scholarly journals The Extracellular Matrix in Heart Failure: The Role of Adamts5 In Proteoglycan Remodelling

Circulation ◽  
2021 ◽  
Author(s):  
Javier Barallobre-Barreiro ◽  
Tamás Radovits ◽  
Marika Fava ◽  
Ursula Mayr ◽  
Wen-Yu Lin ◽  
...  
Keyword(s):  
Heart Failure ◽  
Extracellular Matrix ◽  
Connexin 43 ◽  
Cardiac Fibroblasts ◽  
Ischemia Reperfusion ◽  
Global Longitudinal Strain ◽  
Left Ventricular ◽  
Ang Ii ◽  
Chondroitin Sulphate Proteoglycans ◽  
Β Blockers

Background: Remodelling of the extracellular matrix (ECM) is a hallmark of heart failure (HF). Our previous analysis of the secretome of murine cardiac fibroblasts returned ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5) as one of the most abundant proteases. ADAMTS5 cleaves chondroitin sulphate proteoglycans (CSPGs) such as versican. The contribution of ADAMTS5 and its substrate versican to HF is unknown. Methods: Versican remodelling was assessed in mice lacking the catalytic domain of ADAMTS5 (Adamts5 △Cat ). Proteomics was applied to study ECM remodelling in left ventricular samples from HF patients, with a particular focus on the effects of common medications used for the treatment of HF. Results: Versican and versikine, an ADAMTS-specific versican cleavage product, accumulated in ischemic HF patients. Versikine was also elevated in a porcine model of cardiac ischemia/reperfusion injury and in murine hearts after angiotensin II (Ang II) infusion. In Adamts5 △Cat mice, Ang II infusion resulted in an aggravated versican build-up and hyaluronic acid disarrangement, accompanied by reduced levels of integrin beta 1, filamin A and connexin 43. Echocardiographic assessment of Adamts5 △Cat mice revealed a reduced ejection fraction and an impaired global longitudinal strain upon Ang II infusion. Cardiac hypertrophy and collagen deposition, however, were similar to littermate controls. In a proteomics analysis of a larger cohort of cardiac explants from ischemic HF patients (n=65), the use of β-blockers was associated with a reduction in ECM deposition, with versican being among the most pronounced changes. Subsequent experiments in cardiac fibroblasts confirmed that β1-adrenergic receptor stimulation increased versican expression. Despite similar clinical characteristics, HF patients treated with β-blockers had a distinct cardiac ECM profile. Conclusions: Our results in animal models and patients suggest that ADAMTS proteases are critical for versican degradation in the heart, and that versican accumulation is associated with impaired cardiac function. A comprehensive characterisation of the cardiac ECM in ischemic HF patients revealed that β−blockers may have a previously unrecognized beneficial effect on the cardiac CSPG content.

Dynamic changes in conduction velocity and gap junction properties during development of pacing-induced heart failure

2007 ◽  
Vol 293 (2) ◽  
pp. H1223-H1230 ◽  
Author(s):  
Fadi G. Akar ◽  
Robert D. Nass ◽  
Samuel Hahn ◽  
Eugenio Cingolani ◽  
Manish Shah ◽  
...  
Keyword(s):  
Heart Failure ◽  
Conduction Velocity ◽  
Connexin 43 ◽  
Time Course ◽  
Diastolic Pressure ◽  
Left Ventricular ◽  
Early Event ◽  
Mechanical Function ◽  
Dynamic Changes ◽  
End Stage

End-stage heart failure (HF) is characterized by changes in conduction velocity (CV) that predispose to arrhythmias. Here, we investigate the time course of conduction changes with respect to alterations in connexin 43 (Cx43) properties and mechanical function during the development of HF. We perform high-resolution optical mapping in arterially perfused myocardial preparations from dogs subjected to 0, 3, 7, 14, and 21 days of rapid pacing to produce variable degrees of remodeling. CV is compared with an index of mechanical function [left ventricular end-diastolic pressure (LVEDP)] and with dynamic changes in the expression, distribution, and phosphorylation of Cx43. In contrast to repolarization, CV was preserved during early stages of remodeling (3 and 7 days) and significantly reduced at later stages, which were associated with marked increases in LVEDP. Measurements of differentially phosphorylated Cx43 isoforms revealed early, sustained downregulation of pan-Cx43 that preceded changes in CV and LVEDP, a gradual rise in a dephosphorylated Cx43 isoform to over twofold baseline levels in end-stage HF, and a late abrupt increase in pan-Cx43, but not dephosphorylated Cx43, lateralization. These data demonstrate that 1) CV slowing occurs only at advanced stages of remodeling, 2) total reduction of pan-Cx43 is an early event that precedes mechanical dysfunction and CV slowing, 3) changes in Cx43 phosphorylation are more closely associated with the onset of HF, and 4) Cx43 lateralization is a late event that coincides with marked CV reduction. These data reveal a novel paradigm of remodeling based on the timing of conduction abnormalities relative to changes in Cx43 isoforms and mechanical dysfunction.

Abstract P237: Is Ischemia/Reperfusion an Efficient Method for Producing Heart Failure in Rats?

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Ana Carolina M Omoto ◽  
Fábio N Gava ◽  
Mauro de Oliveira ◽  
Carlos A Silva ◽  
Rubens Fazan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Diastolic Pressure ◽  
Histopathological Examination ◽  
Ischemia Reperfusion ◽  
Mitral Annulus ◽  
Mortality Rates ◽  
Tissue Doppler ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation

Myocardium infarction (MI) elicited by coronary artery ligation (CAL) is commonly used to induce chronic heart failure (HF) in rats. However, CAL shows high mortality rates. Given that ischemia-reperfusion (IR) may cause the development of HF, this approach may be useful for obtaining a model of HF with low mortality rates. Therefore, it was compared the model of CAL vs. IR in rats, evaluating the mortality and cardiac morphological and functional aspects. The IR consisted of 30 minutes of cardiac ischemia. Wistar rats were assigned into three groups: CAL: n=18; IR: n=7; SHAM (fictitious IR): n=7. After four weeks of CAL, the subjects were evaluated by echocardiography and ventriculography as well. The statistical analysis consisted of ANOVA combined with Tukey’s posthoc test (p<0.05). There were no deaths in the IR and SHAM groups, whereas in the CAL group the mortality rate was 33.33% (6 out of 18). In the CAL group echocardiography showed increased left ventricular (LV) cavity during systole (8.3 ± 1mm) and diastole (10.5 ± 1mm); decreased LV free wall during systole (1.4 ± 0.5 mm); increased left atrium/aorta (2.3 ± 0.4) ratio. These changes were not significant in IR (4.8 ± 0.5mm, 7.6 ± 0.6mm, 2.6 ± 0.3 mm, 1.6 ± 0.2) and SHAM (4.6 ± 0.6 mm, 7.7 ± 0.8mm, 2.8 ± 0.4mm, 1.5 ± 0.2) groups. There was also the reduction in the ejection fraction in the CAL group (41 ± 12 %) when compared with IR (65 ± 9%) and SHAM (69 ± 7%) groups. The tissue Doppler analysis from the lateral mitral annulus showed reduction in E′ in CAL (-29 ± 8 mm/s) and IR (-31± 9 mm/s) groups when compared with the SHAM (-48 ± 11 mm/s) group. The ventriculography in the CAL group showed smaller maximum dP/dt (6519 ± 1062) and greater end-diastolic pressure (33 ± 8 mmHg) when compared with IR (8716 ± 756 mmHg/s; 9 ± 9 mmHg) and SHAM (7989 ± 1230 mmHg/s; 9 ± 7 mmHg) groups. The CAL group presented transmural infarct size of 40% of the left ventricular wall, measured under histopathological examination. In conclusion, IR for 30 minutes caused only small changes in LV diastolic function, assessed by tissue Doppler; however, the IR was not effective for promoting HF, as observed with CAL. Thus, it is possible that prolonged IR is necessary for promoting significant HF in rats.

scholarly journals Cardiac mechanics as predictors of left ventricular reverse remodelling in patients with dilated non-ischemic cardiomyopathy

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
M Ferrandez ◽  
F Islas ◽  
A Travieso ◽  
J Diz-Diaz ◽  
A Restrepo ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ischemic Cardiomyopathy ◽  
Multimodality Imaging ◽  
Global Longitudinal Strain ◽  
Cardiac Mechanics ◽  
Left Ventricular ◽  
Cardiac Resynchronization ◽  
Imaging Parameters ◽  
Reverse Remodelling

Abstract Background and purpose The appearance of left ventricular reverse remodelling (LVRR) is associated with a better prognosis in patients with dilated non-ischemic cardiomyopathy (DCM). Our aim was to identify cardiac imaging parameters, including speckle tracking by transthoracic echocardiography (TTE) and feature tracking by CMR, associated with LVRR in a prospective cohort of patients with DCM. Methods From 2014 to 2021, 182 patients with DCM and left ventricle ejection fraction (LVEF) &lt;40% were prospectively evaluated in our hospital. LVRR was defined as an increase in LVEF ≥10 points or absolute LVEF ≥50%, associated with a reduction in left ventricular end- diastolic diameter ≥10%. Patients underwent multimodality imaging evaluation including CMR with a 1.5 Tesla scanner, and TTE. Cardiac mechanics, including global longitudinal strain (GLS), strain rate (SR) and mechanical dispersion (MD) were measured. Results Median age of our cohort was 62.3 (14.4) years, and 67.7% were male. Most patients (&gt;90%) were treated with beta-blockers or RASS blockers, and 67% with mineralocorticoid receptor antagonists. 30% had cardiac resynchronization therapy (CRT) and 37% had ICD as primary prevention. Mean LVEF was 31.3%. During a mean follow-up period of 35.9 (35.4) months, 38.3% of patients had LVRR. Age and gender distribution were similar in both groups. Regarding cardiovascular risk factors and pharmacological treatment, no differences were found between patients with and without LVRR. Baseline CRT therapy was not associated with LVRR (22.6% vs 34.7%; p=0.249). However, there was a trend towards higher LVRR in those who received CRT during follow-up 18.8% vs 0%; p=0.069). Patients who experienced LVRR had lower basal LVEF (23.4% vs 29%; p&lt;0.008), as well as poorer RV function, including lower RVEF (40.5% vs 51%; p=0.006) and lower TAPSE (16 mm vs 19 mm; p=0.021). Regarding cardiac mechanics, those patients with lower GLS (−9% vs −12%; p=0.001), and higher MD (73 mm vs 55 mm; p=0,050) had LVRR more frequently during follow-up. The presence of a left bundle branch block (LBBB) contraction pattern by strain was associated with higher rate of LVRR (83.3% vs 30.4%; p=0.011). The burden of fibrosis measured by LGE with CMR was not associated with LVRR (14% vs 12%; p=NS). Patients with LVRR had a lower cardiovascular mortality (3.3 vs 14.3%; p=0.117), lower mortality due to heart failure (0% vs 12.2%; p=0.046), less heart failure hospitalizations (20% vs 46.9%; p=0.016), and a lower incidence of ventricular tachyarrhythmias (3.3% vs 18.4%; p=0.051). Conclusions LVRR in patients with DCM receiving optimized medical therapy is associated with a better prognosis. Imaging parameters, including a lower basal LVEF, RVEF, GLS and higher MD, as well as LBBB echo pattern, were associated with a higher frequency of LVRR, and might help to identify patients who could benefit from CRT/and may be helpful to stratify patients's risk. FUNDunding Acknowledgement Type of funding sources: None.

scholarly journals Application of the current HFA-ESC consensus guidelines on diagnosis of heart failure with preserved ejection fraction to a population referred for echocardiography

2021 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
K Liang ◽  
R Hearse-Morgan ◽  
S Fairbairn ◽  
Y Ismail ◽  
AK Nightingale
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Ejection Fraction ◽  
Diastolic Function ◽  
Global Longitudinal Strain ◽  
Diagnostic Algorithm ◽  
Left Ventricular ◽  
Lv Function ◽  
Preserved Ejection Fraction ◽  
Consensus Guidelines

Abstract Funding Acknowledgements Type of funding sources: None. BACKGROUND The recent Heart Failure Association (HFA) of the European Society of Cardiology (ESC) consensus guidelines on diagnosis of heart failure with preserved ejection fraction (HFpEF) have developed a simple diagnostic algorithm for clinical use. PURPOSE To assess whether echocardiogram (echo) parameters needed to assess diastolic function are routinely collected in patients referred for assessment of heart failure symptoms. METHODS Retrospective analysis of echo referrals in January 2020 were assessed for parameters of diastolic function as per step 2 of the HF-PEFF diagnostic algorithm.  Echo images and clinical reports were reviewed. Electronic records were utilised to obtain clinical history, blood results (NT-proBNP) and demographic data. RESULTS 1330 patients underwent an echo in our department during January 2020. 83 patients were referred with symptoms of heart failure without prior history of cardiac disease; 20 patients found to have impaired left ventricular (LV) function were excluded from analysis. Of the 63 patients with possible HFpEF, HF-PEFF score was low in 18, intermediate in 33 and high in 12. Median age was 68 years (range 32 to 97 years); 25% had a BMI &gt;30. There was a high prevalence of hypertension (52%), diabetes (19%) and atrial fibrillation (40%) (cf. Table 1). Body surface area (BSA) was documented in 65% of echo reports. Most echo parameters were recorded with the exception of global longitudinal strain (GLS) and indexed LV mass (cf. image 1). NT-proBNP was recorded in only 20 patients (31.7%). 12 patients with an intermediate HF-PEFF score could have been re-categorised to a high score depending on GLS and NT-proBNP (which were not recorded). CONCLUSION More than three quarters of echoes acquired in our department obtained the relevant parameters to assess diastolic function. The addition of BSA, and inclusion of NT-proBNP, and GLS would have been additive to a third of ‘intermediate’ patients to determine definite HFpEF. Our study demonstrates that the current HFA-ESC diagnostic algorithm and HF-PEFF scoring system are easy to use, highly relevant and applicable to current clinical practice. Age &gt;70 years 29 (46.0%) Obesity (BMI &gt;30) 16 (25.4%) Diabetes 12 (19%) Hypertension 33 (52.4%) Atrial Fibrillation 25 (39.7%) ECG abnormalities 18 (28.5%) Table 1. Prevalence of Clinical Risk Factors Abstract Figure. Image 1. HFPEFF score & echo parameters

Abstract 14453: Ventilatory Inefficiency Associated With Stage a Heart Failure

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Elizabeth L Potter ◽  
Mary N Woessner ◽  
Christopher Neil ◽  
Thomas H Marwick ◽  
Erin Howden
Keyword(s):  
Risk Factors ◽  
Heart Failure ◽  
Ventilatory Threshold ◽  
Global Longitudinal Strain ◽  
Prognostic Significance ◽  
Cardiopulmonary Exercise Testing ◽  
Left Ventricular ◽  
Prognostic Information ◽  
Risk Profiling ◽  
Sedentary Subjects

Introduction: Peak oxygen utilisation (VO 2 ) and ventilatory efficiency (VE/VCO 2 slope) provide strong prognostic information in symptomatic heart failure (HF). Transition from subclinical to symptomatic HF is poorly understood. Cardiopulmonary exercise testing (CPET) in subclinical HF may advance risk profiling. Hypothesis: HF risk factors are associated with metabolic and ventilatory abnormalities that may serve as risk markers. Methods: Sedentary subjects (n=81; 67 (66-72) years; 65% female; BMI 29.9[26.6-33.9] kg/m 2 ) with ≥1 HF risk factors (Stage A HF, SAHF) without pulmonary disease and healthy sedentary subjects (controls, n=21; 70 (67-73) years; 52% female; BMI 25.1 [24-25.9] kg/m 2 ) underwent treadmill CPET to determine peak VO 2 , ventilatory threshold (VT, V-slope method) and VE/VCO 2 slope (linear regression). Global longitudinal strain≤16%, diastolic dysfunction or left ventricular hypertrophy defined subclinical left ventricular dysfunction (LVD). Results: LVD was present in 41 (51%) with SAHF. CPET parameters did not differ by presence of LVD. There were no differences in peak RER or VT (% peak VO2) between controls and SAHF. VO 2 peak was higher in controls vs. SAHF (22.1±4.6 vs. 19.9±4.6ml/kg/min, p=0.047). VE/VCO 2 slope was markedly steeper in SAHF vs. controls (40.2±6.2 vs. 29.3±6.1, p<0.001) (Figure). VE/VCO 2 slope was >34 (prognostic in symptomatic HF) in 83% vs. 19% for SAHF vs. controls (p<0.001). BMI was the only independent predictor (β 0.45 (0.19-0.72, p=0.001) (r 2 0.16) of VE/VCO 2 slope (SBP and heart rate reserve were not). BMI was not associated with increment in respiratory rate or tidal volume (β0.18(-0.07-0.42) and β3.9 (-10.8-18.7)). Conclusions: Cardiorespiratory exercise parameters do not differ in SAHF by presence of LVD. Ventilatory inefficiency is pronounced in SAHF compared with healthy controls suggesting it may be a risk marker, but prognostic significance is unknown.

Abstract 478: FGF23 Expression in Cardiac Fibroblasts Is Augmented by S100/Calgranulins-Mediated Inflammation and Associated With Cardiac Hypertrophy, but Not in Angiotensin II-Induced Cardiac Hypertrophy

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Marion Hofmann Bowman ◽  
Brandon Gardner ◽  
Judy Earley ◽  
Debra L Rateri ◽  
Alan Daugherty ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiac Fibroblasts ◽  
Left Ventricular ◽  
Heart Weight ◽  
Ang Ii ◽  
Wild Type ◽  
Wild Type Littermate ◽  
Transgenic Expression ◽  
Significant Difference

Background: Serum S100A12 and fibroblast growth factor (FGF) 23 are biomarkers for cardiovascular mortality in patients with chronic kidney disease (CKD) and are associated with left ventricular hypertrophy (LVH). FGF23 is induced in cultured cardiac fibroblasts in response to cytokines including IL-6, TNF-a, LPS and S100/calgranulins. Moreover, hBAC-S100 transgenic mice with CKD had increased FGF23 in valvular interstitial cells and exhibited LVH. The present study was designed to examine cardiac FGF23 expression in other murine models of LVH in the absence of CKD. Methods: Hearts from five groups of male mice were studied: (i) C57BL6/J with transgenic expression a bacterial artificial chromosome of the human S100/calgranulins (S1008/9 and S100A12, hBAC-S100), (ii) wild type littermates, (iii) LDLR-/- infused with saline (29 days, 0.9%), (iv) LDLR-/- infused with angiotensin (Ang) II (29 days, 1000 ng/kg/min), and (v) fibroblast specific depletion of angiotensin II type 1a receptor (AT1aR) (S100A4-Cre x AT1aR-/- x LDLR-/-) infused with AngII. Results: hBAC-S100, but not wild type littermate mice, developed significant LVH at 10 months by heart weight/body weight (5.9 ±1.1 mg/g vs. 4.2 ±0.8, p<0.04), decreased E/A ratio, and increased LVPW thickness, and associated with increased expression of FGF23 mRNA and protein in cardiac tissue lysates (2-4 fold increase). Similarly, Ang II induced significant LVH compared to saline infused LDLR-/- mice (6.1±1.3 vs. 3.6 ±0.9 mg/g, p<0.01), and associated with increased mRNA for hypertrophic genes (ANP, BNP, b-MHC, CTGF and Col1a1). However, there was no significant difference in FGF23 mRNA and protein between Ang II and saline infused mice. Cardiac hypertrophy was attenuated in AngII-infused mice with deficiency of AT1aR (S100A4-Cre+/-xAT1aRxLDLR-/-). In vitro, Ang II (100nM) did not induce FGF23 in valvular interstitial fibroblasts or myocytes. Summary: Transgenic expression of S100/calgranulins is sufficient to induce LVH in aged mice with normal renal function, and this is associated with FGF23 expression in cardiac interstitial fibroblasts. Future studies are needed to determine whether cardiac FGF23 promotes LVH in a paracrine manner. However, FGF23 does not play a role in Ang II-induced LVH.

scholarly journals P1386 A change in left ventricular global longitudinal strain is a prognostic indicator in congestive heart failure patients with preserved ejection fraction

2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
E Sakaguchi ◽  
A Yamada ◽  
M Hoshino ◽  
K Takada ◽  
N Hoshino ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Ejection Fraction ◽  
Longitudinal Strain ◽  
Global Longitudinal Strain ◽  
Stable Condition ◽  
Left Ventricular ◽  
Operating Characteristics ◽  
Cardiac Events

Abstract Purposes We examined how changes in left ventricular (LV) global longitudinal strain (GLS) were associated with prognosis in patients with preserved LV ejection fraction (LVEF) after congestive heart failure (HF) admission. Methods We studied 123 consecutive patients (age 70 ± 15 years, 55% male) who had been hospitalized due to congestive HF with preserved LVEF (&gt; 50%). The exclusion criteria were atrial fibrillation and inadequate echo image quality for strain analyses. The patients underwent speckle-tracking echocardiography and measurement of plasma NT-ProBNP levels on the same day at the time of hospital admission as well as in the stable condition after discharge. Differences in GLS, LVEF and NT-ProBNP (delta GLS, LVEF and NT-ProBNP ; 2nd – 1st measurements) were calculated. The study end points were all-cause mortality and cardiac events. Results Mean periods of echo performance after hospitalization were 2 ±１days (1st echo) and 240 ± 289 days (2nd echo), respectively. During the follow-up (974 ± 626 days), 12 patients died and 25 patients were hospitalized because of HF worsening. In multivariate analysis, delta GLS and follow-up GLS were prognostic factors, whereas baseline and follow-up LVEF, NT-ProBNP, changes in LVEF and NT-ProBNP could not predict cardiac events. Delta GLS (p = 0.002) turned out to be the best independent prognosticator. Receiver operating characteristics analysis revealed that -0.6% of delta GLS was the optimal cut-off value to predict cardiac events and mortality (sensitivity 76%, specificity 67%, AUC 0.75). Kaplan-Meier analysis showed that patients with delta GLS more than -0.6% experienced significantly less cardiac events during the follow-up period (p &lt; 0.0001, log-rank). Conclusion A change in LV GLS after congestive HF admission was a predictor of the prognosis in patients with preserved LVEF. It would be useful to check the changes in GLS in those with preserved LVEF after discharge.

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