Right ventricular TNF resistance during endotoxemia: the differential effects on ventricular function

Right and left ventricular myocytes originate from different cellular progenitors; however, it is unknown whether these cells differ in their response to endotoxemia. We hypothesized that 1) the percentage of endotoxemic functional depression within the right ventricle (RV) would be smaller than that of the left ventricle; and 2) that better RV function would correlate with lower levels of right ventricular TNF production. Adult Sprague-Dawley rats were divided into right and left control and endotoxin groups. Controls received vehicle, while endotoxin groups received LPS at 20 mg/kg ip. Hearts were excised either 2 or 6 h after injection. Hearts excised at 2 h were assayed for TNF, IL-6, TNF receptor 1 (TNFR1), TNFR2, and via ELISA, while hearts excised at 6 h were assayed via the Langendorff model. The percentage of cardiac functional depression, exhibited as developed pressure, contractility, and rate of relaxation (expressed as a percentage of control) was significantly smaller in right ventricles compared with left ventricles following endotoxin exposure. Tissue levels of TNF were significantly elevated in both right and left ventricles 2 h after endotoxin exposure, and right ventricular endotoxin groups expressed higher levels of TNF compared with their left ventricular counterparts. No significant differences in IL-6, TNFR1, or TNFR2 levels were noted between endotoxin-exposed ventricles. This is the first study to demonstrate that right and left ventricular function differs after endotoxin exposure.     

Regional differences in WT-1 and Tcf21 expression during ventricular development: implications for myocardial compaction

Background

Morphological and functional differences of the right and left ventricle are apparent in the adult human heart. A differential contribution of cardiac fibroblasts and smooth muscle cells (populations of epicardium-derived cells) to each ventricle may account for part of the morphological-functional disparity. Here we studied the relation between epicardial derivatives and the development of compact ventricular myocardium.

Results

Wildtype and Wt1^CreERT2/+ reporter mice were used to study WT-1 expressing cells, and Tcf21^lacZ/+ reporter mice and PDGFRα^-/-;Tcf21^LacZ/+ mice to study the formation of the cardiac fibroblast population. After covering the heart, intramyocardial WT-1+ cells were first observed at the inner curvature, the right ventricular postero-lateral wall and left ventricular apical wall. Later, WT-1+ cells were present in the walls of both ventricles, but significantly more pronounced in the left ventricle. Tcf21-^LacZ + cells followed the same distribution pattern as WT-1+ cells but at later stages, indicating a timing difference between these cell populations. Within the right ventricle, WT-1+ and Tcf21-lacZ+ cell distribution was more pronounced in the posterior inlet part. A gradual increase in myocardial wall thickness was observed early in the left ventricle and at later stages in the right ventricle. PDGFRα^-/-;Tcf21^LacZ/+ mice showed deficient epicardium, diminished number of Tcf21-^LacZ + cells and reduced ventricular compaction.

Conclusions

During normal heart development, spatio-temporal differences in contribution of WT-1 and Tcf21-^LacZ + cells to right versus left ventricular myocardium occur parallel to myocardial thickening. These findings may relate to lateralized differences in ventricular (patho)morphology in humans.     

An Immunohistochemical Analysis of Tissue Thrombin Expression in the Human Atria

Objective

Thrombin, the final coagulation product of the coagulation cascade, has been demonstrated to have many physiological effects, including pro-fibrotic actions via protease-activated receptor (PAR)-1. Recent investigations have demonstrated that activation of the cardiac local coagulation system was associated with atrial fibrillation. However, the distribution of thrombin in the heart, especially difference between the atria and the ventricle, remains to be clarified. We herein investigated the expression of thrombin and other related proteins, as well as tissue fibrosis, in the human left atria and left ventricle.

Methods

We examined the expression of thrombin and other related molecules in the autopsied hearts of patients with and without atrial fibrillation. An immunohistochemical analysis was performed in the left atria and the left ventricle.

Results

The thrombin was immunohistologically detected in both the left atria and the left ventricles. Other than in the myocardium, the expression of thrombin was observed in the endocardium and the subendocardium of the left atrium. Thrombin was more highly expressed in the left atrium compared to the left ventricle, which was concomitant with more tissue fibrosis and inflammation, as detected by CD68 expression, in the left atrium. We also confirmed the expression of prothrombin in the left atrium. The expression of PAR-1 was observed in the endocardium, subendocardium and myocardium in the left atrium. In patients with atrial fibrillation, strong thrombin expression was observed in the left atrium.

Conclusions

The strong expression levels of thrombin, prothrombin and PAR-1 were demonstrated in the atrial tissues of human autopsied hearts.     

Follow-up of implantable cardioverter-defibrillator therapy: comparison of coronary artery disease and dilated cardiomyopathy

Purpose

Since several large trials have proven the effectiveness of implantable cardioverter-defibrillators (ICDs) in patients with left ventricular dysfunction, disadvantages have become more apparent. As the prognosis of patients with cardiovascular diseases is improving, assessment of ICD patients and re-evaluation of the current guidelines is mandatory. We aimed to evaluate differences in mortality and occurrence of (in)appropriate shocks in ICD patients with coronary artery disease (CAD) or dilated cardiomyopathy (DCM).

Methods

In a large teaching hospital, all consecutive patients with systolic dysfunction due to CAD or DCM who received an ICD with and without resynchronisation therapy, were collected in a database.

Results

A total of 320 consecutive patients (age 67 ± 10 years) were classified as CAD patients and 178 (63 ± 11 years) as DCM patients. Median follow-up was 40 months (interquartile range [IQR] 23─57 months). All–cause mortality was 14 % (CAD 15 % vs DCM 13 %). Appropriate shocks occurred in 13 % of all patients (CAD 15 % vs DCM 11 %, p = 0.12) and inappropriate shocks occurred in 10 % (CAD 8 % vs DCM 12 %, p = 0.27). Multivariate analysis demonstrated impaired left ventricular ejection fraction, QRS >120, age ≥75 years and low estimated glomerular filtration rate as predictors for all-cause mortality. Predictors for inappropriate shocks were permanent and paroxysmal atrial fibrillation.

Conclusion

Mortality rates were similar in patients with CAD and DCM who received an ICD. Furthermore, no differences were found in the occurrence of appropriate and inappropriate ICD interventions between these patient groups.     

An anatomic basis for fetal right ventricular dominance and arterial pressure sensitivity

Fetal right ventricular dominance of flow and arterial pressure sensitivity were recently recognized but controversial findings. We investigated ventricular volumes, weights and dimensions in order to understand if there were anatomic differences between the ventricles which might explain these differential functional findings in the fetal sheep. Forty-four near term lambs and their hearts were weighed. Right and left ventricular free wall weights were not different. Volumes were measured by generating in vitro pressure-volume relations and by casting the two ventricles after fixation at equal, physiologic pressures. Right ventricular volume was greater than left ventricular volume by both techniques. Ventricular interaction and a restraining effect of the pericardium were present. Measurements of the fixed ventricles and their casts revealed the following: left ventricular wall thickness was slightly greater than right ventricular wall thickness; lateral ventricular diameters were not different but anteroposterior ventricular diameters were much greater in the right than left ventricle. Because of these findings, the right ventricular circumferential radii of curvature were greater than for the left ventricle as was the radius to wall thickness ratio. Greater right ventricular volume and radius to wall thickness ratio may be important factors in right ventricular flow dominance and greater sensitivity to arterial pressure.     

Cardiac myosin phenotype remodeling following chronic spinal transection

Spinal transection results in profound neural and functional changes of the heart. However, phenotypic alterations in cardiac myosin heavy chains (MyHC) as a result of spinal transection have not been explored. Hearts were removed from 180 day old rats who had their spinal cords transected between T6 and T9 (ST; n = 10) and intact controls (IN; n = 9). Myosin was isolated from the left and right ventricles and separated into its respective heavy chain components (designated as alpha and beta) by SDS-PAGE. The resulting gels were scanned with a laser scanning densitometer to obtain relative concentrations of these two heavy chains. The left ventricles of the ST rats had a significantly higher (p < 0.05) alpha to beta ratio (10.89) than the intact controls (4.20), while the right ventricle of the ST rats had a significantly lower (p < 0.05) alpha to beta ratio (7.49) relative to intact controls (13.62). The left and right ventricular weight to body weight ratios were not different in ST compared to IN. Additionally, there were significant within group differences (p < 0.05) between the alpha and beta MyHC ratios for the left and right ventricles. These data suggest that 1) spinal transection causes remodeling of the right and left ventricles and 2) the two ventricles do not remodel as a unit.     

Effect of ectopic excitation on the ventricular pump function in chicken

The pump function of the heart ventricles was studied in chest-open anaesthetized adult female chickens under sinus rhythm and ectopic excitation of different localization. The intraventricular pressure in the right and left heart ventricles was measured by insertion of catheters through the ventricular free walls. Maximum systolic pressure, end-diastolic pressure, contractility (dP/dtmax) and relaxation (dP/dtmin) of both heart ventricles, and duration of the asynchronous contraction time of the left ventricle were analyzed. It was revealed that reduction of the pump function of the left ventricle tends to be greater under right ventricular ectopic excitation compared with left ventricular one. In comparison with the sinus rhythm, the pump function of the right ventricle was preserved to a greater extent under stimulation of the left ventricular apex and was significantly impaired under right ventricular ectopic excitation. Relaxation of both heart ventricles was more susceptible to ventricular ectopic excitation than contractility, and was more vulnerable in the right ventricle than in the left one. The direction of changes of the pump function of the heart ventricles in chickens under ventricular ectopic excitation was similar to changes of the pump function of mammalian hearts.     

The Relationship between the Severity of Coronary Artery Disease and Epicardial Adipose Tissue Depends on The Left Ventricular Function

Background

Epicardial adipose tissue (EAT) is an active metabolic and endocrine organ. Previous studies focusing mainly on patients with preserved left ventricular function (LVF) could show a correlation between increased amounts of EAT and the extent and activity of coronary artery disease (CAD). However, to date, there are no data available about the relationship between EAT and the severity of CAD with respect to the whole spectrum of LVF impairment. Therefore, we evaluated this relationship in patients with CAD.

Methods

250 patients with CAD and 50 healthy controls underwent CMR examination to assess EAT. The severity of CAD was defined using the angiographic Gensini score (GSS).

Results

The GSS ranged from 2–364. Linear regression analysis revealed a significant correlation between EAT and GSS (r = 0.177, p = 0.01). Patients with mild (GSS≤10) and moderate CAD (GSS>10−≤40) showed comparable EAT to healthy controls. However, in patients with severe CAD (GSS>40) EAT was significantly reduced (p<0.0001) compared to healthy controls. Interestingly, patients with the same GSS revealed different EAT depending on the left ventricular function (LVF). Patients with preserved LVF (LVF≥50%) showed more EAT mass compared to those with reduced LVF (LVF<50%) regardless of the GSS. In patients with preserved LVF and mild CAD, EAT was comparable to healthy controls (61.8±19.4 g vs. 62.9±14.4 g, p = 0.8). In patients with moderate CAD, EAT rose significantly to 83.1±24.9 g (p = 0.01) and started to decline to 66.4±23.6 g in patients with severe CAD (p = 0.03). Contrary, in CAD patients with reduced LVF, EAT was already significantly reduced in patients with mild CAD as compared to healthy controls (p = 0.001) and showed a stepwise decline with increasing CAD severity.

Conclusion

The relationship between EAT and the severity of CAD depends on LVF. These findings emphasize the multifactorial interaction between EAT and the severity of CAD.     

Proteomic analysis of right and left cardiac ventricles under aerobic conditions and after ischemia/reperfusion

Ischemia/reperfusion (I/R) injury is a major consequence of a cardiovascular intervention. The study of changes of the left and right ventricle proteomes from hearts subjected to I/R may be a key to revealing the pathological mechanisms underlying I/R-induced heart contractile dysfunction. Isolated rat hearts were perfused under aerobic conditions or subjected to 25 min global ischemia and 30 min reperfusion. At the end of perfusion, right and left ventricular homogenates were analyzed by 2DE. Contractile function and coronary flow were significantly reduced by I/R. 2DE followed by mass spectrometry identified ten protein spots whose levels were significantly different between aerobic left and right ventricles, eight protein spots whose levels were different between aerobic and I/R left ventricle, ten protein spots whose levels were different between aerobic and I/R right ventricle ten protein spots whose levels were different between the I/R groups. Among these protein spots were ATP synthase beta subunit, myosin light chain 2, myosin heavy chain fragments, peroxiredoxin-2, and heat shock proteins, previously associated with cardiovascular disease. These results reveal differences between proteomes of left and right ventricle both under aerobic conditions and in response to I/R that contribute to a better understanding of I/R injury.     

Endoplasmic Reticulum Stress Induces Different Molecular Structural Alterations in Human Dilated and Ischemic Cardiomyopathy

Background

The endoplasmic reticulum (ER) is a multifunctional organelle responsible for the synthesis and folding of proteins as well as for signalling and calcium storage, that has been linked to the contraction-relaxation process. Perturbations of its homeostasis activate a stress response in diseases such as heart failure (HF). To elucidate the alterations in ER molecular components, we analyze the levels of ER stress and structure proteins in human dilated (DCM) and ischemic (ICM) cardiomyopathies, and its relationship with patient''s functional status.

Methods and Results

We examined 52 explanted human hearts from DCM (n = 21) and ICM (n = 21) subjects and 10 non-failing hearts as controls. Our results showed specific changes in stress (IRE1, p<0.05; p-IRE1, p<0.05) and structural (Reticulon 1, p<0.01) protein levels. The stress proteins GRP78, XBP1 and ATF6 as well as the structural proteins RRBP1, kinectin, and Nogo A and B, were upregulated in both DCM and ICM patients. Immunofluorescence results were concordant with quantified Western blot levels. Moreover, we show a novel relationship between stress and structural proteins. RRBP1, involved in procollagen synthesis and remodeling, was related with left ventricular function.

Conclusions

In the present study, we report the existence of alterations in ER stress response and shaping proteins. We show a plausible effect of the ER stress on ER structure in a suitable sample of DCM and ICM subjects. Patients with higher values of RRBP1 had worse left ventricular function.     

Up-regulation of hexokinase1 in the right ventricle of monocrotaline induced pulmonary hypertension

Background

Pulmonary arterial hypertension (PAH) is a proliferative arteriopathy associated with a glycolytic shift during heart metabolism. An increase in glycolytic metabolism can be detected in the right ventricle during PAH. Expression levels of glycolysis genes in the right ventricle during glycolysis that occur in monocrotaline (MCT)-induced pulmonary hypertension (PH) remain unknown.

Methods

PH was induced by a single subcutaneous injection of MCT (50 mg/kg) into rats, eventually causing right heart failure. Concurrently, a control group was injected with normal saline. The MCT-PH rats were randomly divided into three groups according to MCT treatment: MCT-2 week, 3 week, and 4 week groups (MCT-2w, 3w, 4w). At the end of the study, hemodynamics and right ventricular hypertrophy were compared among experimental groups. Expression of key glycolytic candidate genes was screened in the right ventricle.

Results

We observed an increase in mean pulmonary arterial pressure, right ventricular systolic pressure and right ventricular hypertrophy index three weeks following MCT injection. Alterations in the morphology and structure of right ventricular myocardial cells, as well as the pulmonary vasculature were observed. Expression of hexokinase 1 (HK1) mRNA began to increase in the right ventricle of the MCT-3w group and MCT-4w group, while the expression of lactate dehydrogenase A (LDHA) was elevated in the right ventricle of the MCT-4w group. Hexokinase 2(HK2), pyruvate dehydrogenase complex α1 (PDHα1), and LDHA mRNA expression showed no changes in the right ventricle. HK1 mRNA expression was further confirmed by HK1 protein expression and immunohistochemical analyses. All findings underlie the glycolytic phenotype in the right ventricle.

Conclusions

There was an increase in the protein and mRNA expression of hexokinase-1 (HK1) three and four weeks after the injection of monocrotaline in the right ventricle, intervention of HK1 may be amenable to therapeutic intervention.     

The importance of myocardial amino acids during ischemia and reperfusion in dilated left ventricle of patients with degenerative mitral valve disease

Taurine, glutamine, glutamate, aspartate, and alanine are the most abundant intracellular free amino acids in human heart. The myocardial concentration of these amino acids changes during ischemia and reperfusion due to alterations in metabolic and ionic homeostasis. We hypothesized that dilated left ventricle secondary to mitral valve disease has different levels of amino acids compared to the right ventricle and that such differences determine the extent of amino acids' changes during ischemia and reperfusion. Myocardial concentration of amino acids was measured in biopsies collected from left and right ventricles before cardioplegic arrest (Custodiol HTK) and 10 min after reperfusion in patients undergoing mitral valve surgery. The dilated left ventricle had markedly higher (P < 0.05) concentrations (nmol/mg wet weight) of taurine (17.0 ± 1.5 vs. 10.9 ± 1.5), glutamine (20.5 ± 2.4 vs. 12.1 ± 1.2), and glutamate (18.3 ± 2.2 vs. 11.4 ± 1.5) when compared to right ventricle. There were no differences in the basal levels of alanine or aspartate. Upon reperfusion, a significant (P < 0.05) fall in taurine and glutamine was seen only in the left ventricle. These changes are likely to be due to transport (taurine) and/or metabolism (glutamine). There was a marked increase in the alanine to glutamate ratio in both ventricles indicative of ischemic stress which was confirmed by global release of lactate during reperfusion. This study shows that in contrast to the right ventricle, the dilated left ventricle had remodeled to accumulate amino acids which are used during ischemia and reperfusion. Whether these changes reflect differences in degree of cardioplegic protection between the two ventricles remain to be investigated.     

Assessing Right Ventricular Function in Patients with Hypertrophic Cardiomyopathy with Cardiac MRI: Correlation with the New York Heart Function Assessment (NYHA) Classification

Purpose

To determine whether 3.0-T magnetic resonance imaging (MRI) could assess right ventricular (RV) function in patients with hypertrophic cardiomyopathy (HCM), and if this assessment is correlated with the New York Heart Function Assessment (NYHA) classification.

Materials and Methods

Forty-six patients with HCM and 23 normal individuals were recruited. Left and right ventricular function parameters including end-diastolic and end-systolic volumes (EDV, ESV), stroke volume (SV) and ejection fraction (EF) and dimensions were measured and compared using 3.0-T MRI. RV function parameters between HCM patients and controls were compared using independent sample t tests. A one way ANOVA test with Bonferroni correction was used to determine significant differences among different NYHA groups. Receiver operating characteristic analyses calculated the sensitivity and specificity of RV dysfunction on MRI for the prediction of HCM severity.

Results

Statistical analysis revealed significant differences of left ventricular (LV) and RV volumetric values and masses between the HCM patients and controls (all p<0.05). Within the HCM group, the simultaneously decreased maximum RVEDD correlated well with the LVEDD (r = 0.53; p<0.001). The function and dimension parameters among Class I to III were not determined to be significantly different (all p>0.05). However, significant differences between the Class IV and I-III groups (all P<0.0167) indicated that the diastolic and systolic function in both the RV and LV were impaired in Class IV patients. ROC analyses identified the EDV, ESV and EDD of both the LV and RV with a high sensitivity cutoff value to predict the HCM patients with severe heart failure (Class IV) with high sensitivity and specificity.

Conclusions

RV involvements were comparable to those of LV global function impairments in patients with HCM. The presence of RV dysfunction and decreased dimension on the MRI helped to predict the severe symptomatic HCM with high sensitivity and specificity.     

Serotonin-mediated protein carbonylation in the right heart

Pulmonary hypertension is a devastating disease, which leads to right heart failure. Serotonin (5-HT) plays important roles in the pathogenesis of pulmonary hypertension and pulmonary vascular remodeling. The role of 5-HT in right heart failure, however, is unknown. Since oxidative stress may mediate heart failure, the present study examined the effects of 5-HT on protein oxidation in the adult rat right heart ventricle. Treatment of perfused isolated hearts with 5-HT resulted in the promotion of protein carbonylation, specifically in the right ventricle, but not in the left. While no differences between right and left ventricular antioxidant enzymes and 5-HT receptors/transporter were detected, monoamine oxidase A (MAO-A) expression and activity were found to be lower in the right ventricle compared to the left. These results indicate that differences in neither the reactive oxygen species (ROS) scavenging ability, 5-HT membrane signaling capacity, nor MAO-dependent production of hydrogen peroxide are responsible for varied 5-HT-mediated protein carbonylation in right and left ventricles. Rather, lower MAO-A in the right heart might preserve cytosolic 5-HT which triggers other mechanisms for ROS production. Consistently, inhibition of MAO-A resulted in the promotion of protein carbonylation. We propose that low MAO-A, thus reduced degradation of 5-HT, increases the intracellular 5-HT activity in the right ventricle, leading to the promotion of protein carbonylation.     

Long-term follow-up in adults after tetralogy of Fallot repair

Background

Tetralogy of Fallot (ToF) is the most common cyanotic congenital heart disease and the population of ToF repair survivors is growing rapidly. Adults with repaired ToF develop late complications. The aim of this study was to describe and analyze long-term follow-up of patients with repaired ToF.

Methods

This is a retrospective cohort study. Consecutive 83 patients with repaired ToF who did not undergo pulmonary valve replacement were included. Mean age of all patients was 30.5?±?10.7. There were 49 (59%) male. Patients were divided into two groups according to the time since the repair (<?25 years and?≥?25 years). The electrocardiographic (ECG), cardiopulmonary exercise testing (CPET), echocardiographic and cardiac magnetic resonance (CMR) data were reviewed retrospectively.

Results

In CPET values were not significantly different in the two groups. In CMR volumes of left and right ventricles were not significantly different in the two groups. There were no differences between the groups in ventricular ejection fraction, mass of ventricles, or pulmonary regurgitation fraction. Among all the patients, ejection fraction and left and right ventricle mass, indexed pulmonary regurgitation volume measured by CMR did not correlate with the time since repair. In ECG among all the patients, ejection fraction of the RV, measured in CMR, negatively correlated with QRS duration (r?=???0.43; p?<?0.001). There was a positive correlation between QRS duration and end diastolic volume of the RV (r?=?0.30; p?<?0.02), indexed end diastolic volume of the RV (r?=?0.29; p?=?0.04), RV mass (r?=?0.36; p?<?0.001) and left ventricle mass (r?=?0.26; p?=?0.04).

Conclusion

Long-term survival and clinical condition after surgical correction of ToF in infancy is generally good and the late functional status in ToF – operated patients could be excellent up to 25 years after the repair. QRS duration could be an utility and easy factor to assessment of right ventricular function.

Trial registration

The study protocol was approved by the local Ethics Committee. Each participant provided informed consent to participate in the study (license number 122.6120.88.2016 from 28.04.2016).

     

Ultrasound imaging versus morphopathology in cardiovascular diseases. Myocardial cell damage

Background

Abnormalities in right ventricular function are known to occur in patients with pulmonary arterial hypertension.

Objective

Test the hypothesis that chronic elevation in pulmonary artery systolic pressure delays mechanical activation of the right ventricle, termed dyssynchrony, and is associated with both symptoms and right ventricular dysfunction.

Methods

Fifty-two patients (mean age 46 ± 15 years, 24 patients with chronic pulmonary hypertension) were prospectively evaluated using several echocardiographic parameters to assess right ventricular size and function. In addition, tissue Doppler imaging was also obtained to assess longitudinal strain of the right ventricular wall, interventricular septum, and lateral wall of the left ventricle and examined with regards to right ventricular size and function as well as clinical variables.

Results

In this study, patients with chronic pulmonary hypertension had statistically different right ventricular fractional area change (35 ± 13 percent), right ventricular end-systolic area (21 ± 10 cm²), right ventricular Myocardial Performance Index (0.72 ± 0.34), and Eccentricity Index (1.34 ± 0.37) than individuals without pulmonary hypertension (51 ± 5 percent, 9 ± 2 cm², 0.27 ± 0.09, and 0.97 ± 0.06, p < 0.005, respectively). Furthermore, peak longitudinal right ventricular wall strain in chronic pulmonary hypertension was also different -20.8 ± 9.0 percent versus -28.0 ± 4.1 percent, p < 0.01). Right ventricular dyssynchrony correlated very well with right ventricular end-systolic area (r = 0.79, p < 0.001) and Eccentricity Index (r = 0.83, p < 0.001). Furthermore, right ventricular dyssynchrony correlates with pulmonary hypertension severity index (p < 0.0001), World Health Organization class (p < 0.0001), and number of hospitalizations (p < 0.0001).

Conclusion

Lower peak longitudinal right ventricular wall strain and significantly delayed time-to-peak strain values, consistent with right ventricular dyssynchrony, were found in a small heterogeneous group of patients with chronic pulmonary hypertension when compared to individuals without pulmonary hypertension. Furthermore, right ventricular dyssynchrony was associated with disease severity and compromised functional class.     

Differential regulation of PDE5 expression in left and right ventricles of feline hypertrophy models

Background

Though long known to affect smooth muscle biology, recent studies indicate that phosphodiesterase 5 (PDE5) is also expressed in myocardium. Recognizing that the regulation of PDE5 in hypertrophy is not well understood, we assessed the response of PDE5 expression and the level of cGMP-dependent kinase I (cGKI) in the left and right ventricles of feline hypertrophy models.

Methodology/Principal Findings

Using a cDNA library of feline aortic smooth muscle cells, we identified and cloned PDE5 cDNA for the first time in this species. The sequence shares 98% identity with its human orthologue at the amino acid level. E. coli expression of the cloned allele allowed selection of antibodies with appropriate specificity, facilitating the analysis of PDE5 expression in feline models created by selective proximal aortic (Ao) or pulmonary artery (PA) banding that resulted in hypertrophy of the left ventricle (LV) and right ventricle (RV), respectively. We demonstrated that PDE5 expression responded differentially with a decreased expression in the LV and an increased expression in the RV in the Ao-banded model. Similarly, in the PA-banded model, LV showed reduced expression while the RV expression was unaltered. In addition, the expression of cGKI was significantly decreased in the RV of Ao-banded group, correlating inversely with the increase in PDE5 expression.

Conclusions/Significance

The differential regulation of PDE5 and cGKI expression suggests that the mechanisms involved in hypertrophy could be different in RV vs. LV. Reciprocal PDE5 and cGKI expression in the RV of Ao-banded model suggests functional significance for PDE5 up-regulation.     

磁共振成像对扩张型心肌病转基因模型小鼠左右心室对比分析

目的对cTnTR141W扩张型心肌病转基因模型小鼠左、右心室进行对比分析,研究cTnTR141W转基因小鼠作为右心室心肌病的动物模型的可行性。方法利用7.0 T高场强磁共振成像(MRI)技术,定量分析了2、4、6和8月龄对照组及cTnTR141W转基因模型小鼠左、右心室的舒张末容积(EDV)、收缩末容积(ESV)和射血分数(EF)的变化情况,同时对6月龄对照组cTnTR141W转基因模型小鼠心肌组织进行组织学分析。结果转基因阴性对照小鼠相比,cTnTR141W转基因小鼠左、右心室的容积在2月龄时已有增大趋势,而射血分数有减小趋势。右心室射血分数减小出现最早也最显著(P<0.05)。随年龄增加,cTnTR141W转基因小鼠与转基因阴性对照小鼠相比,右心室的结构和功能的病理生理变化与左心室同时趋于严重。该小鼠左、右心室在4月龄后表现典型的扩张型心肌病表型。结论 cTnTR141W转基因模型小鼠左心室和右心室的扩张性心肌病表型同时出现,该小鼠可作为右室性心肌病等右心室功能下降相关疾病研究的动物模型。