cTnT (homozygous ΔK210cTnT mice) (Du et al, 2007 ; Sugihara et al, 2013 ). Like the D73N (+/−) mice, homozygous ΔK210cTnT mice developed early onset DCM, with decreased Ca 2+ sensitivity of force development, enlarged hearts, left ventricular dilation, and systolic dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Knock-in mice harboring a Ca2+ desensitizing mutation in cardiac troponin C develop early onset dilated cardiomyopathy

et al. 2015

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Citation:McConnell BK, Singh S, Fan Q, Hernandez A, Portillo JP, Reiser PJ and Tikunova SB (2015) Knock-in mice harboring a Ca 2+ desensitizing mutation in cardiac troponin C develop early onset dilated cardiomyopathy. Front. Physiol. 6:242. doi: 10.3389/fphys.2015.00242 Knock-in mice harboring a Ca 2+ desensitizing mutation in cardiac troponin C develop early onset dilated cardiomyopathy The physiological consequences of aberrant Ca 2+ binding and exchange with cardiac myofilaments are not clearly understood. In order to examine the effect of decreasing Ca 2+ sensitivity of cTnC on cardiac function, we generated knock-in mice carrying a D73N mutation (not known to be associated with heart disease in human patients) in cTnC. The D73N mutation was engineered into the regulatory N-domain of cTnC in order to reduce Ca 2+ sensitivity of reconstituted thin filaments by increasing the rate of Ca 2+ dissociation. In addition, the D73N mutation drastically blunted the extent of Ca 2+ desensitization of reconstituted thin filaments induced by cTnI pseudo-phosphorylation. Compared to wild-type mice, heterozygous knock-in mice carrying the D73N mutation exhibited a substantially decreased Ca 2+ sensitivity of force development in skinned ventricular trabeculae. Kaplan-Meier survival analysis revealed that median survival time for knock-in mice was 12 weeks. Echocardiographic analysis revealed that knock-in mice exhibited increased left ventricular dimensions with thinner walls. Echocardiographic analysis also revealed that measures of systolic function, such as ejection fraction (EF) and fractional shortening (FS), were dramatically reduced in knock-in mice. In addition, knock-in mice displayed electrophysiological abnormalities, namely prolonged QRS and QT intervals. Furthermore, ventricular myocytes isolated from knock-in mice did not respond to β-adrenergic stimulation. Thus, knock-in mice developed pathological features similar to those observed in human patients with dilated cardiomyopathy (DCM). In conclusion, our results suggest that decreasing Ca 2+ sensitivity of the regulatory N-domain of cTnC is sufficient to trigger the development of DCM.

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“…Some indicators of HF, such as atrial natriuretic peptide and brain natriuretic peptide, have been found to be more closely correlated with cardiac enlargement than CHF or lung edema (Sugihara et al, 2013;Lourenco et al, 2010). CRP levels are elevated in CHF and increasing levels are associated with increasing morbidity and mortality in ischemic and non-ischemic etiologies (Nakagomi et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Torasemide reduces dilated cardiomyopathy, complication of arrhythmia, and progression to heart failure

Han¹,

Guo²,

Lin³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. The aim of this study was to analyze the incidence and types of arrhythmia and their relationship with the severity and prognosis of chronic heart failure (CHF) in patients with dilated cardiomyopathy (DCM), and to investigate the therapeutic effect of torasemide versus furosemide on CHF and incidence of arrhythmia. DCM patients with NYHA cardiac function II-IV were continuously monitored using a 24-h dynamic electrocardiogram (Holter), and arrhythmia incidence was analyzed by computer automatic analysis combined with manual assessment. In total, 125 participants were evenly divided into two groups: torasemide group which received 10 mg oral torasemide once daily) and regular anti-heart failure treatment (N = 65), and furosemide group which received torasemide (20 mg once daily orally) and regular antiheart failure treatment (N = 60). Another 60 normal healthy persons served as the normal control group. Incidence and severity of arrhythmia increased when degree of CHF was elevated. Size of left atrium was related to atrial fibrillation and size of left ventricle was related to malignant arrhythmia. At 3 months after treatment, cardiac function in both groups improved and incidence and severity of arrhythmia in both groups were reduced. However, left ventricular ejection fraction (LVEF) was higher in the torasemide group than in the furosemide group, while incidence of arrhythmia was lower in the torasemide group. Arrhythmias frequently occurred in patients with DCM and HF. Type of cardiac arrhythmia is closely related to ventricular enlargement and cardiac function grade. Torasemide is better for improving cardiac function to reduce arrhythmia and CHF compared to furosemide.

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Usefulness of Running Wheel for Detection of Congestive Heart Failure in Dilated Cardiomyopathy Mouse Model

Cited by 15 publications

References 29 publications

Effects of Candesartan on Electrical Remodeling in the Hearts of Inherited Dilated Cardiomyopathy Model Mice

Effects of Candesartan on Electrical Remodeling in the Hearts of Inherited Dilated Cardiomyopathy Model Mice

Knock-in mice harboring a Ca2+ desensitizing mutation in cardiac troponin C develop early onset dilated cardiomyopathy

Torasemide reduces dilated cardiomyopathy, complication of arrhythmia, and progression to heart failure

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