Abstract 2459: A Potentially Novel Role Of The Follistatin-activin Pathway In Heart Failure And Myocardial Recovery Following Lvad Combination Therapy

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Enrique Lara-Pezzi ◽  
Leanne E Felkin ◽  
Padmini Sarathchandra ◽  
Robert George ◽  
Jennifer L Hall ◽  
...  
Keyword(s):  
Heart Failure ◽  
Disease Severity ◽  
Calcium Binding ◽  
Cell Signalling ◽  
Immunohistochemical Analysis ◽  
Left Ventricular ◽  
Pharmacologic Therapy ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Real Time Quantitative Pcr

Background - Recent evidence suggests that the activin pathway may play an important role in the pathogenesis of heart failure. Follistatins are potent inhibitors of activin signalling but their role in the heart is unknown. The purpose of this study was to investigate myocardial expression of follistatin (FST) and follistatin-like (FSTL1 and FSTL3) in heart failure and following recovery in patients who received combined mechanical unloading using left ventricular assist device (LVAD) and pharmacologic therapy. Methods and results - Real time quantitative PCR was used to examine gene expression in myocardial samples from donors (n=9), end-stage heart failure patients (n=27) and patients who recovered from heart failure sampled at the time of LVAD implant, at the time of LVAD removal following recovery, and one year post explant. Both FSTL1 and FSTL3 were elevated in heart failure (1.51 and 2.50 fold respectively p<0.005) with expression returning to normal following recovery. Whereas FSTL3 correlated with molecular markers of disease severity, FSTL1 showed negative correlation with skeletal α-actin and positive correlation with the endothelial cell marker CD31, suggesting a potential link with extent of vascularization. FSTL1 expression levels at LVAD implant also correlated with significantly higher ejection fraction following recovery suggesting initial levels may have an influence on long term outcome. Immunohistochemical analysis showed that FST was localised in fibroblasts and endothelium, FSTL1 in myocytes, endothelium and smooth muscle cells, and FSLT3 in myocytes and endothelium. Microarray analysis showed that FST and FSTL1 expression correlate with extracellular matrix-related and calcium binding proteins, whereas FSTL3 is associated with cell signalling and transcription. Conclusion - These data show for the first time that elevated myocardial expression of follistatin-like genes is a feature of heart failure and that this may be linked both to disease severity and to mechanisms underlying recovery thereby revealing new insight into the pathogenesis of heart failure and offering novel therapeutic targets.

scholarly journals Expression of Follistatin-Related Genes Is Altered in Heart Failure

Endocrinology ◽  
2008 ◽  
Vol 149 (11) ◽  
pp. 5822-5827 ◽  
Author(s):  
Enrique Lara-Pezzi ◽  
Leanne E. Felkin ◽  
Emma J. Birks ◽  
Padmini Sarathchandra ◽  
Kalyani D. Panse ◽  
...  
Keyword(s):  
Heart Failure ◽  
Disease Severity ◽  
Calcium Binding ◽  
Muscle Growth ◽  
Left Ventricular ◽  
Pharmacological Therapy ◽  
Term Outcome ◽  
Ventricular Assist ◽  
Long Term Outcome ◽  
Potential Link

Follistatins play roles in diverse biological processes including cell proliferation, wound healing, inflammation, and skeletal muscle growth, yet their role in the heart is currently unknown. We have investigated the myocardial expression profile and cellular distribution of follistatin (FST) and the FST-like genes FSTL1 and FSTL3 in the normal and failing heart. Expression was further analyzed in the novel setting of recovery from heart failure in myocardium obtained from patients who received combined mechanical (left ventricular assist device) and pharmacological therapy. Real-time PCR revealed that FSTL1 and FSTL3 expression was elevated in heart failure but returned to normal after recovery. FSTL3 expression levels correlated with molecular markers of disease severity and FSTL1 with the endothelial cell marker CD31, suggesting a potential link with vascularization. FSTL1 levels before treatment correlated with cardiac function after recovery, suggesting initial levels may influence long-term outcome. Immunohistochemistry revealed that FST was primarily localized to fibroblasts and vascular endothelium within the heart, whereas FSTL1 was localized to myocytes, endothelium, and smooth muscle cells and FSLT3 to myocytes and endothelium. Microarray analysis revealed that FST and FSTL1 were associated with extracellular matrix-related and calcium-binding proteins, whereas FSTL3 was associated mainly with cell signaling and transcription. These data show for the first time that elevated myocardial expression of FST-like genes is a feature of heart failure and may be linked to both disease severity and mechanisms underlying recovery, revealing new insight into the pathogenesis of heart failure and offering novel therapeutic targets.

scholarly journals Systolic blood pressure and outcome in patients admitted with acute heart failure: a pooled analysis from 4 randomized clinical trials

2021 ◽  
Vol 10 (Supplement_1) ◽  
Author(s):  
J Grand ◽  
K Miger ◽  
A Sajadieh ◽  
L Kober ◽  
C Torp-Pedersen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Composite Endpoint ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Term Outcome ◽  
Ventricular Ejection Fraction ◽  
Long Term Outcome ◽  
All Cause Mortality ◽  
Short And Long Term

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The Danish Heart Foundation Background In acute heart failure (AHF), low systolic blood pressure (SBP) has been associated with poor outcome. Less is known of the risk related to normal versus elevated SBP and interaction with left ventricular ejection fraction. Purpose The aim of the present study was to assess the association between baseline SBP and short- and long-term outcome in a large cohort of AHF-patients. Methods A pooled cohort of four randomized controlled trials investigating the vasodilator serelaxin versus placebo in patients admitted with AHF and an SBP from 125 to 180 mmHg. Endpoints were 180-day all-cause mortality and a short-term composite endpoint (worsening heart failure, all-cause mortality or hospital readmission for HF through Day 14). Left ventricular ejection fraction (LVEF) was categorized into HFrEF (&lt;40%) and HFpEF (= &gt;40%). Multivariable Cox regression was used and adjusted for age, sex, baseline body mass index, HFrEF, serum estimated glomerular filtration rate, allocated treatment (placebo/serelaxin), diabetes mellitus, ischemic heart disease, and atrial fibrillation/flutter. Measurements and Main Results A total of 10.533 patients with a mean age of 73 (±12) years and median SBP of 140 (130-150) mmHg were included within mean 8.2 hours from admission. LVEF was assessed in 8493 (81%), and of these, 4294 (51%) had HFrEF. Increasing SBP as a continuous variable was inversely associated with 180-day mortality (HRadjusted: 0.93 [0.88-0.98], p = 0.004 per 10 mmHg increase) and with the composite endpoint (HRadjusted: 0.90 [0.85-0.95], p &lt; 0.0001 per 10 mmHg increase). A significant interaction was observed regarding LVEF, revealing that SBP was not associated with mortality in patients with HFpEF  (HRadjusted: 1.01 [0.94-1.09], p = 0.83 per 10 mmHg increase), but SBP was associated with increased mortality in HFrEF (HRadjusted: 0.80 [0.73-0.88], p &lt; 0.001 per 10 mmHg increase) (Figure). Conclusions Elevated SBP is independently associated with favorable short- and long-term outcome in AHF-patients. The association between SBP and mortality was, however, not present in patients with preserved LVEF. Abstract Figure. Survival plots by SBP and LVEF

Monitoring stroke volume changes in acute heart failure patients

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Barki ◽  
M Losito ◽  
M.M Caracciolo ◽  
F Bandera ◽  
M Rovida ◽  
...  
Keyword(s):  
Heart Failure ◽  
Stroke Volume ◽  
Acute Decompensated Heart Failure ◽  
Hospital Setting ◽  
Left Ventricular ◽  
Term Outcome ◽  
Cross Sectional ◽  
Long Term Outcome ◽  
Group I ◽  
Group Ii

Abstract Background Stroke volume (SV) is the net result of cardiac dynamics and functional capacity. Notably, acute decompensated heart failure (ADHF) patients admitted highly congested and with a reduced SV (primarily wet and cold phenotype) exhibit a poorer prognosis. However, how SV may change in wet and warm phenotype during acute hospital setting remains undefined. Purpose To evaluate, in a cohort of ADHF patients, the pattern of SV changes during hospitalization. Methods Eighty-one ADHF patients (mean age 75.75±10.6 years, 59% males) warm and wet phenotype were prospectively enrolled within 24–48 hours from admission to the emergency department. In either the acute phase and at pre-discharge all patients underwent M-Mode, 2-Dimensions, Doppler and Speckle Tracking echocardiography (STE). SV and SV indexed (SVi) were estimated using the non-invasive doppler method multiplying the left ventricular outflow tract (LVOT) cross-sectional area (CSA) and the velocity time-integral (VTI) of the LVOT. Results From admission to discharge, despite a targeted decongestion we observed only minimal and non-significant changes in the average SV and SVi (SV: from 46.9±14.7 ml at admission to 47.2±15.12 at discharge, p=0.9; SVi: from 26.6±8.5 ml/m2 at admission to 27.1±8.4 ml/m2 at discharge, p=0.73). When we looked at those patients improving (Group I) vs non improving SV (Group II) we observed that subjects in Group I exhibited a significantly lower prevalence of mitral regurgitation (MR) both at admission (Group I: MR adm. 23% vs Group II: MR adm: 53% p&lt;0.05) and at the pre-discharge (Group I: MR disch. 13.4% vs Group II: MR disch. 45% p&lt;0.05), a significantly higher global peak atrial longitudinal strain (GPALS) at pre-discharge (Group I: GPALS disch. 17.25±6.5% vs Group II disch. 11±7.1%; p=0.04), along with a significantly greater improvement in terms of GPALS (ΔGPLAS) during hospitalization (Group I: from 13±6.9% to 17.25±6.5%, p=0.04; Group II: from 13.85±8.4% to 11±7.1%, p=0.6) (Figure 1). Interestingly, when evaluated with Pearson's coefficient, in the whole population a significant direct correlation was observed between ΔSV and ΔGPALS (r=0.67 95% CI 0.4–0.7, p&lt;0.001) (Figure 2). Conclusions In ADHF patients, the wet and warm phenotype displays a decreased forward SV which does not improve after decongestion therapy on average variations. In this context, the coexistence of LA impairment and hemodynamically significant MR seems to play a key role whereas, LA functional properties recover at least in part in patients who are able to show a SV improvement. Further analysis are necessary to test whether a lack of SV improvement in the short term may impact the long-term outcome. Funding Acknowledgement Type of funding source: None

Long-term outcome in patients with congestive heart failure and intact systolic left ventricular performance

1992 ◽  
Vol 69 (14) ◽  
pp. 1212-1216 ◽  
Author(s):  
John F. Setaro ◽  
Robert Soufer ◽  
Michael S. Remetz ◽  
Robin A. Perlmutter ◽  
Barry L. Zaret
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Left Ventricular ◽  
Left Ventricular Performance ◽  
Term Outcome ◽  
Ventricular Performance ◽  
Long Term Outcome

scholarly journals Aetiology-dependent impairment of mitochondrial function in the failing human heart

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
J Borger ◽  
D Scheiber ◽  
P Horn ◽  
D Pesta ◽  
U Boeken ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mitochondrial Function ◽  
Human Study ◽  
Left Ventricular ◽  
Myocardial Tissue ◽  
Funding Source ◽  
Ros Production ◽  
German Research Foundation ◽  
Long Term Outcome ◽  
Tissue Specimens

Abstract Background Alterations of mitochondrial function have been identified to play a role in Heart Failure (HF) pathophysiology. Oxidative phosphorylation (OXPHOS) capacity of the myocardium was shown to be reduced in the failing heart. Ineffective mitochondrial function promotes formation of reactive oxygen species (ROS) that may affect remodelling in ischemia. Thus far, human mitochondrial function comparing dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) resembling the main aetiologies of heart failure with reduced ejection fraction (HFrEF) has not been investigated. Purpose We hypothesised that 1. ROS production is elevated in left ventricular myocardial tissue specimens of ICM patients compared to DCM. 2. Mitochondrial OXPHOS capacity is higher in left ventricular myocardial tissue specimens of DCM compared to ICM patients. Methods Myocardial tissue was obtained from the left ventricular apex from 63 patients (38 ICM, 25 DCM) with advanced HFrEF requiring implantation of a Left Ventricular Assist Device (LVAD). We performed high-resolution respirometry (HRR, OROBOROS Oxygraph-2k) in saponine-permeabilised myocardial fibres and measured ROS production fluoroscopically via the Amplex Red method. Statistical analysis was conducted using GraphPad Prism 7 and IBM SPSS v26.0. Results Groups were of comparable age (61.5±1.2 vs. 59.3±2.4 years, p=n.s.), sex (87% vs 85% male, p=n.s.), diabetic status (32% vs 38.4% type 2 diabetes mellitus, p=n.s.), and body mass index (28.1±0.8 vs. 26.3±1.1 kg/m2, p=n.s.). We detected reduced myocardial mitochondrial OXPHOS capacity in ICM under state 3 conditions by about 15% (68.7±34.0 vs. 80.9±30.5 pmol/(s*mg), p&lt;0.05), after addition of Glutamate by 25% (78.9±38.7 vs. 104.8±41.2 pmol/(s*mg), p&lt;0.01) as well as after Succinate (115.5±65.5 vs. 155±62.0 pmol/(s*mg), p&lt;0.01), uncoupling agent FCCP (114.1±56.8 vs. 150.5±47.3 pmol/(s*mg), p&lt;0.01), and by about 40% after addition of Complex I inhibitor Rotenone (55.5±25.9 vs. 96.9±28.0 pmol/(s*mg), p&lt;0.001). We detected no difference in ROS production between ICM and DCM (0.6±0.05 vs. 0.76±0.08 pmol/(s*ml), p=n.s.). Conclusion This is the first human study deciphering distinct alterations in mitochondrial function (OXPHOS capacity) in ventricular myocardium of HFrEF patients. Future studies may address how distinct metabolic patterns at the time of implantation may relate to long-term outcome of HFrEF in terms of remodelling and recovery. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): DFG (German Research Foundation)

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