Non-ischemic HF Research Articles

Comparison of Long-Term Effects of Cell Therapy in Patients with Ischemic and. Nonischemic Heart Failure

Purpose Short-term data suggest a beneficial effect of cell therapy in chronic heart failure (CHF) patients. However, long-term effects of cell therapy in this patient cohort remain largely unexplored. We sought to investigate the long-term effects of transendocardial cell therapy in patients with CHF. Methods We reviewed five-year stem cell registry data from 108 patients. Clinical, laboratory and echocardiographic parameters were analysed. At baseline all patients were NYHA class III with LVEF 8.3 mV and linear local shortening Results Of 108 included patients 68 (63%) had non-ischemic HF (Group A) and 40 (37%) patients had ischemic HF (Group B). At baseline the two groups did not differ regarding age (51±11 years in Group A vs. 55±10 years in Group B;p=0.1), gender (male; 80% vs. 87%;p=0.4), creatinine (88±20 µmol/L vs. 92±25 µmol/L;p=0.49), bilirubine (18±10 µmol/L vs. 19±11 µmol/L;p=0.62), LVEF (28±7% vs. 27±8%;p=0.15), and LVEDD (6.6±0.8 cm vs. 6.7±0.6 cm;p=0.62). At 5 years, the overall and transplant-free survival of the groups were comparable (overall: 87% in Group A vs. 86% in Group B;p=0.85; transplant-free: 58% vs. 57%;p=0.87). Overall 5-year survival was 86% and transplant-free 5-year survival was 58%. Of 15 patients that died 4 (29%) suffered sudden cardiac death (SCD) and 11 (71%) died of pump failure. SCD occurred in 67% of all deaths in Group B vs. 0% of Group A patients (p Conclusion In chronic heart failure of either ischemic or nonischemic etiology transendocardial CD34+ cell therapy appears to be associated with favorable long-term effects. Prospective validation of our registry-based results is warranted.

Abstract 390: Mitochondrial ROS Drive Sudden Cardiac Death and Chronic Proteome Remodeling in Heart Failure

Intro: Sudden cardiac death (SCD) from ventricular arrhythmias (VT/VF) claims more lives each year than all other disease-related causes of death combined. The underlying links between HF and SCD remain unclear. Reactive oxygen species (ROS) are central to SCD pathophysiology, but their effects depend on where and how ROS are generated. Employing innovative approaches, we hypothesized that mitochondrial ROS (mROS) is a principal source of oxidative stress in HF and in vivo reduction of mROS mitigates SCD. Methods: In a unique guinea pig model that mimics human non-ischemic HF with a high incidence of SCD, we performed a randomized 2x2 crossover study with MitoTEMPO therapy. We employed novel, genetically encoded ratiometric redox sensors for quantitative measurement of cytosol (cROS) or mROS of cardiomyocytes. Results: We show for the first time that mROS is elevated in failing hearts and that a mitochondrially targeted antioxidant (MitoTEMPO) normalizes cellular ROS, while NADPH oxidase inhibition is effective in correcting only the cROS component. in vivo mitoTEMPO treatment can prevent or reverse HF while eliminating SCD by decreasing T-wave dispersion and suppressing premature ventricular complexes (PVCs). Scavenging mROS suppressed chronic HF-induced remodeling of the expression proteome and prevented specific phosphoproteome alterations. Pathway analysis of mROS-sensitive networks indicated that, in HF, increased mROS disrupts the normal coupling between cytosolic signals and the nuclear gene programs driving mitochondrial function, antioxidant enzymes, Ca2+ handling and action potential repolarization. Conclusions: mROS drive both acute emergent events, such as electrical instability leading to SCD, and mediates chronic HF remodeling, characterized by suppression or altered phosphorylation of metabolic, antioxidant and ion transport protein networks. Impaired mROS scavenging cause failing hearts to become more vulnerable to demand-induced oxidative stress and promote arrhythmic SCD. Maintaining global redox balance by enhanced mROS scavenging may be an effective strategy for SCD therapy in HF.

Mitochondrial Ca2+ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy.

BackgroundHeart failure (HF) is associated with increased arrhythmia risk and triggered activity. Abnormal Ca2+ handling is thought to underlie triggered activity, and mitochondria participate in Ca2+ homeostasis.Methods and ResultsA model of nonischemic HF was induced in C57BL/6 mice by hypertension. Computer simulations were performed using a mouse ventricular myocyte model of HF. Isoproterenol‐induced premature ventricular contractions and ventricular fibrillation were more prevalent in nonischemic HF mice than sham controls. Isolated myopathic myocytes showed decreased cytoplasmic Ca2+ transients, increased mitochondrial Ca2+ transients, and increased action potential duration at 90% repolarization. The alteration of action potential duration at 90% repolarization was consistent with in vivo corrected QT prolongation and could be explained by augmented L‐type Ca2+ currents, increased Na+‐Ca2+ exchange currents, and decreased total K+ currents. Of myopathic ventricular myocytes, 66% showed early afterdepolarizations (EADs) compared with 17% of sham myocytes (P<0.05). Intracellular application of 1 μmol/L Ru360, a mitochondrial Ca2+ uniporter–specific antagonist, could reduce mitochondrial Ca2+ transients, decrease action potential duration at 90% repolarization, and ameliorate EADs. Furthermore, genetic knockdown of mitochondrial Ca2+ uniporters inhibited mitochondrial Ca2+ uptake, reduced Na+‐Ca2+ exchange currents, decreased action potential duration at 90% repolarization, suppressed EADs, and reduced ventricular fibrillation in nonischemic HF mice. Computer simulations showed that EADs promoted by HF remodeling could be abolished by blocking either the mitochondrial Ca2+ uniporter or the L‐type Ca2+ current, consistent with the experimental observations.ConclusionsMitochondrial Ca2+ handling plays an important role in EADs seen with nonischemic cardiomyopathy and may represent a therapeutic target to reduce arrhythmic risk in this condition.

Morbidity and mortality of chronic heart failure (CHF) patients with sleep apnoea (SA) treated by adaptive servo-ventilation (ASV): Interim results of FACE cohort study_ UPDATE

Sleep disorder breathing is associated with a worse prognosis of CHF. The multicentre cohort study FACE is collecting real-world clinical data of CHF patients with reduced (HF-rEF), mid-range (HF-mrEF) and preserved (HFpEF) left ventricular ejection fraction (LVEF) with predominant CSA or coexisting central and obstructive sleep apnea (CSA-OSA), eligible for ASV therapy. Morbidity and mortality, cardiac function, quality of life are assessed over a period of 2 years depending on whether the patient was compliant (≥ 3 h/night) with ASV therapy (ResMed, AutoSet CS) or not (control). Primary endpoint is all-cause death or unplanned hospitalization for worsening HF. Cumulative incidence will be estimated by Kaplan–Meier method and compared using log-rank test between ASV & control group. An update of the interim 2-year follow-up (FU) data is presented here. Three hundred and ninety-one CHF patients were included in the mITT analysis. Median FU for analysis was 21.6 months. Baseline characteristics were: age 70.7 ± 11.0 y, 87.5% male, body mass index 28.3 ± 5.2 kg/m 2 . Patients with HF-rEF, HF-mrEF and HFpEF were 38.7%, 22.1% and 39.2% respectively. Patients with an ischemic etiology were 55.2%. Sixty-nine percent had predominant CSA and 31% had CSA-OSA. Patients with severe sleep apnoea (AHI >30/h) were 76.2%. Sixty-six percent of patients were compliant to ASV therapy. In the global population, ASV therapy seemed to be beneficial in inpatients who had the highest level of nocturnal oxygen desaturation (T90, ODI) at baseline ( P = 0.013), in obese ( P = 0.009) & non-ischemic patientss ( P = 0.014) compared to control group. However, the subgroup analysis identified significant improvement of prognosis with ASV only in HFpEF but not in HF-rEF or HF-mrEF. ASV therapy is associated with a better prognosis in CHF patients with high level of oxygen desaturation during sleep, non-ischemic HF aetiology and with preserved LVEF. FACE study is a useful tool to better understand which CHF populations with CSA can benefit of ASV therapy.

Serum corin is associated with the risk of chronic heart failure.

It has been well documented that corin is a critical protease involved in the regulation of blood pressure and cardiac function. We performed a case-control study to determine whether serum corin is associated with the risk of chronic heart failure (CHF). We included 484 consecutive CHF patients and 484 control subjects to investigate the potential relationship between serum corin and CHF using logistic regression analysis. Compared with healthy controls, the CHF patients were more likely to have histories of hypertension and diabetes, and had higher levels of N-terminal pro-brain natriuretic peptide and lower levels of corin. The odds ratios of ischemic and non-ischemic HF were significantly reduced with the growing levels of serum corin after multivariate adjustment. Moreover, the decrease in serum corin levels seemed to be associated with the severity of CHF. In conclusion, our study suggested that serum corin levels were reduced in CHF patients and inversely correlated with the incidence of ischemic and non-ischemic HF.

The Endothelial Nitric Oxide Synthase (NOS3-786T>C) Genetic Polymorphism in Chronic Heart Failure: Effects of Mutant -786C allele on Long-term Mortality.

Nitric oxide plays an important role in the regulation of basal vascular tone and cardiac myocyte function. We investigated the NOS3-786T>C polymorphism in chronic heart failure (CHF) and its effects on long-term mortality. Ninety-one patients with CHF who were referred to the Department of Cardiology of Siyami Ersek Cardiovascular and Thoracic Surgery Center for cardiopulmonary exercise testing between April 2001 and January 2004 and 30 controls were enrolled in this study. Patient were followed prospectively for a period of 1 to 12 years. Patients and controls were divided into three groups: TT, TC and CC, according to their NOS3-786T>C polymorphism. We noted that there was no significant difference in the genotype distribution between patients and controls. There was also no significant difference in endothelial nitric oxide synthase (eNOS) gene polymorphism between ischemic HF and nonischemic HF. During the follow-up period, 61 (67%) deaths occurred. The nonsurvivor group had lower left ventricular ejection fraction (LVEF) (p = 0.01), reduced peak oxygen consumption (p = 0.04) and were of older age (p = 0.001). Age, LVEF, peak oxygen consumption and genotype were found to be predictors of mortality (p < 0.05). Additionally, mortality was significantly increased in -786CC genotype patients compared to TT genotype patients (hazard ratio = 2.2; p = 0.03). By multivariate analysis, age and eNOS genotype were determined to be significant independent predictors of death. Additionally, Kaplan-Meier analysis confirmed that homozygote -786C genotype was associated with an increased risk of death (χ2 = 4.6, p = 0.03). Our findings showed that the NOS3-786T>C polymorphism was associated with an increased risk of mortality in patients with CHF.

Accelerated cellular senescence as underlying mechanism for functionally impaired bone marrow-derived progenitor cells in ischemic heart disease

Background and aimsBone marrow (BM)-derived progenitor cells are functionally impaired in patients with ischemic heart disease (IHD), thereby hampering the outcome of autologous stem cell therapy. In search for underlying mechanisms for this BM dysfunction, accelerated cellular senescence was explored. MethodsWe analysed telomere length of BM-derived mononuclear cells (MNC) by MMqPCR in patients with coronary artery disease (n = 12), ischemic heart failure (HF; n = 9), non-ischemic HF (n = 7) and controls (n = 10), and related it to their myeloid differentiation capacity. Expressions of senescence-associated genes p53, p21Cip1 and p16lnk4A; and telomere maintenance genes TERT, TRF1/2, Sirt1 in BM-MNC were evaluated using qPCR. Pro-inflammatory cytokine levels (TNFα, IFNy, IL-6) in BM were measured by MSD. ResultsBM-MNC telomere length was shortened in patients with IHD, irrespective of associated cardiomyopathy, and shortened further with increasing angiographic lesions. This telomere shortening was associated with reduced myeloid differentiation capacity of BM-MNC, suggesting accelerated senescence as underlying cause for progenitor cell dysfunction in IHD. Both p16lnk4A and p21Cip1 were activated in IHD and inversely related to myeloid differentiation capacity of BM-MNC; hence, the BM-MNC functional impairment worsens with increasing senescence. While BM-MNC telomere attrition was not related with alterations in TERT, TRF1/2 and Sirt1 expression, IFNy levels were associated with p21Cip1/p16lnk4A upregulation, suggesting a link between inflammation and cellular senescence. Still, the trigger for telomere shortening in IHD needs to be elucidated. ConclusionsAccelerated replicative senescence is associated with a functional impairment of BM-derived progenitor cells in IHD and could be targeted to improve efficacy of stem cell therapy.

Prognostic Implications of Type 2 Diabetes Mellitus in Ischemic and Nonischemic Heart Failure

BackgroundHeart failure (HF) is a common and serious complication in type 2 diabetes mellitus (T2DM). The prognosis of ischemic HF and impact of revascularization in such patients have not been investigated fully in a patient population representing everyday practice. ObjectivesThis study examined the impact of ischemic versus nonischemic HF and previous revascularization on long-term prognosis in an unselected population of patients with and without T2DM. MethodsPatients stratified by diabetes status and ischemic or nonischemic HF and history of revascularization in the Swedish Heart Failure Registry (SwedeHF) from 2003 to 2011 were followed up for mortality predictors and longevity. A propensity score analysis was applied to evaluate the impact of previous revascularization. ResultsAmong 35,163 HF patients, those with T2DM were younger, and 90% had 1 or more associated comorbidities. Ischemic heart disease (IHD) occurred in 62% of patients with T2DM and 47% of those without T2DM, of whom 53% and 48%, respectively, had previously undergone revascularization. T2DM predicted mortality regardless of the presence of IHD, with adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of 1.40 (1.33 to 1.46) and 1.30 (1.22 to 1.39) in those with and without IHD, respectively. Patients with both T2DM and IHD had the highest mortality, which was further accentuated by the absence of previous revascularization (adjusted HR: 0.82 in favor of such treatment; 95% CI: 0.75 to 0.91). Propensity score adjustment did not change these results (HR: 0.87; 95% CI: 0.78 to 0.96). Revascularization did not abolish the impact of T2DM, which predicted mortality in those with (HR: 1.36; 95% CI: 1.24 to 1.48) and without (HR: 1.45; 95% CI: 1.33 to 1.56) a history of revascularization. ConclusionsNinety percent of HF patients with T2DM have preventable comorbidities. IHD in patients with T2DM had an especially negative influence on mortality, an impact that was beneficially influenced by previous revascularization.

Abstract 284: Ovariectomy Exacerbates Mitochondrial Dysfunction, Oxidative Stress and Fibrosis to Cause Diastolic Dysfunction

Heart failure with preserved ejection fraction, characterized by diastolic dysfunction (DD) is most common in post-menopausal women, suggesting a link with estrogen (E2). However, the underlying mechanisms are not well understood. In this study we tested how ovariectomy (OVX)-induced E2-deficiency exacerbates DD. Female C57BL6/J mice (12 weeks old) underwent a sham or OVX surgery, and were administered either normal drinking water or L-N G -Nitroarginine methyl ester (L-NAME, 0.3 mg/ml in 1% NaCl solution) in the drinking water and Angiotensin II (AngII, 1.2 mg/kg/day) via subcutaneous osmotic pumps for 5 weeks to induce DD. Subsets of the OVX-DD mice were treated with E2, E2-receptor (ER) α agonist PPT, ERβ agonist DPN or G-protein ER-1 agonist G1. Echocardiography revealed reduced left ventricular (LV) internal diameter, LV volume, cardiac output but increased LV posterior wall thickness in OVX-DD mice compared with sham-DD mice. However, ejection fractions and fractional shortening were normal in all groups. Doppler studies showed E/A ratios dramatically suppressed and E/e’ ratios increased in mice treated with L-NAME+AngII, with larger changes in OVX mice. Extensive fibrosis was seen in OVX-DD hearts than sham-DD hearts. ADP-supported cardiac mitochondrial function with pyruvate-malate was moderately reduced in OVX-DD mice along with greater production of reactive oxygen species. Ionoptix studies revealed delayed relaxation but maintained contraction in cardiomyocytes isolated from OVX-DD mice, similar to effects of low-dose oligomycin in control mice. These data suggest that E2 deficiency is associated with impaired mitochondrial function to cause small decreases in ATP formation, which impair diastolic relaxation but not contraction. Treatment with E2, PPT, DPN and G1 reduced E/e’ ratios in OVX-DD mice, with the greatest effects of G1. Treatment of mice with L-NAME in this model excludes the previously described action of G1 through nitric oxide. In conclusion, OVX exacerbates mitochondrial dysfunction, oxidative stress and fibrosis in non-ischemic HF, leading to exacerbated DD. These may be some of the mechanisms by which E2 protects the myocardium in females. Activation of GPER1 offers a novel therapeutic target for DD after menopause.

Impact of septal flash and left ventricle contractile reserve on positive remodeling during 1 year cardiac resynchronization therapy: the multicenter ViaCRT study

IntroductionCardiac resynchronization therapy (CRT) has been shown to improve outcomes in patients with systolic heart failure (HFREF). However, the relatively high non-responder rate results in a need for more precise qualification for CRT. The ViaCRT study was designed to determine the role of contractile reserve and dyssynchrony parameters in predicting CRT response. The purpose of this analysis was to determine the effect of baseline septal flash and contractile reserve (CR) on clinical and echocardiographic parameters of response to CRT in 12-month follow-up.Material and methodsOne hundred thirty-three guideline-selected CRT candidates (both ischemic and non-ischemic heart failure with reduced ejection fraction) were enrolled in the study. Baseline study population characteristics were: left ventricle ejection fraction (LVEF) 25 ±6%, QRS 165 ±25 ms, NYHA class III (90%) and IV (10%).ResultsIn subjects with septal flash (SF) registered before CRT implantation improvement in LVEF (14 ±2% vs. 8 ±1%, p < 0.05) and left ventricle (LV) systolic (63 ±10 ml vs. 36 ±6 ml, p < 0.05) and diastolic (46 ±10 ml vs. 32 ±7, p < 0.05) volumes was more pronounced than in patients without SF. In patients with CR (defined as LVEF increase by 20% or 4 viable segments) improvement in echo parameters was not significantly different then in the CR– group. Neither SF nor CR was associated with improvement in NYHA class. Subgroup analysis revealed that only in non-ischemic HF patients is presence of septal flash associated with LV function improvement after CRT.ConclusionsIn non-ischemic HF patients septal flash is a helpful parameter in prediction of LV remodeling after 12 months of resynchronization therapy.

Endomyocardial expression of SDF-1 predicts mortality in patients with suspected myocarditis.

Risk stratification in patients with suspected myocarditis is pivotal for optimizing therapy. Stromal cell-derived factor 1 (SDF-1) is an inflammatory chemokine expressed in the inflamed and failing myocardium. Therefore, we aimed to investigate whether endomyocardial expression of SDF-1 identifies high-risk patients with suspected myocarditis. We prospectively enrolled 174 patients with non-ischemic HF who underwent endomyocardial biopsy for suspected myocarditis. Biopsies were analyzed using established histopathological and immunohistological criteria together with SDF-1 staining. SDF-1 was significantly enhanced in patients with inflammatory cardiomyopathy (65.4% positive biopsies) as compared to patients with non-inflammatory cardiomyopathy (19.1%, p<0.001). SDF-1 expression levels correlated significantly with the degree of myocardial fibrosis (correlation coefficient r=0.196; p=0.010) since patients with severe myocardial fibrosis displayed high myocardial SDF-1 expression. During a mean follow-up of 27.5months, 20 patients (11.5%) died. The 4-year mortality rate was 26.0% among the 92 SDF-1-positive patients vs. 9.5% among the 82 SDF-1-negative patients (p=0.001). On multivariable analysis which considered clinical (NYHA functional class, left ventricular ejection fraction), laboratory (brain natriuretic peptide, troponin I) and biopsy staining, SDF-1 was the strongest independent predictor of mortality (hazard ratio 6.1; 95% confidence interval 1.4-27.5; p=0.018). Subgroup analysis revealed SDF-1 as a predictor of mortality in both patients with inflammatory and non-inflammatory cardiomyopathy. Endomyocardial expression of SDF-1 is enhanced in inflammatory cardiomyopathy, positively correlates with myocardial fibrosis and identifies high-risk patients with suspected myocarditis.

(846) - Identification of Emerging Micro RNA Markers for Heart Failure Development Using a Bioinformatic Approach

Advances in bioinformatics have accelerated the pre-analytic phase of biomarker research by data mining public access databases. However, this approach has not been reported for the study of HF. We aim to identify potential microRNA (miR) biomarkers in serum of non-ischemic HF patients using an in silico approach.

Abstract 20350: Discordant Left Bundle Branch Block is Associated With Left Ventricular Dyssyncrhony at Cardiac Magnetic Resonance Imaging in Patients With Nonischemic Cardiomyopathy

LBBB is frequently linked to left ventricular (LV) dyssynchrony and adverse prognosis in HF. LBBB has been defined as concordant (cLBBB) or discordant (dLBBB), when associated in lead I and V5, V6 with a positive or negative T wave respectively. dLBBB has been associated with a worse clinical and prognostic profile in HF patients. We sought to evaluate association between different patterns of LV dV/dT curves at CMR, LBBB morphology, clinical correlates and prognostic role in patients with nonischemic systolic HF. Methods and Results: One hundred and fifteen consecutive patients with LBBB were submitted between 2004 and 2014 to a complete cardiological evaluation, including CMR with analysis of dV/dT curves of LV contraction, and follow-up for cardiac events. We distinguished two different patterns of global and segmental LV systole: a “narrow” pattern (NP) generated by synchronous contraction of wall segments; a “wide” pattern (WP), when delay in contraction between wall segments resulted in a prolungation of systolic peak with a flat or notched morphology. Fourteen patients presenting with normal LV dimensions and function all had cLBBB and NP, while out of 101 patients with HF, those with dLBBB (65%) presented with shorter QRS duration (p &lt; .01) and higher level of NT-proBNP (p &lt; .001). WP was observed more frequent in dLBBB patients (p &lt; .003) as a mark of greater intraventricular dyssynchrony. According to systolic pattern, those with WP had higher levels of NT-proBNP, lower EF and higher LV volumes than those with NP, whereas no significant difference was found in QRS duration. At multivariate analysis only dLBBB (p=.006) and EF (p=.001) were independent predictors of WP. At Kaplan-Meier analysis, the presence of WP was associated with a worse prognosis considering a composite end-point of cardiac death, hospitalization for HF and ICD shock (p&lt;.005). At Cox analysis only presence of WP (p = .029) and level of NT-proBNP (p= .004) were independent predictors. Conclusions: In nonischemic systolic HF patients with LBBB, presence of a WP at CMR dV/dT curves is associated with dLBBB, identifies greater LV dyssynchrony with possible major benefits from resynchronization therapy and is an independent prognosticator.

Abstract 60: The Role of Mononuclear Phagocytes in Pressure Overload Heart Failure

We previously reported that chronic ischemic HF induced by coronary ligation results in an exacerbated pro-inflammatory cell profile in the systemic circulation, spleen, and failing heart. In addition, this pro-inflammatory cell profile was strongly influenced by the cardiosplenic axis; however, the role of this axis in other etiologies of HF is unknown. Immune cells infiltrate the heart early (1-4 weeks) after pressure-overload injury, but it is unknown whether these cells persist and are of pathological import during chronic pressure-overload HF. We hypothesized that phenotypic changes in mononuclear phagocytes are necessary for the transition from compensatory hypertrophy to chronic HF during sustained pressure-overload, and that inhibition of myocardial immune cell infiltration would ameliorate this progression. Pressure-overload was induced by transverse aortic constriction (TAC) in wild-type (WT) C57BL/6 mice, and in macrophage Fas-induced apoptosis (MAFIA) Tg mice, which allows ablation of c-fms expressing cells upon administration of the AP20187 dimerizer. Compared to sham mice, TAC mice developed progressive cardiac dysfunction beginning at 2 w with significantly (p&lt;0.05) reduced LVEF (59 ± 10 vs 67 ± 3 %), increased left atrial size (2.29 ± 0.1 vs 2.04 ± 0.1 mm), and increased E/E’ Doppler ratio (31.8 ± 6 vs 24.0 ± 3). Circulating CD11b+Lineage- monocytes were elevated in TAC mice at 2 w (1.7 ± 0.2 vs 1.0 ± 0.1 %, p&lt;0.05); however, these levels normalized by 8 w. Moreover, at 8 w, no significant differences in the levels of splenic and cardiac mononuclear phagocytes were seen between TAC and sham mice. Systemic ablation of mononuclear phagocytes beginning 2 w after TAC in MAFIA AP20187-treated mice did not rescue cardiac function or delay HF progression compared to TAC MAFIA vehicle-treated mice over the course of 16 w (LVEF 43 ± 18 vs 45 ± 18 %). We conclude that in contrast to chronic ischemic HF, inflammatory cell-mediated cardiac injury does not have primacy in chronic non-ischemic HF induced by pressure-overload. These findings highlight the importance of the index injury in regard to immune cell activation in HF, and suggest that therapeutic immunomodulatory approaches may not be equivalent across the various etiologies of this disease.

LDL- Cholesterol and Outcome Prediction in Patients with Congestive Heart Failure

There are still controversial data mainly based mainly on previous studies [3-6]. The findings of the BEST trial [7] showed that cholesterol reduction by statins was independently associated with decrease in all-cause and cardiovascular mortality in patients with nonischemic dilated cardiomyopathy (EF 115 mg/dl) was reduced by 24% (in comparison to those with LDL<90) despite the fact that the percent of patients with a NYHA class 3.5-4 was higher in this group. Even after adjusting for multiple known predictors of HF mortality, high LDL levels remained a significant novel independent predictor of improved survival. Neither low total cholesterol nor low triglycerides levels were significant in predicting mortality. The relationship between LDL levels and HF outcomes among the elderly, which was documented in the current study, seems to be contradictory to the findings in patients with coronary artery disease [3-4] and in patients enrolled in other HF studies [2,4,5,7]. Patients with ischemic and non-ischemic HF appear to have an opposite pattern (“reverse epidemiology”), with low levels being associated with worse prognosis independent of other prognostic factors [8,9].

PP-367 Evaluation of Diastolic and Systolic Functions by Echocardiography in Patients with Ischemic and Non-ischemic Heart Failure

At least half of patients with HF have a low ejection fraction (EF). The cause of two-thirds of cases of systolic HF is coronary artery disease. Furthermore, there are also many other causes which is non-ischemic (e.g viral infection, chemotherapy). Besides, clinical course may be changing to the etiology of systolic HF. Systolic and diastolic functions are important for symptoms and prognosis in HF. Therefore, we aimed to compare systolic and diastolic functions in ischemic and non-ischemic HF.

Effects of Trimetazidine in Nonischemic Heart Failure: A Randomized Study

ObjectivesHeart failure (HF) is associated with changes in myocardial metabolism that lead to impairment of contractile function. Trimetazidine (TMZ) modulates cardiac energetic efficiency and improves outcomes in ischemic heart disease. We evaluated the effects of TMZ on left ventricular ejection fraction (LVEF), cardiac metabolism, exercise capacity, O2 uptake, and quality of life in patients with nonischemic HF. Methods and ResultsSixty patients with stable nonischemic HF under optimal medical therapy were included in this randomized double-blind study. Patients were randomized to TMZ (35 mg orally twice a day) or placebo for 6 months. LVEF, 6-minute walk test (6MWT), maximum O2 uptake in cardiopulmonary exercise test, different markers of metabolism, oxidative stress, and endothelial function, and quality of life were assessed at baseline and after TMZ treatment. Left ventricular peak glucose uptake was evaluated with the use of the maximum standardized uptake value (SUV) by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Etiology was idiopathic in 85% and hypertensive in 15%. Both groups were similar in age, functional class, LVEF, and levels of N-terminal pro–B-type natriuretic peptide at baseline. After 6 months of TMZ treatment, no changes were observed in LVEF (31 ± 10% vs 34 ± 8%; P = .8), 6MWT (443 ± 25 m vs 506 ± 79 m; P = .03), maximum O2 uptake (19.1 ± 5.0 mL kg−1 min−1 vs 23.0 ± 7.2 mL kg−1 min−1; P = .11), functional class (percentages of patients in functional classes I/II/III/IV 10/3753/0 vs 7/40/50/3; P = .14), or quality of life (32 ± 26 points vs 24 ± 18 points; P = .25) in TMZ versus placebo, respectively. In the subgroup of patients evaluated with 18FDG-PET, no significant differences were observed in SUV between both groups (7.0 ± 3.6 vs 8.2 ± 3.4 respectively; P = .47). ConclusionsIn patients with nonischemic HF, the addition of TMZ to optimal medical treatment does not result in significant changes of LVEF, exercise capacity, O2 uptake, or quality of life.

Study of Adipose Tissue-Derived Mesenchymal Stem Cells Transplantation for Rats with Dilated Cardiomyopathy

Increasing evidences indicated that adipose-derived mesenchymal stem cells (ADMSCs) can stay survive, then gradually proliferate and differentiate into myocardial cells after transplanted into damaged areas and improve function of heart. In this article, ADMSCs were isolated from adipose tissue of Wistar rats and cultured. When treated with 5-azacytidine (5-aza), ADMSCs were differentiated into myocardial cells, then we implant these cells into myocardium of rats of DCM to observe cell population and differentiation and compare cardiac function and hemodynamics changes before and after transplantation. The expression of Cardiac-specific markers indicated that ADMSCs which were isolated from adipose tissue of Wistar rats can differentiate into various cell types. Meanwhile, the treatment group displayed a higher level of LVESP, left ventricular intraventricular pressure (+dP/dt max), left ventricular intraventricular pressure (-dP/dt max) and left ventricular EF (%) than the control group. Altogether, these results indicate that heart systolic and diastolic function of rats of DCM was significantly improved meanwhile ventricular dilatation remodeling was inhibited after ADMSCs transplantation. Therefore, this research provides an experimental basis for further clinical application of ADMSCs transplantation for the treatment of DCM and non-ischemic HF.

Clinical assessment of complementary treatment with Qishen Yiqi dripping pills on ischemic heart failure: study protocol for a randomized, double-blind, multicenter, placebo-controlled trial (CACT-IHF)

BackgroundHeart failure (HF) is associated with decreased quality of life, high re-admission rate and poor prognosis. In particular, ischemic heart failure (IHF) has a worse prognosis than nonischemic HF. The use of traditional Chinese medicine (TCM) alongside Western medicine to treat HF has developed into an integrative treatment model in China. There have been small clinical trials and experimental studies to demonstrate the efficacy of TCM for treating HF; however, there is still a lack of high-quality trials. Qishen Yiqi dripping pills (QSYQ), a TCM drug, have been commonly used alongside standardized Western medicine to treat IHF. This paper describes the protocol for the clinical assessment of QSYQ in IHF patients.MethodA randomized, double-blind, multicenter, placebo-controlled trial will assess the efficacy and safety of QSYQ in the treatment of IHF. The trial is to enroll 640 IHF patients from 32 hospitals in China. Besides their standardized Western medicine, patients will be randomized to receive treatment of either QSYQ or placebo for 6 months and follow-up monitoring for at least a further 6 months. The primary outcome is increased exercise capacity of patients, which will be measured using the 6-minute walking test (6MWT). The secondary outcomes include composite endpoints: all-cause mortality, frequency of hospitalization or emergency due to cardiovascular events, brain natriuretic peptide levels, left ventricular ejection fraction, and cardiothoracic ratio will be documented, as well as scores on the New York Heart Association classification and Minnesota quality of life index, and information obtained from the four TCM diagnostic methods. Blood lipid tests will also be administered.DiscussionThe integrative treatment model of TCM alongside Western medicine has developed into a treatment model in China. The rigorous design of the trial will assure an objective and scientific assessment of the efficacy and safety of QSYQ in the treatment of IHF.Trial registrationClinical trials.gov number: NCT01555320

The Risk Model for Prediction of Survival in Heart Failure

The Risk Model for Prediction of Survival in Heart Failure