Expression of Follistatin-Related Genes Is Altered in Heart Failure

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.

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

Circulation ◽

10.1161/circ.116.suppl_16.ii_541-a ◽

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.

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

European Heart Journal Acute Cardiovascular Care ◽

10.1093/ehjacc/zuab020.045 ◽

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 (<40%) and HFpEF (= >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 < 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 < 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

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