Cardiac aging is regulated by autophagic disorder mediated by chronic inflammation via the Rubicon/NOX4 pathway

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
T Kamihara ◽  
Y.K Bando ◽  
T Murohara
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Chronic Inflammation ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Cardiomyocyte Hypertrophy ◽  
Autophagic Flux ◽  
Cardiac Aging ◽  
Ventricular Ejection Fraction ◽  
The Impact

Abstract Background and introduction Aging is known to one of the primary causes of heart failure, in particular in the case of heart failure with preserved left-ventricular ejection fraction (HFpEF). Interestingly, recent evidences demonstrated that DNA damage occurred in aging causes autophagic disorder that contributes to aging phenotype via Rubicon (Run domain Beclin-1 interacting and cysteine-rich containing protein) in non-cardiac tissues. Purpose To elucidate whether aging-related autophagic disorder may lead to myocardial remodeling via chronic inflammation by Rubicon activation. Methods As an aging model with DNA injury, we employed mice model of progeria (mouse model of Werner syndrome that was generated by amino acid mutation exhibiting the functional deletion of DNA helixase; WRN-K577M). Results Cardiac aging markers (PARP-1, p53 and γ H2AX), and apoptosis (TUNEL) were augmented in WRN-K577M (male 18 week-old) as compared to the wild type counterpart. Consistently, cardiac oxidative stress that was measured by DHE was elevated in WRN-K577M with significant increase in oxidative stress enhancer NOX4. WRN-K577M exhibited cardiomegaly and diastolic left-ventricular (LV) dysfunction with preserved systolic LV function. Histological analysis revealed that WRN-K577M exhibited enhanced cardiac fibrosis and cardiomyocyte hypertrophy. Consistently, DNA microarray revealed significant upregulation of sixteen genes, of which ontology was hypertrophy, fibrosis, inflammation. Changes in autophagic activity was assessed by use of LC3 turnover assay and autophagic flux was evaluated by application of pharmacological inhibitor of autolysosome fusion (chloroquine) and fluorescence indicators for monitoring turnover of autophagosome (DAP green) and autolysosome (DAL green) to specify the essential step(s) of the aging-induced changes in the autophagic flux of heart. The LC3 turnover assay revealed that autophagic turnover was pathologically increased in myocardium of WRN-K577M at baseline and chloroquine (50 microg/g body weight) had no effect in WRN-K577M. Furthermore, DAL-positive spots were decreased in cardiomyocytes of WRN-K577M at rest, indicating that the impairment of autophagic flux particularly via impaired lysosome fusion may be responsible for the augmented autophagic turnover in WRN-K577M. Furthermore, we tested the impact of Rubicon. Rubicon was upregulated in heart of WRN-K577M and, more interestingly, Rubicon was found to be co-localized specifically with NOX4 in heart. Using CRISPER-CAS9 system, we generated Rubicon-KD H9C2 and Rubicon-activated HEK293. Upregulation of Rubicon revealed augmented LC3II, p62 and Beclin1 similar to WRN-K577M and augmented oxidative stress and, in contrast, downregulation of Rubicon had no effect on autophagy markers. Conclusion(s) Rubicon, the dual regulator of autophagy and inflammation is essential for autophagic disorder occurred in cardiac aging and the related oxidative stress via NOX4. Funding Acknowledgement Type of funding source: None

scholarly journals Biomarkers-based personalized follow-up in chronic heart failure improves patient’s outcomes and reduces care associate cost

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Antonio Leon-Justel ◽  
Jose I. Morgado Garcia-Polavieja ◽  
Ana Isabel Alvarez-Rios ◽  
Francisco Jose Caro Fernandez ◽  
Pedro Agustin Pajaro Merino ◽  
...  
Keyword(s):  
Heart Failure ◽  
Hospital Admissions ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Secondary Outcome ◽  
Ventricular Ejection Fraction ◽  
Number Of Patients ◽  
Ed Visits ◽  
The Impact

Abstract Background Heart failure (HF) is a major and growing medical and economic problem, with high prevalence and incidence rates worldwide. Cardiac Biomarker is emerging as a novel tool for improving management of patients with HF with a reduced left ventricular ejection fraction (HFrEF). Methods This is a before and after interventional study, that assesses the impact of a personalized follow-up procedure for HF on patient’s outcomes and care associated cost, based on a clinical model of risk stratification and personalized management according to that risk. A total of 192 patients were enrolled and studied before the intervention and again after the intervention. The primary objective was the rate of readmissions, due to a HF. Secondary outcome compared the rate of ED visits and quality of life improvement assessed by the number of patients who had reduced NYHA score. A cost-analysis was also performed on these data. Results Admission rates significantly decreased by 19.8% after the intervention (from 30.2 to 10.4), the total hospital admissions were reduced by 32 (from 78 to 46) and the total length of stay was reduced by 7 days (from 15 to 9 days). The rate of ED visits was reduced by 44% (from 64 to 20). Thirty-one percent of patients had an improved functional class score after the intervention, whereas only 7.8% got worse. The overall cost saving associated with the intervention was € 72,769 per patient (from € 201,189 to € 128,420) and €139,717.65 for the whole group over 1 year. Conclusions A personalized follow-up of HF patients led to important outcome benefits and resulted in cost savings, mainly due to the reduction of patient hospitalization readmissions and a significant reduction of care-associated costs, suggesting that greater attention should be given to this high-risk cohort to minimize the risk of hospitalization readmissions.

scholarly journals Clinical Outcomes in Patients with Ischemic versus Non-Ischemic Cardiomyopathy after Angiotensin-Neprilysin Inhibition Therapy

2021 ◽  
Vol 10 (21) ◽  
pp. 4989
Author(s):  
Mohammad Abumayyaleh ◽  
Christina Pilsinger ◽  
Ibrahim El-Battrawy ◽  
Marvin Kummer ◽  
Jürgen Kuschyk ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Ischemic Cardiomyopathy ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Tachyarrhythmias ◽  
Ventricular Ejection Fraction ◽  
One Year ◽  
The Impact

Background: The angiotensin receptor-neprilysin inhibitor (ARNI) decreases cardiovascular mortality in patients with chronic heart failure with a reduced ejection fraction (HFrEF). Data regarding the impact of ARNI on the outcome in HFrEF patients according to heart failure etiology are limited. Methods and results: One hundred twenty-one consecutive patients with HFrEF from the years 2016 to 2017 were included at the Medical Centre Mannheim Heidelberg University and treated with ARNI according to the current guidelines. Left ventricular ejection fraction (LVEF) was numerically improved during the treatment with ARNI in both patient groups, that with ischemic cardiomyopathy (n = 61) (ICMP), and that with non-ischemic cardiomyopathy (n = 60) (NICMP); p = 0.25. Consistent with this data, the NT-proBNP decreased in both groups, more commonly in the NICMP patient group. In addition, the glomerular filtration rate (GFR) and creatinine changed before and after the treatment with ARNI in both groups. In a one-year follow-up, the rate of ventricular tachyarrhythmias (ventricular tachycardia and ventricular fibrillation) tended to be higher in the ICMP group compared with the NICMP group (ICMP 38.71% vs. NICMP 17.24%; p = 0.07). The rate of one-year all-cause mortality was similar in both groups (ICMP 6.5% vs. NICMP 6.6%; log-rank = 0.9947). Conclusions: This study shows that, although the treatment with ARNI improves the LVEF in ICMP and NICMP patients, the risk of ventricular tachyarrhythmias remains higher in ICMP patients in comparison with NICMP patients. Renal function is improved in the NICMP group after the treatment. Long-term mortality is similar over a one-year follow-up.

scholarly journals Profile of Hospitalized Hypertensives with Preserved and Reduced Left Ventricular Ejection Fraction in Nigeria

2019 ◽  
Vol 14 ◽  
Author(s):  
Akinsanya Daniel Olusegun-Joseph ◽  
Kamilu M Karaye ◽  
Adeseye A Akintunde ◽  
Bolanle O Okunowo ◽  
Oladimeji G Opadijo ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Ventricular Ejection Fraction ◽  
Ejection Fraction ◽  
Left Ventricular ◽  
Ventricular Ejection ◽  
Teaching Hospitals ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Hypertensive Patients ◽  
The Impact

Introduction The impact of preserved and reduced left ventricular ejection fraction (LVEF) has been well studied in heart failure, but not in hypertension. We aimed to highlight the prevalence, clinical characteristics, comorbidities and outcomes of hospitalized hypertensives with preserved and reduced LVEF from three teaching hospitals in Nigeria. Methods: This is a retrospective study of hypertensives admitted in 2013 in three teaching hospitals in Lagos, Kano and Ogbomosho, who had echocardiography done while on admission. Medical records and echocardiography parameters of the patients were retrieved and analyzed. Results: 54 admitted hypertensive patients who had echocardiography were recruited, of which 30 (55.6%) had reduced left ventricular ejection fraction (RLVEF), defined as ejection fraction <50%; while 24 (44.4%) had preserved left ventricular ejection fraction (PLVEF). There were 37(61.5%) females and 17 (31.5%) males. Of the male patients 64.7% had RLVEF, while 35.3% had PLVEF. 19(51.4%) of females had RLVEF, while 48.6% had PLVEF. Mean age of patients with PLVEF was 58.83±12.09 vs 54.83± 18.78 of RLVEF; p-0.19. Commonest comorbidity was Heart failure (HF) followed by stroke (found among 59.3% and 27.8% of patients respectively). RLVEF was significantly commoner than PLVEF in HF patients (68.8% vs 31.3%; p- 0.019); no significant difference in stroke patients (46.7% vs 53.3%; p-0.44). Mortality occurred in 1 (1.85%) patient who had RLVEF.         Conclusion: RLVEF was more common than PLVEF among admitted hypertensive patients; they also have more comorbidities. In-hospital mortality is, however, very low in both groups.

Comparison of the prognosis and outcome of heart failure with reduced ejection fraction patients treated with sacubitril/valsartan according to age

2021 ◽  
Author(s):  
Mohammad Abumayyaleh ◽  
Ibrahim El-Battrawy ◽  
Marvin Kummer ◽  
Christina Pilsinger ◽  
Katherine Sattler ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Ejection Fraction ◽  
Older Patients ◽  
Left Ventricular ◽  
Adult Patients ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Reduced Ejection Fraction ◽  
The Impact

The treatment with sacubitril/valsartan in patients suffering from chronic heart failure with reduced ejection fraction increases left ventricular ejection fraction and decreases the risk of sudden cardiac death. We conducted a retrospective analysis regarding the impact of age differences on the treatment outcome of sacubitril/valsartan in patients with chronic heart failure with reduced ejection fraction. Patients were defined as adults if ≤65 years (n = 51) and older if >65 years of age (n = 76). The incidence of ventricular arrhythmias at 1-year follow-up was comparable in both groups (30.8 vs 26.5%; p = 0.71). The mortality rate in adult patients is significantly lower as compared with older patients (2 vs 14.5%; log-rank = 0.04). Older patients may suffer remarkably more side effects than adult patients (21.1 vs 11.8%; p = 0.03).

scholarly journals Are we aiming for different metabolic targets in heart failure patients?

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
J Brito ◽  
J.R Agostinho ◽  
C Duarte ◽  
B Silva ◽  
S Pereira ◽  
...  
Keyword(s):  
Heart Failure ◽  
High Risk ◽  
Ejection Fraction ◽  
Cardiovascular Events ◽  
Cox Regression ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
The Impact ◽  
Very High

Abstract Introduction Metabolic control plays an important role on major cardiovascular events (MACE) prevention. The 2019 ESC guidelines on dyslipidaemia management recommend tighter LDL-cholesterol (LDL-C) control in order to prevent cardiovascular events. However, it is not yet proven that thigh control of dyslipidaemia, glycaemic levels and body mass index (BMI) in Heart Failure (HF) patients (pts) have an impact on prognosis. Objective To evaluate the impact of LDL-C, HbA1c and BMI values on HF pts mortality and MACE rates. Methods Single centre study that included consecutive pts hospitalized for acute / decompensated chronic HF in a tertiary Hospital between January 2016 to December 2018 and followed for 12 months. The impact of LDL-C, HbA1c and BMI on mortality and MACE was assessed using Cox regression and Kaplan-Meier curve, after adjustment for age, sex, functional class and ejection fraction. A safety cut-off was established when any of these variables was deemed protective using ROC curve analysis. Results Two hundred twenty-four patients (71.68±13.45 years, 63.8% males) were included. Eighty-four (37.5%) pts had type 2 diabetes, 39.7% had ischemic heart disease and the median left ventricular ejection fraction was 34% (IQR 25–49.5; 60.3% HFrEF; 13.8% HFmrEF; 22.3% HFpEF). The median BMI was 25.4 kg/m2 (IQR 23.1–30.5), HbA1c, 6.4% (IQR 5.6–6.8) and LDL-C, 89.5 mg/dL (IQR 64–106); 145 (64.7%) pts were medicated with statins. The overall mortality and MACE rates during follow-up were 16.1% and 21.0%, respectively. According to the CV risk classification 39.7% pts were at very high risk and 19.6% pts at high risk. On multivariate analysis HbA1c (HR 1.5 IQR 1.1–1.9; p=0.007) and female sex (HR 9.453 IQR 2.4–37.2; p=0.001) were independent predictors of mortality, whereas LDL-C (OR 1.05 IQR 1.022–1.075; p&lt;0.001) and BMI (OR 1.23 IQR 1.075–1.404; p=0.002) were independent protective factors. LDL-C and BMI had no effect on MACE rates, although HbA1c was an independent predictor of MACE (HR 1.27 IQR 1.03–1.57; p=0.026). For high and very high-risk pts there was still a protective trend on mortality, although non-significant, for higher levels of LDL-C (OR 1.04 IQR 0.99–1.075; P=NS). Protective LDL-C cut-off were estimated for the whole population (LDL-C 88mg/dL; AUC 0.819; sn 56.6%, sp 100%) and for the high and very-high CV risk pts (LDL-C 84mg/dL; AUC 0.815; sn 59.3%; sp 100%). A BMI safety cut-off for mortality of 25.75 kg/m2 was found (AUC 0.627; sn 61.2%; sp 58.3%). Conclusion This study supports the theory of the obesity and LDL-C paradox in HF. Lower LDL-C and BMI increased mortality and there is no trade-off effect on MACE rates, supporting the idea that LDL-C and BMI should not be aggressively addressed in HF pts. In our cohort a cut-off level of LDL-C below 88mg/dL is associated with higher mortality. On the other hand, diabetes should be actively treated as HbA1c predicts death and MACE in HF pts. Funding Acknowledgement Type of funding source: None

scholarly journals Prevalence and outcome of cardiac amyloidosis in an all-comer population of patients with non-ischaemic heart failure

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
S Goebel ◽  
S Schwuchow-Thonke ◽  
O Hahad ◽  
M Brandt ◽  
U Von Henning ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Cardiac Amyloidosis ◽  
Troponin I ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Unknown Etiology ◽  
Ventricular Ejection Fraction ◽  
All Cause Mortality ◽  
The Impact

Abstract Background Cardiac amyloidosis (CA) is increasingly recognized as an underlying cause of heart failure with preserved ejection fraction (HFpEF), associated with high morbidity and mortality. However, most studies, solely investigated the prevalence of CA in special subgroups including HFpEF and severe aortic valve disease. Purpose With the present study we sought to investigate prevalence of different phenotypes of CA in an all comer-population of patients with non-ischaemic heart failure (HF) and to analyze the impact of CA on all-cause mortality. Methods The My Biopsy HF-Study (German clinical trials register number: 22178) is a retrospective monocentric study investigating the underlying etiology of HF in an all-comer population of patients with HF of unknown etiology. Patients presenting with symptoms of HF at the University Medical Centre between 14/10/2012 and 01/03/2021, who underwent endomyocardial biopsy (EMB) were enrolled in the present study. Ischaemic HF and valvular HF were ruled out prior to EMB. Specimens were sent for further examination to a specialized laboratory approved by the Food and Drug Administration Results Between October 2012 and March 2021, 767 patients (71.6% men) with HF of unknown etiology were included. Mean age at the time of presentation was 55.4 years (±14.4). Altogether, 72.5% of the patients presented with HF with reduced ejection fraction (HFrEF), 7.1% were diagnosed with HF with mid-range ejection fraction (HFmrEF) and 20.4% with HFpEF. Based on histological examination and genotyping, CA was diagnosed in 44 (5.7%) patients (immunglobulin light chain [AL] CA: 15 patients; variant transthyretin [ATTRv] CA: 6 patients; wild type transthyretin [ATTRwt] CA: 21 patients; de novo CA: 2 patients). Patients with CA were older compared with patients without CA (69.4±11.4 vs. 54.1±14.5; p&lt;0.0001), had a higher prevalence of arterial hypertension (68.2% vs. 50.9%; p=0.045) and showed a better left ventricular ejection fraction based on echocardiographic examination (47.5% vs. 32.6%; p&lt;0.0001). With respect to biomarker expression, levels of both brain natriuretic peptide and high-sensitive troponin I were significantly higher in patients without CA (BNP: 914.1 vs 612; p=0.01; troponin I: 812.8 vs. 171.7; p=0.006). In univariate logistic regression analysis CA was associated with a significant all-cause mortality (hazard ratio [HR] per unit increase [ui], 5.17, 95% CI, 2.93–9.08; p&lt;0.0001), even after adjustment for classical cardiovascular risk factors (HRperui 3.12, 95% CI, 1.11–8.76; p=0.03) and comorbidities like chronic obstructive pulmonary disease, chronic kidney disease and stroke (HRperui 2.93, 95% CI, 1.2–7.15; p=0.018). Conclusions Among patients presenting with HF of unknown etiology, including patients with HFpEF, HFmrEF and HFrEF, cardiac amyloidosis is the underlying cause of HF in 5.7% of patients and is independently associated with all-cause mortality. FUNDunding Acknowledgement Type of funding sources: None.

Impact of left atrial appendage closure on left atrial hemodynamics: a prospective single center study

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
E Mertens ◽  
N Bouziri ◽  
P Guedeney ◽  
G Duthoit ◽  
A Redheuil ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Atrial ◽  
Left Ventricular ◽  
Volume Index ◽  
Left Ventricular Ejection ◽  
Clinical Issue ◽  
Ventricular Ejection Fraction ◽  
Mean Pressure ◽  
The Impact

Abstract Background Percutaneous left atrial (LA) appendage closure is increasingly used to prevent strokes in patients with atrial fibrillation (AF). While LA appendage plays a key role in LA physiology, data regarding the impact of LA appendage occlusion on LA hemodynamics are lacking. The alteration of LA compliance by LA appendage occlusion may represent a clinical issue in AF patients which are at high risk of heart failure. Purpose To describe the impact of LA appendage occlusion on LA hemodynamics. Material and methods From july 2015 to january 2020, all patients undergoing LA occlusion procedure at Pitié-Salpêtrière Hospital (Paris, France) in whom LA pressure curves were recorded, before and immediately after device implantation, were included. The LA mean pressure was measured at baseline and after LA appendage occlusion during the same procedure. Abnormal LA mean pressure was defined as &gt;15mmHg. We also recorded cardiovascular death and hospitalization for congestive heart failure at longest follow-up. Results We enrolled 85 patients (78±8 years, 46 men), the CHA2DS2-VASc score was 5±1 and the HAS-BLED score was 4±1. The mean LA volume index was 51±15mL/m2, the left ventricular ejection fraction was 60±7%. The LA mean pressure increased significatively after LA appendage closure from 12.6±3.9mmHg to 15.5±5.2mmHg (p&lt;0.0001, Figure). The prevalence of abnormal LA pressure was 20% (17/85) at baseline and 45% (38/85) after LA appendage closure (p=0.005). Post procedural LA pressure elevation was not related to procedure duration nor to fluid expansion volume. During a median follow-up of 364 [124–726] days, 3 (3.5%) patients died from a cardiovascular cause. Hospitalization for heart failure occurred in 6 (16%) of the 38 patients with abnormal postprocedural LA pressure, whereas no congestive episode was observed in the rest of the study population (p=0.006). Conclusion Catheter-based LA appendage occlusion induces an acute alteration of LA hemodynamics. Post procedural abnormal LA pressure may be linked to heart failure episodes in some patients. Further studies are warranted to investigate heart failure as a potential late complication of LA appendage closure. Variations of mean LA pressure Funding Acknowledgement Type of funding source: None

Residual inflammation is a major determinant of myocardial recovery and cardiovascular outcome in takotsubo patients

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
L Lachmet-Thebaud ◽  
B Marchandot ◽  
K Matsushita ◽  
C Sato ◽  
C Dagrenat ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Death ◽  
Left Ventricular ◽  
Cardiovascular Outcome ◽  
Left Ventricular Ejection ◽  
Funding Source ◽  
Ventricular Ejection Fraction ◽  
Cox Regression Analysis ◽  
The Impact

Abstract Background Recent insights have emphasized the importance of myocardial and systemic inflammation in Takotsubo Syndrome (TTS). Objective In a large registry of unselected patients, we sought to evaluate whether residual high inflammatory response (RHIR) could impact cardiovascular outcome after TTS. Methods Patients with TTS were retrospectively included between 2008 and 2018 in three general hospitals. 385 patients with TTS were split into three subgroups, according to tertiles of C-reactive protein (CRP) levels at discharge (CRP&lt;5.2 mg/l, CRP range 5.2 to 19 mg/l, and CRP&gt;19 mg/L). The primary endpoint was the impact of RHIR, defined as CRP&gt;19 mg/L at discharge, on cardiac death or hospitalization for heart failure. Results Follow-up was obtained in 382 patients (99%) after a median of 747 days. RHIR patients were more likely to have a history of cancer or a physical trigger. Left ventricular ejection fraction (LVEF) at admission and at discharge were comparable between groups. By contrast, RHIR was associated with lower LVEF at follow-up (61.7 vs. 60.7 vs. 57.9%; p=0.004) and increased cardiac late mortality (0% vs. 0% vs. 10%; p=0.001). By multivariate Cox regression analysis, RHIR was an independent predictor of cardiac death or hospitalization for heart failure (hazard ratio: 1.97; 95% confidence interval: 1.11 to 3.49; p=0.02). Conclusions RHIR was associated with impaired LVEF recovery and was evidenced as an independent factor of cardiovascular events. All together these findings underline RHIR patients as a high-risk subgroup, to target in future clinical trials with specific therapies to attenuate RHIR. Main results Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): GERCA (Groupe pour l'Enseignement, la prévention et la Recherche Cardiovasculaire en Alsace)

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