Multistep ion channel remodeling and lethal arrhythmia precede heart failure in a mouse model of inherited dilated cardiomyopathy

Background

Patients with inherited dilated cardiomyopathy (DCM) frequently die with severe heart failure (HF) or die suddenly with arrhythmias, although these symptoms are not always observed at birth. It remains unclear how and when HF and arrhythmogenic changes develop in these DCM mutation carriers. In order to address this issue, properties of the myocardium and underlying gene expressions were studied using a knock-in mouse model of human inherited DCM caused by a deletion mutation ΔK210 in cardiac troponinT.

Methodology/Principal Findings

By 1 month, DCM mice had already enlarged hearts, but showed no symptoms of HF and a much lower mortality than at 2 months or later. At around 2 months, some would die suddenly with no clear symptoms of HF, whereas at 3 months, many of the survivors showed evident symptoms of HF. In isolated left ventricular myocardium (LV) from 2 month-mice, spontaneous activity frequently occurred and action potential duration (APD) was prolonged. Transient outward (I_to) and ultrarapid delayed rectifier K⁺ (I_Kur) currents were significantly reduced in DCM myocytes. Correspondingly, down-regulation of Kv4.2, Kv1.5 and KChIP2 was evident in mRNA and protein levels. In LVs at 3-months, more frequent spontaneous activity, greater prolongation of APD and further down-regulation in above K⁺ channels were observed. At 1 month, in contrast, infrequent spontaneous activity and down-regulation of Kv4.2, but not Kv1.5 or KChIP2, were observed.

Conclusions/Significance

Our results suggest that at least three steps of electrical remodeling occur in the hearts of DCM model mice, and that the combined down-regulation of Kv4.2, Kv1.5 and KChIP2 prior to the onset of HF may play an important role in the premature sudden death in this DCM model. DCM mice at 1 month or before, on the contrary, are associated with low risk of death in spite of inborn disorder and enlarged heart.     

Mutations of presenilin genes in dilated cardiomyopathy and heart failure

Two common disorders of the elderly are heart failure and Alzheimer disease (AD). Heart failure usually results from dilated cardiomyopathy (DCM). DCM of unknown cause in families has recently been shown to result from genetic disease, highlighting newly discovered disease mechanisms. AD is the most frequent neurodegenerative disease of older Americans. Familial AD is caused most commonly by presenilin 1 (PSEN1) or presenilin 2 (PSEN2) mutations, a discovery that has greatly advanced the field. The presenilins are also expressed in the heart and are critical to cardiac development. We hypothesized that mutations in presenilins may also be associated with DCM and that their discovery could provide new insight into the pathogenesis of DCM and heart failure. A total of 315 index patients with DCM were evaluated for sequence variation in PSEN1 and PSEN2. Families positive for mutations underwent additional clinical, genetic, and functional studies. A novel PSEN1 missense mutation (Asp333Gly) was identified in one family, and a single PSEN2 missense mutation (Ser130Leu) was found in two other families. Both mutations segregated with DCM and heart failure. The PSEN1 mutation was associated with complete penetrance and progressive disease that resulted in the necessity of cardiac transplantation or in death. The PSEN2 mutation showed partial penetrance, milder disease, and a more favorable prognosis. Calcium signaling was altered in cultured skin fibroblasts from PSEN1 and PSEN2 mutation carriers. These data indicate that PSEN1 and PSEN2 mutations are associated with DCM and heart failure and implicate novel mechanisms of myocardial disease.     

Exercise during transition from compensated left ventricular hypertrophy to heart failure in aortic stenosis rats

We evaluated the influence of aerobic exercise on cardiac remodelling during the transition from compensated left ventricular (LV) hypertrophy to clinical heart failure in aortic stenosis (AS) rats. Eighteen weeks after AS induction, rats were assigned into sedentary (AS) and exercised (AS‐Ex) groups. Results were compared to Sham rats. Exercise was performed on treadmill for 8 weeks. Exercise improved functional capacity. Echocardiogram showed no differences between AS‐Ex and AS groups. After exercise, fractional shortening and ejection fraction were lower in AS‐Ex than Sham. Myocyte diameter and interstitial collagen fraction were higher in AS and AS‐Ex than Sham; however, myocyte diameter was higher in AS‐Ex than AS. Myocardial oxidative stress, evaluated by lipid hydroperoxide concentration, was higher in AS than Sham and was normalized by exercise. Gene expression of the NADPH oxidase subunits NOX2 and NOX4, which participate in ROS generation, did not differ between groups. Activity of the antioxidant enzyme superoxide dismutase was lower in AS and AS‐Ex than Sham and glutathione peroxidase was lower in AS‐Ex than Sham. Total and reduced myocardial glutathione, which is involved in cellular defence against oxidative stress, was lower in AS than Sham and total glutathione was higher in AS‐Ex than AS. The MAPK JNK was higher in AS‐Ex than Sham and AS groups. Phosphorylated P38 was lower in AS‐Ex than AS. Despite improving functional capacity, aerobic exercise does not change LV function in AS rats. Exercise restores myocardial glutathione, reduces oxidative stress, impairs JNK signalling and further induces myocyte hypertrophy.     

Current approaches to unravel the mystery of dilated cardiomyopathy,a common cause of hereditary heart failure

As is well known, adipose tissue is an important site for lipid metabolism and insulin-responsive glucose uptake. The recent discovery of the endocrine function of adipose tissue and the association of obesity with chronic low-grade inflammation in adipose tissue has reinforced the concept of the central role of adipose tissue in mediating obesity-linked insulin resistance and metabolic dysregulation. The study of adipose cells has provided new insights into the mechanism underlying insulin resistance as well as the therapeutic strategies for diabetes. Numerous efforts have been made in identifying key molecular regulators of insulin action and metabolism, including the utilization of advanced proteomics technology. Various proteomic approaches have been applied to identify the adipose secretome, protein-expression profiling and post-translational modifications in adipose cells in the pathological state. In this review, we summarize the recent advances in the proteomics of adipose tissue, and discuss the identified proteins that potentially play important roles in insulin resistance and diabetes.     

Association of galectin-3 with changes in left ventricular function in recent-onset dilated cardiomyopathy

Abstract

Background: The course of newly diagnosed dilated cardiomyopathy (DCM) varies from persistent reduction of left ventricular ejection fraction (LVEF) to recovery or even worsening. The aim of the present study was to examine the prognostic value of selected biomarkers with regard to changes in LVEF.

Methods: Main inclusion criterion was LVEF ≤45% with exclusion of coronary artery or valvular heart disease. The primary endpoint was LVEF ≤35% in the follow-up echocardiogram. Galectin-3, N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) were related to the endpoint.

Results: Data from 80 DCM patients (55 male, mean age 53 years) were analyzed. Median LVEF was 25% (IQR 25–30). The endpoint was met for 24 patients (30%). These had higher baseline levels of galectin-3 (median 20.3?ng/mL [IQR 14.3–26.9] vs. 14.7?ng/mL [IQR 10.9–17.7], p?=?0.007) and NT-proBNP (3089?pg/mL [IQR 1731–6694] vs. 1498?pg/mL [IQR 775–3890]; p?=?0.004) in univariate Cox regression analysis. ROC analysis revealed that CRP (median 0.4?mg/dL [IQR 0.2–1.2]) was also related to the endpoint (p?=?0.043).

Conclusion: Higher levels of galectin-3, NT-proBNP, and CRP were associated with LVEF ≤35% in our cohort. An approach utilizing a combination of biomarkers for patient management should be assessed in further studies.     

Differential expression profiles of plasma exosomal microRNAs in dilated cardiomyopathy with chronic heart failure

As one of the most prevalent heritable cardiovascular diseases, dilated cardiomyopathy (DCM) induces cardiac insufficiency and dysfunction. Although genetic mutation has been identified one of the causes of DCM, the usage of genetic biomarkers such as RNAs for DCM early diagnosis is still being overlooked. In addition, the alternation of RNAs could reflect the progression of the diseases, as an indicator for the prognosis of patients. Therefore, it is beneficial to develop genetic based diagnostic tool for DCM. RNAs are often unstable within circulatory system, leading to the infeasibility for clinical application. Recently discovered exosomal miRNAs have the stability that is then need for diagnostic purpose. Hence, fully understanding of the exosomal miRNA within DCM patients is vital for clinical translation. In this study, we employed the next generation sequencing based on the plasma exosomal miRNAs to comprehensively characterize the miRNAs expression in plasma exosomes from DCM patients exhibiting chronic heart failure (CHF) compared to healthy individuals. A complex landscape of differential miRNAs and target genes in DCM with CHF patients were identified. More importantly, we discovered that 92 differentially expressed miRNAs in DCM patients undergoing CHF were correlated with several enriched pathways, including oxytocin signalling pathway, circadian entrainment, hippo signalling pathway-multiple species, ras signalling pathway and morphine addiction. This study reveals the miRNA expression profiles in plasma exosomes in DCM patients with CHF, and further reveal their potential roles in the pathogenesis of it, presenting a new direction for clinical diagnosis and management of DCM patients with CHF.     

Cardiac protein changes in ischaemic and dilated cardiomyopathy: a proteomic study of human left ventricular tissue

The development of heart failure (HF) is characterized by progressive alteration of left ventricle structure and function. Previous works on proteomic analysis in cardiac tissue from patients with HF remain scant. The purpose of our study was to use a proteomic approach to investigate variations in protein expression of left ventricle tissue from patients with ischaemic (ICM) and dilated cardiomyopathy (DCM). Twenty-four explanted human hearts, 12 from patients with ICM and 12 with DCM undergoing cardiac transplantation and six non-diseased donor hearts (CNT) were analysed by 2DE. Proteins of interest were identified by mass spectrometry and validated by Western blotting and immunofluorescence. We encountered 35 differentially regulated spots in the comparison CNT versus ICM, 33 in CNT versus DCM, and 34 in ICM versus DCM. We identified glyceraldehyde 3-phophate dehydrogenase up-regulation in both ICM and DCM, and alpha-crystallin B down-regulation in both ICM and DCM. Heat shock 70 protein 1 was up-regulated only in ICM. Ten of the eleven differentially regulated proteins common to both aetiologies are interconnected as a part of a same network. In summary, we have shown by proteomics analysis that HF is associated with changes in proteins involved in the cellular stress response, respiratory chain and cardiac metabolism. Although we found altered expression of eleven proteins common to both ischaemic and dilated aetiology, we also observed different proteins altered in both groups. Furthermore, we obtained that seven of these eleven proteins are involved in cell death and apoptosis processes, and therefore in HF progression.     

Detection of mitochondrial dysfunction by EPR technique in mouse model of dilated cardiomyopathy

Tgalphaq44 mice with targeted overexpression of activated Galphaq protein in cardiomyocytes mimic many of the phenotypic characteristics of dilated cardiomyopathy in humans. However, it is not known whether the phenotype of Tgalphaq44 mice would also involve dysfunction of cardiac mitochondria. The aim of the present work was to examine changes in EPR signals of semiquinones and iron in Fe-S clusters, as compared to classical biochemical indices of mitochondrial function in hearts from Tgalphaq44 mice in relation to the progression of heart failure. Tgalphaq44 mice at the age of 14 months displayed pulmonary congestion, increased heart/body ratio and impairment of cardiac function as measured in vivo by MRI. However, in hearts from Tgalphaq44 mice already at the age of 10 months EPR signals of semiquinones, as well as cyt c oxidase activity were decreased, suggesting alterations in mitochondrial electron flow. Furthermore, in 14-months old Tgalphaq44 mice loss of iron in Fe-S clusters, impaired citrate synthase activity, and altered mitochondrial ultrastructure were observed, supporting mitochondrial dysfunction in Tgalphaq44 mice. In conclusion, the assessment of semiquinones content and Fe(III) analysis by EPR represents a rational approach to detect dysfunction of cardiac mitochondria. Decreased contents of semiquinones detected by EPR and a parallel decrease in cyt c oxidase activity occurs before hemodynamic decompensation of heart failure in Tgalphaq44 mice suggesting that alterations in function of cardiac mitochondria contribute to the development of the overt heart failure in this model.     

Cardiac calcineurin during transition from hypertrophy to heart failure in rats

We studied an alteration of calcineurin expression in the heart and its modification by cyclosporin A and an ACE inhibitor, temocapril, using Dahl salt-sensitive (DS) rats with hypertensive left ventricular hypertrophy (LVH) and congestive heart failure (CHF). Calcineurin protein expression in the LV myocardium was increased in the LVH stage, but then decreased during CHF transition. Chronic cyclosporin A treatment (10 mg/kg/day), which inhibits calcineurin activity, could not block the increases of LV weight and dimensions and did not improve the LV systolic function during the CHF transition. In contrast, chronic temocapril treatment (20 mg/kg/day) restored the downregulation of calcineurin expression, but progression of the hypertrophic process was inhibited. Therefore, cardiac calcineurin is increased in the hypertensive LVH and may be involved in the development of the adaptive hypertrophic process. However, calcineurin expression is downregulated during CHF transition and may no longer play a major role in the pathogenesis of myocardial hypertrophy in the failing hearts.     

Right ventricular function in dilated cardiomyopathy and ischemic heart disease: assessment with non-invasive imaging

Background

Dilated cardiomyopathy and ischaemic heart disease can both lead to right ventricular (RV) dysfunction. Direct comparisons of the two entities regarding RV size and function using state-of-the-art imaging techniques have not yet been performed. We aimed to determine RV function and volume in dilated cardiomyopathy and ischaemic heart disease in relation to left ventricular (LV) systolic and diastolic function and systolic pulmonary artery pressure.

Methods and results

A well-characterised group (cardiac magnetic resonance imaging, echocardiography, coronary angiography and endomyocardial biopsy) of 46 patients with dilated cardiomyopathy was compared with LV ejection fraction (EF)-matched patients (n = 23) with ischaemic heart disease. Volumes and EF were determined with magnetic resonance imaging, diastolic LV function and pulmonary artery pressure with echocardiography.After multivariable linear regression, four factors independently influenced RVEF (R² = 0.51, p < 0.001): LVEF (r = 0.54, p < 0.001), ratio of peak early and peak atrial transmitral Doppler flow velocity as measure of LV filling pressure (r = − 0.52, p < 0.001) and tricuspid regurgitation flow velocity as measure of pulmonary artery pressure (r = − 0.38, p = 0.001). RVEF was significantly worse in patients with dilated cardiomyopathy compared with ischaemic heart disease: median 48 % (interquartile range (IQR) 37–55 %) versus 56 % (IQR 48–63 %), p < 0.05.

Conclusions

In patients with dilated cardiomyopathy and ischaemic heart disease, RV function is determined by LV systolic and diastolic function, the underlying cause of LV dysfunction, and pulmonary artery pressure. It was demonstrated that RV function is more impaired in dilated cardiomyopathy.     

Quinapril inhibits progression of heart failure and fibrosis in rats with dilated cardiomyopathy after myocarditis

The cardioprotective properties of quinapril, an angiotensin-converting enzyme inhibitor, were studied in a rat model of dilated cardiomyopathy. Twenty-eight days after immunization of pig cardiac myosin, four groups rats were given 0.2 mg/kg (Q0.2, n = 11), 2 mg/kg (Q2, n = 11) or 20 mg/kg (Q20, n = 11) of quinapril or vehicle (V, n = 15) orally once a day. After 1 month, left ventricular end-diastolic pressure (LVEDP), ±dP/dt, area of myocardial fibrosis, and myocardial mRNA expression of transforming growth factor (TGF)-1, collagen-III and fibronectin were measured. Four of 15 (27%) rats in V and two of 11 (18%) in Q0.2 died. None of the animals in Q2 or Q20 died. The LVEDP was higher and ±dP/dt was lower in V (14.1 ± 2.0 mmHg and +2409 ± 150/–2318 ± 235 mmHg/sec) than in age-matched normal rats (5.0 ± 0.6 mmHg and +6173 ± 191/–7120 ± 74 mmHg/sec; all p < 0.01). After quinapril treatment, LVEDP was decreased and ±dP/dt was increased in a dose-dependent manner (10.8 ± 1.8 mmHg and +3211 ± 307/–2928 ± 390 mmHg/sec in Q0.2, 9.4 ± 1.5 mmHg and +2871 ± 270/–2966 ± 366 mmHg/sec in Q2, and 6.6 ± 1.5 mmHg, and +3569 ± 169/–3960 ± 203 mmHg/sec in Q20). Increased expression levels of TGF-1, collagen-III and fibronectin mRNA in V were reduced in Q20. Quinapril improved survival rate and cardiac function in rats with dilated cardiomyopathy after myocarditis. Furthermore, myocardial fibrosis was regressed and myocardial structure returned to nearly normal in animals treated with quinapril.     

Autophagic vacuoles in cardiomyocytes of dilated cardiomyopathy with initially decompensated heart failure predict improved prognosis

Autophagy is a process of bulk protein degradation and organelle turnover, and is a current therapeutic target in several diseases. The present study aimed to clarify the significance of myocardial autophagy of patients with dilated cardiomyopathy (DCM). Left ventricular endomyocardial biopsy was performed in 250 consecutive patients with DCM (54.9±13.9 years; male, 79%), initially presenting with decompensated heart failure (HF). The association of these findings with HF mortality or recurrence was examined. Myofilament changes, which are apparent in the degenerated cardiomyocytes of DCM, were recognized in 164 patients (66%), and autophagic vacuoles in cardiomyocytes were identified in or near the area of myofilament changes in 86 patients (34%). Morphometrically, fibrosis (odds ratio [OR], 0.96; 95% confidence interval [CI], 0.93 to 0.99) and mitochondrial abnormality (OR, 2.24; 95% CI, 1.23 to 4.08) were independently related with autophagic vacuoles. During the follow-up period of 4.9±3.9 y, 24 patients (10%) died, including 10 (4%) who died of HF, and 67 (27%) were readmitted for HF recurrence. Multivariate analysis identified a family history of DCM (hazard ratio [HR], 2.117; 95% CI, 1.199 to 3.738), hemoglobin level (HR, 0.845; 95% CI, 0.749 to 0.953), myofilament changes (HR, 13.525; 95% CI, 5.340 to 34.255), and autophagic vacuoles (HR, 0.214; 95% CI, 0.114 to 0.400) as independent predictors of death or readmission due to HF recurrence. In conclusion, autophagic vacuoles in cardiomyocytes are associated with a better HF prognosis in patients with DCM, suggesting autophagy may play a role in the prevention of myocardial degeneration.     

Calcineurin-induced energy wasting in a transgenic mouse model of heart failure

Overexpression of calcineurin (CLN) in the mouse heart induces severe hypertrophy that progresses to heart failure, providing an opportunity to define the relationship between energetics and contractile performance in the severely failing mouse heart. Contractile performance was studied in isolated hearts at different pacing frequencies and during dobutamine challenge. Energetics were assessed by 31P-NMR spectroscopy as ATP and phosphocreatine concentrations ([ATP] and [PCr]) and free energy of ATP hydrolysis (|Delta G( approximately ATP)|). Mitochondrial and glycolytic enzyme activities, myocardial O2 consumption, and myocyte ultrastructure were determined. In transgenic (TG) hearts at all levels of work, indexes of systolic performance were reduced and [ATP] and capacity for ATP synthesis were lower than in non-TG hearts. This is the first report showing that myocardial [ATP] is lower in a TG mouse model of heart failure. [PCr] was also lower, despite an unexpected increase in the total creatine pool. Because Pi concentration remained low, despite lower [ATP] and [PCr], |Delta G( approximately ATP)| was normal; however, chemical energy did not translate to systolic performance. This was most apparent with beta-adrenergic stimulation of TG hearts, during which, for similar changes in |Delta G( approximately ATP)|, systolic pressure decreased, rather than increased. Structural abnormalities observed for sarcomeres and mitochondria likely contribute to decreased contractile performance. On the basis of the increases in enzyme activities of proteins important for ATP supply observed after treatment with the CLN inhibitor cyclosporin A, we also conclude that CLN directed inhibition of ATP-producing pathways in non-TG and TG hearts.     

Cellular and functional defects in a mouse model of heart failure

Heart failure and dilated cardiomyopathy develop in mice that lack the muscle LIM protein (MLP) gene (MLP(-/-)). The character and extent of the heart failure that occurs in MLP(-/-) mice were investigated using echocardiography and in vivo pressure-volume (P-V) loop measurements. P-V loop data were obtained with a new method for mice (sonomicrometry) using two pairs of orthogonal piezoelectric crystals implanted in the endocardial wall. Sonomicrometry revealed right-shifted P-V loops in MLP(-/-) mice, depressed systolic contractility, and additional evidence of heart failure. Cellular changes in MLP(-/-) mice were examined in isolated single cells using patch-clamp and confocal Ca(2+) concentration ([Ca(2+)]) imaging techniques. This cellular investigation revealed unchanged Ca(2+) currents and Ca(2+) spark characteristics but decreased intracellular [Ca(2+)] transients and contractile responses and a defect in excitation-contraction coupling. Normal cellular and whole heart function was restored in MLP(-/-) mice that express a cardiac-targeted transgene, which blocks the function of beta-adrenergic receptor (beta-AR) kinase-1 (betaARK1). These data suggest that, despite the persistent stimulus to develop heart failure in MLP(-/-) mice (i.e., loss of the structural protein MLP), downregulation and desensitization of the beta-ARs may play a pivotal role in the pathogenesis. Furthermore, this work suggests that the inhibition of betaARK1 action may prove an effective therapy for heart failure.     

Epicardial adipose tissue assessed by cardiac magnetic resonance imaging in patients with heart failure due to dilated cardiomyopathy

Objective:

We sought to investigate the association of the EAT with CMR parameters of ventricular remodelling and left ventricular (LV) dysfunction in patients with non‐ischemic dilated cardiomyopathy (DCM).

Design and Methods:

One hundred and fifty subjects (112 consecutive patients with DCM and 48 healthy controls) underwent CMR examination. Function, volumes, dimensions, the LV remodelling index (LVRI), the presence of late gadolinium enhancement (LGE) and the amount of EAT were assessed.

Results:

Compared to healthy controls, patients with DCM revealed a significantly reduced indexed EAT mass (31.7 ± 5.6 g/m² vs 24.0 ± 7.5 g/m², p<0.0001). There was no difference in the EAT mass between DCM patients with moderate and severe LV dysfunction (23.5 ± 9.8 g/m² vs 24.2 ± 6.6 g/m², P = 0.7). Linear regression analysis in DCM patients showed that with increasing LV end‐diastolic mass index (LV‐EDMI) (r = 0.417, P < 0.0001), increasing LV end‐diastolic volume index (r = 0.251, P = 0.01) and increasing LV end‐diastolic diameter (r = 0.220, P = 0.02), there was also a significantly increased amount of EAT mass. However, there was no correlation between the EAT and the LV ejection fraction (r = 0.0085, P = 0.37), right ventricular ejection fraction (r = 0.049, P = 0.6), LVRI (r = 0.116, P = 0.2) and the extent of LGE % (r = 0.189, P = 0.1). Among the healthy controls, the amount of EAT only correlated with increasing age (r = 0.461, P = 0.001), BMI (r = 0.426, P = 0.003) and LV‐EDMI (r = 0.346, P = 0.02).

Conclusion:

In patients with DCM the amount of EAT is decreased compared to healthy controls irrespective of LV function impairment. However, an increase in LV mass and volumes is associated with a significantly increase in EAT in patients with DCM.     

A targeted metabolomics assay for cardiac metabolism and demonstration using a mouse model of dilated cardiomyopathy

Metabolomics can be performed either as an ‘open profiling’ tool where the aim is to measure, usually in a semi-quantitative manner, as many metabolites as possible or perform ‘closed’ or ‘targeted’ analyses where instead a pre-defined set of metabolites are measured. Targeted methods can be designed to be more sensitive and quantitative and so are particularly appropriate to systems biology for quantitative models of systems or when metabolomics is performed in a hypothesis driven manner to test whether a particular pathway is perturbed. We describe a targeted metabolomics assay that quantifies a broad range of over 130 metabolites relevant to cardiac metabolism including the pathways of the citric acid cycle, fatty acid oxidation, glycolysis, the pentose phosphate pathway, amino acid metabolism, the urea cycle, nucleotides and reactive oxygen species using tandem mass spectrometry to produce quantitative, sensitive and robust data. This assay is illustrated by profiling cardiac metabolism in a lamin A/C (Lmna) mouse model of dilated cardiomyopathy (DCM). The model of DCM was characterised by increases in concentrations of proline and methyl-histidine suggestive of increased myofibrillar and collagen degradation, as well as decreases in a number of citric acid cycle intermediates and carnitine derivatives indicating reduced energy metabolism in the dilated heart. These assays could be used for any other cardiac or cardiovascular disease in that they cover central core metabolism and key pathways involved in cardiac metabolism, and may provide a general start for many mammalian systems.     

Fluid dynamics of the left ventricular filling in dilated cardiomyopathy

Modifications in diastolic function occur in a broad range of cardiovascular diseases and there is an increasing evidence that abnormalities in left ventricular function may contribute significantly to the symptomatology. The flow inside the left ventricle during the diastole is here investigated by numerical solution of the Navier-Stokes equations under the axisymmetric assumption. The equation are written in a body-fitted, moving prolate spheroid, system of coordinates and solved using a fractional step method. The system is forced by a given volume time-law derived from clinical data, and varying the two-degrees-of-freedom ventricle geometry on the basis of a simple model. The solution under healthy conditions is analysed in terms of vorticity dynamics, showing that the flow field is characterised by the presence of a vortex wake; it is attached to the mitral valve during the accelerating phase of the E-wave, and it detaches and translate towards the ventricle apex afterwards. The flow evolution is discussed, results are also reported as an M-mode representation of colour-coded Doppler velocity maps. In the presence of ventricle dilatation the mitral jet extends farther inside the ventricle, propagation velocity decreases, and the fluid stagnates longer at the apex.     

Dynamic microRNA expression during the transition from right ventricular hypertrophy to failure

MicroRNAs (miRs) are small, noncoding RNAs that are emerging as crucial regulators of cardiac remodeling in left ventricular hypertrophy (LVH) and failure (LVF). However, there are no data on their role in right ventricular hypertrophy (RVH) and failure (RVF). This is a critical question given that the RV is uniquely at risk in patients with congenital right-sided obstructive lesions and in those with systemic RVs. We have developed a murine model of RVH and RVF using pulmonary artery constriction (PAC). miR microarray analysis of RV from PAC vs. control demonstrates altered miR expression with gene targets associated with cardiomyocyte survival and growth during hypertrophy (miR 199a-3p) and reactivation of the fetal gene program during heart failure (miR-208b). The transition from hypertrophy to heart failure is characterized by apoptosis and fibrosis (miRs-34, 21, 1). Most are similar to LVH/LVF. However, there are several key differences between RV and LV: four miRs (34a, 28, 148a, and 93) were upregulated in RVH/RVF that are downregulated or unchanged in LVH/LVF. Furthermore, there is a corresponding downregulation of their putative target genes involving cell survival, proliferation, metabolism, extracellular matrix turnover, and impaired proteosomal function. The current study demonstrates, for the first time, alterations in miRs during the process of RV remodeling and the gene regulatory pathways leading to RVH and RVF. Many of these alterations are similar to those in the afterload-stressed LV. miRs differentially regulated between the RV and LV may contribute to the RVs increased susceptibility to heart failure.