Ivabradine Ameliorates Cardiac Function in Heart Failure with Preserved and Reduced Ejection Fraction via Upregulation of miR-133a

Heart failure (HF) is a clinical syndrome caused by impairment of ventricular filling, ejection of blood, or both and is categorized as HF with reduced ejection fraction (HFrEF) or HF with preserved ejection fraction (HFpEF) based on left ventricular function. Cardiac fibrosis contributes to left ventricular dysfunction and leads to the development of HF. Ivabradine, an If current selective specific inhibitor, has been shown to improve the prognosis of patients with HF. However, the effects of ivabradine on cardiac function and fibrosis in HFpEF and HFrEF and the underlying mechanism remain unclear. In the present study, we utilized mouse models to mimic HFpEF and HFrEF and evaluated the therapeutic effects of ivabradine. By treating mice with different doses (10 mg/kg/d and 20 mg/kg/d) of ivabradine for 4 or 8 weeks, we found that a high dose of ivabradine improved cardiac diastolic function in HFpEF mice and ameliorated cardiac diastolic and systolic function and ventricular tachycardia incidence in HFrEF mice. Moreover, ivabradine significantly reduced the activation of cardiac fibroblasts and myocardial fibrosis in mice. Mechanistically, microRNA-133a, which was upregulated by ivabradine, targeted connective tissue growth factor and collagen 1 in cardiac fibroblasts and might contribute to the protective role of ivabradine. Together, our work utilized mouse models to study HFpEF and HFrEF, demonstrated the protective role of ivabradine in HFpEF and HFrEF, and elucidated the potential underlying mechanism, which provides an effective strategy for related diseases.

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Mid- to Late-Life Time-Averaged Cumulative Blood Pressure and Late-Life Cardiac Structure, Function, and Heart Failure

Hypertension ◽

10.1161/hypertensionaha.120.14833 ◽

2020 ◽

Vol 76 (3) ◽

pp. 808-818

Author(s):

Kanako Teramoto ◽

Wilson Nadruz Junior ◽

Kunihiro Matsushita ◽

Brian Claggett ◽

Jenine E. John ◽

...

Keyword(s):

Heart Failure ◽

Blood Pressure ◽

Ejection Fraction ◽

Cardiac Function ◽

Specific Effect ◽

Late Life ◽

Left Ventricular ◽

Observation Time ◽

Preserved Ejection Fraction ◽

Reduced Ejection Fraction

Limited data exist regarding systolic blood pressure (SBP) through mid- to late-life and late-life cardiac function and heart failure (HF) risk. Among 4578 HF-free participants in the ARIC study (Atherosclerosis Risk in Communities) attending the fifth visit (2011–2013; age 75±5 years), time-averaged cumulative SBP was calculated as the sum of averaged SBPs from adjacent consecutive visits (visits 1–5) indexed to total observation time (24±1 years). Calculations were performed using measured SBPs and also incorporating antihypertensive medication specific effect constants (underlying SBP). Outcomes included comprehensive echocardiography at visit 5 and post-visit 5 incident HF, HF with preserved ejection fraction, and reduced ejection fraction. Higher cumulative SBP was associated with greater left ventricular mass and worse diastolic measures (all P <0.001), associations that were stronger with underlying compared with cumulative SBP (all P <0.05). At 5.6±1.2 years follow-up post-visit 5, higher cumulative measured and underlying SBP were associated with incident HF (hazard ratio per 10 mm Hg for measured: 1.12 [1.01–1.24]; underlying: 1.19 [95% CI, 1.10–1.30]) and HF with preserved ejection fraction (measured: 1.15 [1.00–1.33]; underlying: 1.28 [1.14–1.45]), but not HF with reduced ejection fraction (measured: 1.11 [0.94–1.32]; underlying: 1.11 [0.96–1.24]). Associations with HF and HF with preserved ejection fraction were more robust with cumulative underlying compared with measured SBP (all P <0.05). Time-averaged cumulative SBP in mid to late life is associated with worse cardiac function and risk of incident HF, especially HF with preserved ejection fraction, in late life. These associations were stronger considering underlying as opposed to measured SBP, highlighting the importance of prevention and effective treatment of hypertension to prevent late-life cardiac dysfunction and HF.

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Heart failure with preserved ejection fraction: the role of diastolic stress test in diagnostic algorithms

Russian Journal of Cardiology ◽

10.15829/1560-4071-2021-4147 ◽

2021 ◽

Vol 26 (2) ◽

pp. 4147

Author(s):

E. N. Pavlyukova ◽

D. A. Kuzhel

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Stress Test ◽

Left Ventricular ◽

Moderate Increase ◽

Preserved Ejection Fraction ◽

Reduced Ejection Fraction ◽

Existing Problems ◽

Non Invasive

Heart failure (HF) with preserved ejection fraction (HFpEF) is currently the most common type of this condition, especially among elderly patients. Despite the preserved left ventricular (LV) and a moderate increase in natriuretic peptide, patients with HFpEF have the same out-of-hospital mortality as those with HF with reduced ejection fraction (HFrEF). Diagnosis of HFpEF is difficult due to nonspecific symptoms, expensive blood tests, and questionable rest echocardiographic data on diastolic function. In addition, the reason for poor diagnosis of HfpEF in clinical practice may be old age and comorbidities, which can also cause nonspecific symptoms of moderate chronic shortness of breath, weakness, and palpitations. The consequence is the detection of HFpEF only in every fourth patient with an acute or chronic heart failure. The use of simplified clinical diagnostic protocols along with a non-invasive ultrasound stress test can help overcome the existing problems in the diagnosis of HFpEF.

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Alpha-Klotho is a novel predictor of treatment responsiveness in patients with heart failure

Scientific Reports ◽

10.1038/s41598-021-81517-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Manabu Taneike ◽

Makoto Nishida ◽

Kaori Nakanishi ◽

Fusako Sera ◽

Hidetaka Kioka ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Left Ventricular ◽

University Hospital ◽

Left Ventricular Ejection ◽

Ventricular Ejection Fraction ◽

Reduced Ejection Fraction ◽

Patients With Heart Failure ◽

Male Patients

AbstractHeart failure is a major cause of death with an increasing population of elderly individuals. Several studies have demonstrated the involvement of soluble alpha-Klotho (sαKl) in various diseases. However, the correlation between sαKl and heart failure remains to be understood. The aim of this study is to investigate the levels and role of sαKl in patients with heart failure. Twenty-eight consecutive patients with acute heart failure (19 male, 9 female), admitted to the Osaka University Hospital from 2010 to 2018, were enrolled in this study. Mean NYHA score, left ventricular ejection fraction and BNP were 3.3, 17.0% and 588 pg/mL, respectively. SαKl significantly increased in heart failure patients. SαKl on admission were significantly higher in patients with heart failure who showed improvement after intensive treatment than that in patients who did not show improvement after the treatment. SαKl levels decreased significantly in patients who showed improvement. Interestingly, sαKl levels increased in male patients with heart failure, but not in female patients. Our data suggest that soluble αKl may be a novel biomarker for the responsiveness against treatment in patients with heart failure with reduced ejection fraction. Our findings may help developing a personalized therapy for different patients with heart failure.

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Protective role of peroxiredoxin-4 in heart failure

Clinical Science ◽

10.1042/cs20191072 ◽

2020 ◽

Vol 134 (1) ◽

pp. 71-72

Author(s):

Naseer Ahmed ◽

Masooma Naseem ◽

Javeria Farooq

Keyword(s):

Heart Failure ◽

Cardiac Fibroblasts ◽

Protective Role ◽

Oxidative Stress Markers ◽

Stress Markers ◽

Total Antioxidant ◽

Galectin 3 ◽

Consequent Increase ◽

And Oxidative Stress

Abstract Recently, we have read with great interest the article published by Ibarrola et al. (Clin. Sci. (Lond.) (2018) 132, 1471–1485), which used proteomics and immunodetection methods to show that Galectin-3 (Gal-3) down-regulated the antioxidant peroxiredoxin-4 (Prx-4) in cardiac fibroblasts. Authors concluded that ‘antioxidant activity of Prx-4 had been identified as a protein down-regulated by Gal-3. Moreover, Gal-3 induced a decrease in total antioxidant capacity which resulted in a consequent increase in peroxide levels and oxidative stress markers in cardiac fibroblasts.’ We would like to point out some results stated in the article that need further investigation and more detailed discussion to clarify certain factors involved in the protective role of Prx-4 in heart failure.

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Heart Failure with Preserved Ejection Fraction – A Review

US Cardiology Review ◽

10.15420/usc.2012.9.2.90 ◽

2012 ◽

Vol 9 (1) ◽

pp. 90-95 ◽

Cited By ~ 1

Author(s):

Otto A Smiseth ◽

Anders Opdahl ◽

Espen Boe ◽

Helge Skulstad

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Diastolic Heart Failure ◽

The Elderly ◽

Left Ventricular ◽

Filling Pressure ◽

Left Ventricular Ejection ◽

Ventricular Ejection Fraction ◽

Reduced Ejection Fraction ◽

Objective Evidence

Heart failure with preserved left ventricular ejection fraction (HF-PEF), sometimes named diastolic heart failure, is a common condition most frequently seen in the elderly and is associated with arterial hypertension and left ventricular (LV) hypertrophy. Symptoms are attributed to a stiff left ventricle with compensatory elevation of filling pressure and reduced ability to increase stroke volume by the Frank-Starling mechanism. LV interaction with stiff arteries aggravates these problems. Prognosis is almost as severe as for heart failure with reduced ejection fraction (HF-REF), in part reflecting co-morbidities. Before the diagnosis of HF-PEF is made, non-cardiac etiologies must be excluded. Due to the non-specific nature of heart failure symptoms, it is essential to search for objective evidence of diastolic dysfunction which, in the absence of invasive data, is done by echocardiography and demonstration of signs of elevated LV filling pressure, impaired LV relaxation, or increased LV diastolic stiffness. Antihypertensive treatment can effectively prevent HF-PEF. Treatment of HF-PEF is symptomatic, with similar drugs as in HF-REF.

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Faculty Opinions recommendation of Role of left ventricular stiffness in heart failure with normal ejection fraction.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1107053.563027 ◽

2008 ◽

Author(s):

Jan Poelaert

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Left Ventricular ◽

Normal Ejection Fraction ◽

Left Ventricular Stiffness

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Prognostic role of myocardial work in patients with heart failure and reduced ejection fraction treated by sacubitril/valsartan

European Heart Journal ◽

10.1093/ehjci/ehaa946.0040 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

E Galli ◽

Y Bouali ◽

C Laurin ◽

A Gallard ◽

A Hubert ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Rank Test ◽

Reduced Ejection Fraction ◽

Non Invasive ◽

Patients With Heart Failure ◽

Increase Risk ◽

Echocardiographic Examination ◽

Constructive Work

Abstract Background The non-invasive assessment of myocardial work (MW) by pressure-strain loops analysis (PSL) is a relative new tool for the evaluation of myocardial performance. Sacubitril/Valsartan is a treatment for heart failure with reduced ejection fraction (HFrEF) which has a spectacular effect on the reduction of cardiovascular events (MACEs). Purposes of this study were to evaluate 1) the short and medium term effect of Sacubitril/Valsartan treatment on MW parameters; 2) the prognostic value of MW in this specific group of patients. Methods 79 patients with HFrEF (mean age: 66±12 years; LV ejection fraction: 28±9%) were prospectively included in the study and treated with Sacubitril/Valsartan. Echocardiographic examination was performed at baseline, and after 6- and 12-month of therapy with Sacubitril/Valsartan. Results Sacubitril/Valsartan significantly increased global myocardial constructive work (CW) (1023±449 vs 1424±484 mmHg%, p<0.0001) and myocardial work efficiency (WE) [87 (78–90) vs 90 (86–95), p<0.0001]. During FU (2.6±0.9 years), MACEs occurred in 13 (16%) patients. After correction for LV size, LVEF and WE, CW was the only predictor of MACEs (Table 1). A CW<910 mmHg (AUC=0.81, p<0.0001, Figure 1A) identified patients at particularly increase risk of MACEs [HR 11.09 (1.45–98.94), p=0.002, log-rank test p<0.0001] (Figure 1 B). Conclusions In patients with HFrEF who receive a comprehensive background beta-blocker and mineral-corticoid receptor antagonist therapy, Sacubitril/Valsartan induces a significant improvement of myocardial CW and WE. In this population, the estimation of CW before the initiation of Sacubitril/Valsartan therapy allows the prediction of MACEs. Funding Acknowledgement Type of funding source: None

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Prognostic value of global longitudinal layer specific strain for patients with heart failure with reduced ejection fraction

European Heart Journal ◽

10.1093/ehjci/ehaa946.0117 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

C Johnsen ◽

M Sengeloev ◽

P Joergensen ◽

N Bruun ◽

D Modin ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Prognostic Value ◽

Left Ventricular ◽

Volume Index ◽

Funding Source ◽

Reduced Ejection Fraction ◽

Patients With Heart Failure ◽

All Cause Mortality ◽

Echocardiographic Parameters

Abstract Background Novel echocardiographic software allows for layer-specific evaluation of myocardial deformation by 2-dimensional speckle tracking echocardiography. Endocardial, epicardial- and whole wall global longitudinal strain (GLS) may be superior to conventional echocardiographic parameters in predicting all-cause mortality in patients with heart failure with reduced ejection fraction (HFrEF). Purpose The purpose of this study was to investigate the prognostic value of endocardial-, epicardial- and whole wall GLS in patients with HFrEF in relation to all-cause mortality. Methods We included and analyzed transthoracic echocardiographic examinations from 1,015 patients with HFrEF. The echocardiographic images were analyzed, and conventional and novel echocardiographic parameters were obtained. A p value in a 2-sided test <0.05 was considered statistically significant. Cox proportional hazards regression models were constructed, and both univariable and multivariable hazard ratios (HRs) were calculated. Results During a median follow-up time of 40 months, 171 patients (16.8%) died. A lower endocardial (HR 1.17; 95% CI (1.11–1.23), per 1% decrease, p<0.001), epicardial (HR 1.20; 95% CI (1.13–1.27), per 1% decrease, p<0.001), and whole wall (HR 1.20; 95% CI (1.14–1.27), per 1% decrease, p<0.001) GLS were all associated with higher risk of death (Figure 1). Both endocardial (HR 1.12; 95% CI (1.01–1.23), p=0.027), epicardial (HR 1.13; 95% CI (1.01–1.26), p=0.040) and whole wall (HR 1.13; 95% CI (1.01–1.27), p=0.030) GLS remained independent predictors of mortality in the multivariable models after adjusting for significant clinical parameters (age, sex, total cholesterol, mean arterial pressure, heart rate, ischemic cardiomyopathy, percutaneous transluminal coronary angioplasty and diabetes) and conventional echocardiographic parameters (left ventricular (LV) ejection fraction, LV mass index, left atrial volume index, deceleration time, E/e', E-velocity, E/A ratio and tricuspid annular plane systolic excursion). No other echocardiographic parameters remained an independent predictors after adjusting. Furthermore, endocardial, epicardial and whole wall GLS had the highest C-statistics of all the echocardiographic parameters. Conclusion Endocardial, epicardial and whole wall GLS are independent predictors of all-cause mortality in patients with HFrEF. Furthermore, endocardial, epicardial and whole wall GLS were superior prognosticators of all-cause mortality compared with all other echocardiographic parameters. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Herlev and Gentofte Hospital

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