Cardiac Function In Dilated Cardiomyopathy Research Articles

Abstract 16898: Myocardial Recovery Associated Gene Cdcp1 Expression Attenuates Cardiac Fibrosis in a Pressure Over-Load Mouse Model

Background: We have previously demonstrated by performing a genome-wide association study that a genetic locus resulting in ↓CDCP1 expression was associated with myocardial recovery in patients with dilated cardiomyopathy (DCM). We have subsequently shown that ↓CDCP1 decreases human cardiac fibroblast proliferation in vitro , however, its potential role in modulating cardiac fibrosis and function in vivo is unknown. Methods: A Cdcp1 knock-out (KO) mouse was generated on FVB/NJ background. Angiotensin II/Phenylephrine (AngII/PE) or saline was infused by an osmotic pump into mice ( Cdcp1 KO n=20; wild type/wt n=18) for 4 weeks. Echocardiography was performed at 0 and 4 weeks. Picrosirius red (PSR) staining was performed on cross-sectional heart tissue to identify cardiac fibrosis, which was quantified, using ImageJ software, as a percentage of left ventricular (LV) area stained by PSR. Results: LV mass index (LVMI) significantly increased in AngII/PE wt mice as compared to saline wt (figure a. 3.65±0.15 mg/g vs 3.05±0.17mg/g, p=0.01), however, AngII/PE Cdcp1 KO mice had significantly decreased LVMI as compared to AngII/PE wt mice (figure a. 3.17±0.09 mg/g vs 3.65±0.15 mg/g, p=0.01). In addition, fractional shortening trended higher in AngII/PE Cdcp1 KO mice as compared to AngII/PE wt mice (figure b. 50.36±2.06% vs 45.48±1.43%, p=0.07). Extent of cardiac fibrosis was significantly higher in AngII/PE wt mice as compared to saline wt (figure c. 15.79±0.49% vs 7.93±0.39%, p<0.0001), however AngII/PE Cdcp1 KO mice had significantly reduced cardiac fibrosis as compared to AngII/PE wt mice (figure c. 9.41±0.43%, p<0.0001). Conclusions: CDCP1 KO significantly reduces pressure over-load induced LV hypertrophy and cardiac fibrosis. Its role as a novel therapeutic target in attenuating fibrosis and improving cardiac function in DCM needs to be further explored.

Dapagliflozin protects against dilated cardiomyopathy progression by targeting NLRP3 inflammasome activation

Dilated cardiomyopathy (DCM) is the major cause of heart failure and has a poor prognosis. The accumulating evidence points to an essential role of the inflammatory component in the process of DCM. Inhibitors of sodium-glucose cotransporter 2 (SGLT2) are widely used to treat heart failure patients due to their cardiac benefits. However, their role in DCM remains unclear. We used the doxorubicin (Dox)-induced DCM model for our study. The SGLT2 inhibitor dapagliflozin (Dapa) improved cardiac function in mice treated with doxorubicin and attenuated the activation of the nucleotide-binding oligomerization domain-like receptor family protein 3 (NLRP3) inflammasome pathway and the expression of inflammatory factors. In addition, dapagliflozin suppresses NLRP3 activation by decreasing p38-dependent toll-like receptor 4 (TLR4) expression. In our study, dagliflozin improves cardiac function in DCM by inhibiting the activity of the NLRP3 inflammasome.Graphical

Apelin improves cardiac function mainly through peripheral vasodilation in a mouse model of dilated cardiomyopathy

There is growing evidence that apelin plays a role in the regulation of the cardiovascular system by increasing myocardial contractility and acting as a vasodilator. However, it remains unclear whether apelin improves cardiac contractility in a load-dependent or independent manner in pathological conditions. For this purpose we investigated the cardiovascular effects of apelin in α-actin transgenic mice (mActin-Tg mice), a model of cardiomyopathy. [Pyr1]apelin-13 was administered by continuous infusion at 2 mg/kg/d for 3 weeks. Effects on cardiac function were determined by echocardiography and a Pressure-Volume (PV) analysis. mActin-Tg mice showed a dilated cardiomyopathy (DCM) phenotype similar to that encountered in patients expressing the same mutation. Compared to WT animals, mActin-Tg mice displayed cardiac systolic impairment [significant decrease in ejection fraction (EF), cardiac output (CO), and stroke volume (SV)] associated with cardiac ventricular dilation and diastolic dysfunction, characterized by an impairment in mitral flow velocity (E/A) and in deceleration time (DT). Load-independent myocardial contractility was strongly decreased in mActin-Tg mice while total peripheral vascular resistance (TPR) was significantly increased. As compared to vehicle-treated animals, a 3-week treatment with [Pyr1]apelin-13 significantly improved EF%, SV, E/A, DT and corrected TPR, with no significant effect on load-independent indices of myocardial contractility, blood pressure and heart rate. In conclusion [Pyr1]apelin-13 displayed no intrinsic contractile effect but improved cardiac function in dilated cardiomyopathy mainly by reducing peripheral vascular resistance, with no change in blood pressure.

Up-regulating autophagy by targeting the mTOR-4EBP1 pathway: a possible mechanism for improving cardiac function in mice with experimental dilated cardiomyopathy

BackgroundAutophagy plays a crucial role in the pathological process of cardiovascular diseases. However, little is known about the pathological mechanism underlying autophagy regulation in dilated cardiomyopathy (DCM).MethodsWe explored whether up-regulating autophagy could improve cardiac function in mice with experimental DCM through the mTOR-4EBP1 pathway. Animal model of DCM was established in BALB/c mice by immunization with porcine cardiac myosin. Both up- or down-regulation of autophagy were studied by administration of rapamycin or 3-MA in parallel. Morphology, Western blotting, and echocardiography were applied to confirm the pathological mechanisms.ResultsAutophagy was activated and autophagosomes were significantly increased in the rapamycin group. The collagen volume fraction (CVF) was decreased in the rapamycin group compared with the DCM group (9.21 ± 0.82% vs 14.38 ± 1.24%, P < 0.01). The expression of p-mTOR and p-4EBP1 were significantly decreased in rapamycin-induced autophagy activation, while the levels were increased by down-regulating autophagy with 3-MA. In the rapamycin group, the LVEF and FS were significantly increased compared with the DCM group (54.12 ± 6.48% vs 45.29 ± 6.68%, P < 0.01; 26.89 ± 4.04% vs 22.17 ± 2.82%, P < 0.05). As the inhibitor of autophagy, 3-MA aggravated the progress of maladaptive cardiac remodeling and declined cardiac function in DCM mice.ConclusionsThe study indicated a possible mechanism for improving cardiac function in mice with experimental DCM by up-regulating autophagy via the mTOR-4EBP1 pathway, which could be a promising therapeutic strategy for DCM.

Evaluation of nonscarred myocardial T1 value using contrast-enhanced look-locker cardiac MRI and its relationship to cardiac function in dilated cardiomyopathy: Comparison of 1.5 and 3.0 Tesla MRI

To assess relationship between nonscarred myocardial T1 value measured using contrast-enhanced Look-Locker MRI and cardiac function in dilated cardiomyopathy (DCM) at 1.5 Tesla (T) and 3.0T MRI. Contrast-enhanced Look-Locker MRI was performed in 35 DCM patients. Nonscarred myocardial and blood T1 values were calculated from the signal intensity values and the delay time obtained on Look-Locker MRI. We assessed the correlation between the myocardial T1 value or myocardial T1 minus blood T1 value and cardiac function estimated using cine MRI (e.g., end-diastolic volume: EDV, left ventricular ejection fraction: LVEF) or brain natriuretic peptide (BNP). With 1.5T MRI (n = 16), the myocardial T1 value correlated negatively with the EDV(r = -0.66) and end-systolic volume (ESV; r = -0.68), and positively with the LVEF (r = 0.51); the myocardial T1 minus blood T1 value correlated inversely with EDV (r = -0.70), ESV (r = -0.62), and brain natriuretic peptide (BNP; r = -0.56). With 3.0T MRI (n = 17), the myocardial T1 value correlated negatively with ESV (r = -0.44), septal thickness (r = -0.60), and BNP (r = -0.51), and positively with LVEF (r = 0.61); the myocardial T1 minus blood T1 value negatively correlated with BNP (r = -0.50) and positively with LVEF (r = 0.54). The nonscarred myocardial T1 value measured with either 1.5T or 3.0T contrast-enhanced Look-Locker MRI is significantly related to cardiac dysfunction in DCM.

Myocardial alterations and clinical implications associated with recovery of cardiac function in dilated cardiomyopathy with obesity

BackgroundObesity is associated with an increased risk of heart failure (HF) but the relationship between changes in cardiac function and the specific pathological features of dilated cardiomyopathy (DCM) with obesity, remains unknown. MethodsEndomyocardial biopsies from the left ventricle (LV) were obtained from 50 patients with DCM, at the first-onset of decompensated HF. Thirty patients were obese (obese-group: body mass index >30kg/m2) and 20 were non-obese (lean-group). Clinical data were acquired at the admission, after one month and one year. ResultsThe obese-group had higher systolic blood pressure (142.8±33.9 vs 113.6±18.7mmHg; p<0.001) and serum troponin-T level (0.049±0.07 vs 0.020±0.03ng/mL; p=0.022) than the lean-group. LV ejection fraction (LVEF) was not significantly different between groups, but after one year the obese-group had an improved LVEF (57.0±11.4 vs 44.3±17.1; p=0.003). Light microscopy revealed that the obese-group had larger cardiomyocytes (17.2±1.7 vs 16.4±1.4μm; p=0.033) and less myofilament lysis (37 vs 75%; p=0.008) with a higher density of lipid droplets (1.93±0.8 vs 0.94±0.7 /μm2; p<0.001). Multivariate regression analysis revealed that independent predictors of LVEF improvement after 12months were diuretics use, nuclear diameter, and absence of myofilament lysis (p=0.024, 0.012 and 0.028, respectively). ConclusionsCardiac function in most patients with DCM with obesity is reversible and myocardial structural changes are trivial even at the ultrastructural level.

Evaluation of diffuse myocardial fibrosis using contrast-enhanced look-locker cardiac MRI and its relation with cardiac function in dilated cardiomyopathy: comparison between 1.5T and 3T

The purpose of this study was to evaluate diffuse myocardial fibrosis by measuring myocardial and blood T1-values using contrast-enhanced Look-Locker cardiac MRI and comparing these values with left cardiac function in dilated cardiomyopathy (DCM). We also sought to assess the relation between the diffuse myocardial fibrosis and cardiac function on 1.5T and 3.0T.

Immunoadsorption as treatment option in dilated cardiomyopathy

Abnormalities of the cellular and humoral immune system have been described in patients with dilated cardiomyopathy (DCM). Various circulating cardiac autoantibodies have been detected among DCM patients. Circulating antibodies are extractable by immunoadsorption (IA). Recent open controlled pilot studies have consequently shown that removal of circulating antibodies by IA induces improvement of cardiac function in DCM. IA, furthermore, decreases myocardial inflammation. In vitro data indicate that cardiodepressive antibodies play an important role in cardiac dysfunction of DCM patients; removal of these antibodies may accordingly represent the essential mechanism of IA in DCM. Furthermore, detection of cardiodepressive antibodies predicts hemodynamic benefits during IA. These antibodies belong to immunoglobulin G subclass 3. Recent data indicate that newly detected sarcolemmal Fcγ receptors IIa are involved in the functional effects of cardiac autoantibodies.

Immunadsorption als Therapieverfahren der dilatativen Kardiomyopathie

Abnormalities of the cellular and humoral immune system have been described in patients with dilated cardiomyopathy (DCM). For patients with DCM, immunochemical analyses of myocardial biopsies have demonstrated myocardial inflammation. Various circulating cardiac antibodies have been detected among DCM patients. Circulating antibodies are extractable by immunoadsorption. Recent open controlled pilot studies showed that removal of antibodies by immunoadsorption induces improvement of cardiac function in DCM. Furthermore, it decreases myocardial inflammation. This may offer a new therapeutic option for patients with severe heart failure due to dilated cardiomyopathy.

Combined Strategy Using Myoblasts and Hepatocyte Growth Factor in Dilated Cardiomyopathic Hamsters

There are few reports on treating dilated cardiomyopathy (DCM) with myoblast transplantation, and these show limited efficacy. Hepatocyte growth factor has cardioprotective effects on failed myocardium. Here, we combined these two treatments and analyzed cardiac function in DCM hamsters. Twenty-seven-week-old BIO TO-2 hamsters, which show moderate cardiac remodeling, were divided into four treatment groups: myoblast transplantation (T group, n = 24), human hepatocyte growth factor gene transfection (H group, n = 29), combined treatment (T+H group, n = 21), and medium alone (C group, n = 26). Significantly better fractional shortening was observed in the T+H group compared with the others (14.9% +/- 1.0%, 11.7% +/- 1.5%, 11.3% +/- 1.3%, and 8.6% +/- 1.1 %, in the T+H, H, T, and C groups, respectively). Immunohistochemical analysis showed alpha- and beta-sarcoglycan expression in the hearts of the H and T+H groups but not in the other groups. There was less myocardial fibrosis in the H and T+H groups than in the other two, and neovascularization in the T+H group was significantly greater than in the other groups (266 +/- 24, 209 +/- 27, 199 +/- 36, and 96 +/- 17 vessels/mm2, in the T+H, H, T, and C groups, respectively). Survival was significantly prolonged in the H and T+H groups compared with the other groups. Hepatocyte growth factor gene transfection and myoblast transplantation preserved the cardiac function of DCM hamsters, probably through different mechanisms, and the combined treatments preserved cardiac performance better than either treatment alone. The combined therapy is a promising strategy for treating DCM.

Effects of antibodies obtained from patients with dilated cardiomyopathy on the function of isolated rat hearts

Cardiac autoantibodies may play a pathophysiological role in cardiac dysfunction of patients suffering from dilated cardiomyopathy (DCM). Immunoadsorption (IA), which removes antibodies from patients' plasma, may consequently improve cardiac function in DCM. The functional effects of DCM antibodies are only partly understood. DCM patients (n = 10) were treated with IA by application of antibody columns directed against human immunoglobulin (Ig). IA was also performed with plasma taken from 10 healthy donors (controls). The antibodies eliminated and purified by IA were collected and dialysed. Rat hearts were isolated and perfused retrogradely via the aorta in Langendorff mode. During constant-pressure and constant-volume perfusion of the hearts, the influence of diluted antibodies on contractility, relaxation, and on coronary perfusion was analysed. Antibodies obtained from controls had no effect on contractility and relaxation of isolated perfused hearts during constant-pressure and constant-volume perfusion. In contrast, during constant-pressure perfusion, collected DCM antibodies caused immediate and dose-related reduction of contractility (dLVP/dtmax: dilution -1:32 = -7.1 +/- 1.1%; dilution -1:2 = -20.1 +/- 2.1%; P < 0.001) and diastolic relaxation (dLVP/dtmin: dilution -1:32 = -11.1 +/- 1.5%; dilution -1:2 = -23.9 +/- 2.2%; P < 0.001). The heart rate did not change significantly in either group. The effects of DCM antibodies on contractility and relaxation remained detectable during constant-volume perfusion. The observed reduction of contractility and diastolic relaxation was accompanied by impairment of coronary perfusion. In the rat heart, antibodies obtained from DCM patients may impair contractility and relaxation, and thereby probably also coronary perfusion.

Immunomodulatory effect of pentoxifylline in suppressing experimental autoimmune myocarditis.

Although a recent clinical study reported the beneficial effects of pentoxifylline (PTX), a phosphodiesterase inhibitor, on both symptoms and cardiac function in dilated cardiomyopathy (DCM), the precise mechanism of the drug has not been delineated. This study examined the efficacy of PTX in the treatment of experimental autoimmune myocarditis (EAM), as a model of the autoimmune mechanism involved in DCM. Oral PTX, or saline as control, was administered to Lewis rats at 150mg/kg body weight per day bid daily from 5 days before immunization with cardiac myosin until death on Day 21. Histological examination of the hearts showed PTX significantly reduced the severity of EAM. mRNA expression of tumor necrosis factor (TNF)-alpha, interleukin (IL)-4, IL-6, and IL-10 was significantly reduced in peripheral blood mononuclear cells, but expression of IL-4 and IL-6 was upregulated in heart tissue. PTX in vitro could suppress T cell proliferation and inhibit TNF-alpha and interferon-gamma production. In conclusion, the immunomodulatory effects of PTX had a significant therapeutic result in EAM. This is the first report to describe such an effect of PTX in a specific animal model for DCM.

Resting heart rate and cardiac function in dilated cardiomyopathy

We hypothesized that, within the normal range of resting heart rate, heart rate and left ventricular ejection fraction would be inversely correlated and heart rate and left ventricular filling would be correlated in patients with dilated cardiomyopathy and not correlated in patients with normal cardiac function. At rest, heart rate, left ventricular ejection fraction, and three measures of diastolic filling (time to peak filling rate, peak filling rate, and first half filling fraction) were recorded using radionuclide ventriculography in subjects with no cardiac disease, patients with idiopathic dilated cardiomyopathy, and patients with dilated cardiomyopathy associated with ischemic heart disease. Heart rate had significant inverse correlations with left ventricular ejection fraction ( r=−0.55, P=0.0007) and time to peak filling rate ( r=−0.47, P=0.005) and a positive correlation with peak filling rate ( r=0.73, P<0.0001) in patients with idiopathic dilated cardiomyopathy; heart rate was correlated only weakly with these measures in the absence of cardiac disease and essentially was not correlated in dilated cardiomyopathy due to ischemic heart disease. The change in resting heart rate with left ventricular ejection fraction and time to peak filling rate were significantly ( P<0.05) different between patients with no cardiac disease and those with idiopathic dilated cardiomyopathy. Thus, resting heart rate correlated significantly with left ventricular ejection fraction and diastolic filling in patients with idiopathic dilated cardiomyopathy.

Abnormal coronary hemodynamics and myocardial energetics in patients with chronic heart failure caused by ischemic heart disease and dilated cardiomyopathy

Coronary sinus blood flow, transmyocardial oxygen extraction, myocardial oxygen consumption, and transmyocardial lactate extraction were determined, along with systemic hemodynamics, in 34 patients with chronic stable angina without heart failure (group 1), in 66 patients with heart failure associated with coronary artery disease (group 2), and in 28 patients with heart failure caused by dilated cardiomyopathy without coronary artery disease (group 3). Compared with group 1 patients, in patients with heart failure in groups 2 and 3, resting coronary sinus blood flow was 30% and 24% higher, respectively ( p < 0.05), myocardial oxygen consumption was 25% higher ( p < 0.01), and coronary sinus oxygen content was 33% lower ( p < 0.01). The rate-pressure product was not different between the three groups. In eight patients with heart failure (five in group 2 and three in group 3), myocardial lactate production was observed without angina. Thus in patients with chronic heart failure resulting from either chronic coronary artery disease or dilated cardiomyopathy, resting coronary blood flow and myocardial oxygen consumption tend to increase probably because of an increase in myocardial oxygen requirements. Silent myocardial ischemia may also occur in both the presence and absence of coronary artery disease in patients with chronic heart failure. The abnormal coronary hemodynamics and myocardial metabolic function may play a role in causing progressive deterioration in cardiac function in dilated cardiomyopathy.