scholarly journals Cardiac muscle activation; the role of length dependent activation and the novel myosin activator danicamtiv

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
K Bell ◽  
A.R Anto ◽  
R.L Anderson ◽  
C.L Del Rio ◽  
M Henze
Keyword(s):  
Muscle Activation ◽  
Left Ventricular ◽  
Lv Function ◽  
Muscle Fibres ◽  
Funding Source ◽  
Fiber Types ◽  
Passive Stiffness ◽  
Release Rates ◽  
Private Company ◽  
Length Dependent Activation

Abstract   B: Alterations in the length dependent activation (LDA) of left ventricular (LV) muscle fibres, the mechanistic driver of the Frank-Starling Law of the heart, are thought to mediate impaired LV function in heart failure (HF). However, little is known about LDA's role in the left atria (LA). Given the concomitant presence of LA dysfunction in HF, the purpose of this study was to compare/assess LDA on LA and LV muscle, as well to evaluate the effects of a novel small-molecule acto-myosin activator, danicamtiv (formerly known as MYK-491). M: LA and LV myofibrils from healthy Yucatan mini-pigs were used to determine biomechanical function with ATPase assays, with and without danicamtiv. Skinned LA and LV muscle fibres from these same animals were prepared to study contractile force, Ca2+ sensitivity, active/passive stiffness, and responsiveness to increasing sarcomere length (2.0 and 2.3). These parameters were also evaluated in the presence of danicamtiv. R: LA myofibrils had significantly faster ATPase and Pi release rates compared to LV, consistent with their respective alpha/beta myosin-isoform content. Despite increased metabolic rate, LA fibres generated less maximum isometric tension (12.3±1.96 vs 35.2±3.07 mN/mm2) and had a lower pCa50 than LV fibres (5.66±0.02 vs 5.82±0.02), demonstrating reduced force-generating capability and Ca2+ sensitivity. Stretch of LV fibres resulted in a gain in tension over a range of pCas (pCa6.4, 6.2, 6.0, and 5.8, all p<0.05). However, in LA, LDA-induced gain was not significant at submaximal pCas (pCa6.4, 6.2, 6.0, all p>0.05). Stretch had no effect on active stiffness, but increased passive stiffness in both muscle types. Stretched LA fibres showed grater passive stiffness compared to LV (196.7±21.5 vs. 138.5±22.3 kN/m3). A stiffer myofilament would in part explain the blunted ability of the LA to generate force in response to stretch. Danicamtiv activated both LA and LV myofibrils, increasing ATPase and Pi release rates, and increased Ca2+ sensitivity in fibres (ΔpCa; LV, 0.320±0.032; LA, 0.149±0.028, p<0.01). Unlike with stretch, danicamtiv had no effect on passive stiffness, yet altered the active stiffness/tension (S/T) relationship in both fiber types, but, differentially. In LV, danicamtiv increased the number of available heads (Y0; 129.9±26.3 vs 10.1±4.2 kN/m3, p<0.001) with no significant effect on slope. In the LA, Y0 was largely unchanged with a significant increase in the slope of the S/T relationship (slope: 34.0±2.9 vs. 20.0±1.9 au, p<0.01). Together, these data suggest an increased number of force producing cross-bridges, without altering passive stiffness. C: These data confirm the functional differences between LA and LV muscle fibres and demonstrate a blunted ability of LA tissue to recruit force when stretched. The acto-myosin activator danicamtiv increased biochemical activity, Ca2+ sensitivity, and the active S/T relationship in LA and LV fibres without altering passive strain. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): MyoKardia Inc.

scholarly journals Acute effects of a mavacamten-like myosin-inhibitor (MYK-581 in a feline model of obstructed hypertrophic cardiomyopathy: evidence of improved ventricular filling (beyond obstruction reprieve)

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
B.S Ferguson ◽  
J.A Stern ◽  
M.S Oldach ◽  
Y Ueda ◽  
E.S Ontiveros ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Acute Treatment ◽  
Left Ventricular ◽  
Funding Source ◽  
Private Company ◽  
Cardiac Phenotype ◽  
Diastolic Stiffness ◽  
Cardiac Hemodynamics ◽  
Feline Model ◽  
Ventricular Filling

Abstract Introduction Hypertrophic cardiomyopathy (HCM) is a progressive disease characterized by cardiac remodeling, hyperdynamic contraction, and impaired ventricular filling that can lead to dynamic left-ventricular outflow-track (LVOT) obstruction and exertional intolerance. Direct myosin-inhibition with mavacamten can normalize contractility and improve exercise capacity in patients with oHCM, providing sustained symptomatic relief. However, mavacamten can also improve ventricular filling by limiting residual cross-bridges during diastole, and therefore, may offer cardiac benefits beyond obstruction reprieve. This study leveraged a feline model of oHCM, cats with the A31P MYBPC3 variant, to study the acute in vivo effects of MYK-581, a mavacamten surrogate, on cardiac hemodynamics and filling. Methods A31P-homozygous cats with HCM (A31P, n=10) and wild-type healthy controls (CTRL, n=9) were anesthetized and instrumented for invasive pressure-volume (PV) measurements as well as trans-thoracic echocardiographic recording. A subset of cats were assigned to receive either vehicle (VEH, n=7) or MYK-581 (MYK, n=8) with a short IV infusion. Cardiac hemodynamics, function, and geometry were assessed at steady state before and during dobutamine challenges (2.5 μg/kg/min IV). Results A31P cats had thicker ventricular walls (6.4±0.1 vs. 5.2±0.2 mm, P<0.05) and hyperdynamic contraction (FS: 61±4 vs. 50±3%, P<0.05) relative to controls and presented with dynamic LVOT obstruction in 54% of cases. HCM cats had elevated end-diastolic pressures (17±1.4 vs. 9±1.0 mmHg, P<0.05), with prolonged time constants of relaxation (60±4.1 vs. 36±2.4 ms, P<0.05) and elevated end-diastolic stiffness (Eed: 0.44±0.06 vs. 0.25±0.01 mmHg/mL). Acute treatment with MYK-581 alleviated LVOT obstruction (0% vs. 38%), normalized contractility (FS: −7±2%), and increased systolic/diastolic chamber dimensions (e.g., LVIDd: +13±4%) (all P<0.05), while reducing EDP (15±2 to 13±2 mmHg, P<0.05), suggesting acute improvement in ventricular distensibility. Indeed, MYK-581 treatment reduced end-diastolic stiffness (Eed: 0.48±0.11 vs. 0.36±0. 10 mmHg/mL, P<0.05) and normalized trans-mitral motion patterns during filling. Conclusions Bred cats, homozygous for the A31P MYBPC3 variant, presented a cardiac phenotype that models multiple characteristics of the human oHCM phenotype including dynamic LVOT obstruction. Acute treatment with the mavacamten surrogate, MYK-581, not only alleviated hypercontractility and LVOT obstruction, but improved ventricular filling and end-diastolic pressures. Taken together, these pre-clinical observations show potential salutary effects beyond obstruction relief in patients with HCM. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): MyoKardia

scholarly journals Evolution of left ventricular function after Wharton's jelly mesenchymal stem cells transcoronary administration: 5-year follow up in a pilot cohort of CIRCULATE-AMI Randomized Trial

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
E Kwiecien ◽  
L Drabik ◽  
A Mazurek ◽  
M Sikorska ◽  
L Czyz ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Infarct Size ◽  
Troponin T ◽  
Left Ventricular ◽  
Lv Function ◽  
Funding Source ◽  
Double Blind ◽  
Wharton's Jelly

Abstract Introduction CIRCULATE-Acute Myocardial Infarction is a double-blind controlled trial randomizing (RCT) in 105 consecutive patients with their first, large AMI (cMRI-LVEF ≤45% and/or cMRI-infarct size ≥10% of LV) with successful infarct-related artery (IRA) primary percutaneous coronary intervention (pPCI) to transcoronary administration of Wharton's Jelly Mesenchymal Stem Cells (WJMSCs) vs. placebo (2:1). The pilot study cohort (PSC) preceded the RCT. Aim To evaluate WJMSCs long-term safety, and evolution of left-ventricular (LV) function in CIRCULATE-AMI PSC. Material and methods 30 000 000 WJMSCs (50% labelled with 99mTc-exametazime) were administered via IRA in a ten-patient PCS (age 32–65 years, peak hs-Troponin T 17.3±9.1ng/mL and peak CK-MB 533±89U/L, cMRI-LVEF 40.3±2.7% and infarct size 20.1±2.8%) at ≈5–7 days after AMI using a cell delivery-dedicated, coronary-non-occlusive method. Other treatments were per guidelines. WJMSCs showed an unprecedented high myocardial uptake (30.2±5.3%; 95% CI 26.9–33.5%), corresponding to ≈9×10 000 000 cells retention in the infarct zone – in absence of epicardial flow or myocardial perfusion impairment (TIMI-3 in all; cTFC 45±8 vs. 44±9, p=0.51) or any hs-Troponin T elevation. Five-year follow up included cardiac Magnetic Resonance Imaging (cMRI) (at baseline, 1 year and 3 years) and detailed echocardiography (echo) at baseline, 1 year, 3 years and 5 years. Results By 5 years, one patient died from a new, non-index territory AMI. There were no other cardiovascular events and MACCE that might be related to WJMSCs transplantation. On echo (Fig), there was an increase in left ventricular ejection fraction (LVEF) between WJMSCs administration point and 1 year (37.7±2.9% vs. 48.3±2.5%, p=0.002) that was sustained at 3 years (47.2±2.6%, p=0.005 vs. baseline) and at 5 years: (44.7±3.2%, p=0.039 vs. baseline). LVEF reached a peak at 1 year after the AMI and WJMSCs transfer (Fig). cMRI data (obtained up to 3 years; 1 year 41.9±2.6% vs. 51.0±3.3%, p<0.01; 3 years 52.2±4.0%, p<0.01 vs. baseline) were consistent with the echo LVEF assessment. Conclusions 5-year follow up in CIRCULATE-AMI PSC indicates that WJMSC transcoronary application is safe and may be associated with an LVEF improvement. The magnitude of LV increase appears to peak at 1 year, suggesting a potential role for repeated WJMSCs administration(s). Currently running double-blind RCT will provide placebo-controlled insights into the WJMSCs effect(s) on changes in LV function, remodelling, scar reduction and clinical outcomes. Echo-LVEF evolution Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): STRATEGMED 265761 “CIRCULATE” National Centre for Research and Development/Poland/ZDS/00564 Jagiellonian University Medical College

Caregiver burden of patients with heart failure with a left-ventricular ejection fraction (LVEF) less than or equal to 60%: a cross-sectional survey in the EU

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
R Lahoz ◽  
S Corda ◽  
C Proudfoot ◽  
A.F Fonseca ◽  
S Cotton ◽  
...  
Keyword(s):  
Heart Failure ◽  
Caregiver Burden ◽  
Nyha Class ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Funding Source ◽  
Cross Sectional Survey ◽  
Private Company ◽  
Cross Sectional ◽  
Patients With Heart Failure

Abstract Background and purpose The majority of patients with heart failure (HF) have difficulties in independently carrying out activities of daily living and hence, require support from caregivers (CGs). This study assessed the quality of life (QoL) of CGs of HF patients with sub-normal LVEF (≤60%). Methods A cross-sectional survey of HF patients and their CGs was conducted in France, Germany, Italy, Spain and the UK. Cardiologists and primary care physicians completed patient record forms (PRF) between June and November 2019. Caregivers of the same patients were invited to complete a caregiver self-completion survey, which included the Family Caregiver QoL Scale (FAMQOL) and EQ-5D. Patient demographics were derived from PRFs. Results 361 CGs (73.1% female, mean age: 58.8 yrs) and HF patients (39.9% female, mean age: 71.2 yrs) were included. 58.2% of the CGs were spouses, 23.4% a child of the patient. On average, CGs devoted 20 hrs/week in the care of HF patients; this CG time increased from 12 to 26 hrs/week with NYHA class I to III/IV of the HF patient. Further, anxiety/stress was experienced overall by 29/31% of CGs which increased from 27/17% for NYHA I to 40/41% for NYHA III/IV of the HF patient (Table 1). Conclusions Caregivers of patients with HF and LVEF ≤60% spend a significant amount of time to provide daily support to HF patients. Patients with progressive disease were older, more polymorbid and had a higher disease duration. These factors likely contributed towards increased caregiver burden of HF patients with increased NYHA class. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Novartis Pharma AG

Right ventricular speckle tracking in patients with heart failure – a comparison of right ventricular measures

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
I.J Lundorff ◽  
M Sengeloev ◽  
S Pedersen ◽  
D Modin ◽  
N.E Bruun ◽  
...  
Keyword(s):  
Risk Factors ◽  
Heart Failure ◽  
Right Ventricular ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Funding Source ◽  
Private Company ◽  
Ventricular Ejection Fraction ◽  
Risk Of Mortality ◽  
Patients With Heart Failure

Abstract Background RV dysfunction is associated with increased mortality and morbidity in patients with heart failure. Due to the complex shape and position of the RV, assessing RV function from echocardiographic images remains a challenge. Purpose We have previously found that global longitudinal strain from 2DSTE is superior to left ventricular ejection fraction (LVEF) in identifying HFrEF patients with high risk of mortality. In this study we wanted to examine RV 2DSTE in patients with HFrEF and compare its prognostic value to conventional RV measures. Methods and results Echocardiographic examinations were retrieved from 701 patients with HFrEF. RV estimates were analysed offline, and end point was all-cause mortality. During follow-up (median 39 months) 118 patients (16.8%) died. RV GLS and RV FWS remained associated with mortality after multivariable adjustment, independent of TAPSE (RV GLS: HR 1.07, 95% CI 1.02–1.13, p=0.010, per 1% decrease) (RV FWS: HR 1.05, 95% CI 1.01–1.09, p=0.010, per 1% decrease). This seemed to be caused by significant associations in men as TAPSE remained as the only independent prognosticator in women. All RV estimates provided prognostic information incremental to established risk factors and significantly increased C-statistics (TAPSE: 0.74 to 0.75; RVFAC: 0.74 to 0.75; RVFWS: 0.74 to 0.77; RVGLS: 0.74 to 0.77). Conclusions RV strain from 2DSTE was associated with mortality in patients with HFrEF, independent of TAPSE and established risk factors. Our results indicate that RV strain is particularly valuable in male patients, whereas in women TAPSE remains a stronger prognosticator. RV GLS and the risk of mortality Funding Acknowledgement Type of funding source: Private company. Main funding source(s): PGJ reports receiving lecture fee from Novo Nordisk.

miR-673/menin/JunD axis modulates hyperglycemia-induced oxidative stress and inflammation in the diabetic heart

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
R Suades ◽  
S Hussain ◽  
A.W Khan ◽  
S Costantino ◽  
F Paneni ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factor ◽  
Protein Expression ◽  
Myocardial Dysfunction ◽  
Reactive Oxygen Species Generation ◽  
Left Ventricular ◽  
Diabetic Heart ◽  
Lv Function ◽  
Funding Source ◽  
Mrna And Protein Expression

Abstract Background Hyperglycemia-induced reactive oxygen species generation in diabetic heart contributes to myocardial dysfunction. JunD, a member of the activated protein 1 (AP-1) family of transcription factors, is emerging as a major gatekeeper against oxidative stress. Previous studies have shown that downregulation of AP-1 transcription factor JunD is involved in vascular aging and heart failure. However, the role of JunD in diabetes-induced myocardial dysfunction is unknown. Purpose The present study was designed to investigate whether hyperglycemia-driven epigenetic regulation of JunD contributes to oxidative stress, inflammation and myocardial dysfunction in the diabetic heart. Methods Diabetes (DB) was induced in C57BL/6 wild-type (WT) mice by streptozotocin. After four weeks of DB, left ventricular (LV) function was assessed by standard and 2D speckle-tracking echocardiography in both groups (n=10). Then, the animals were euthanized and LV specimens were collected to determine JunD mRNA and protein expression as well as superoxide anion production by ESR spectroscopy. Chromatin modifications of JunD gene promoter were assessed by chromatin immunoprecipitation. Isolated DNA was analyzed for promoter methylation following Methylminer kit. Cardiac biopsies were collected from age-matched patients with and without diabetes. Results DB mice showed LV dysfunction with reduced ejection fraction and fractional shortening. JunD mRNA and protein expression were reduced in the myocardium of DB as compared to control mice. JunD downregulation was associated with oxidative stress, increased NF-kB binding activity and expression of inflammatory mediators. Accordingly, expression of free radical scavenger superoxide dismutase 1 and aldehyde dehydrogenase 2 was reduced, whereas nicotinamide adenine dinucleotide phosphate oxidase subunits NOX2 and NOX4 were upregulated in DB. A reduction of JunD mRNA and protein expression was confirmed in LV specimens obtained from patients with diabetes. The downregulation of JunD was epigenetically regulated by promoter hypermethylation and histone modifications. Post-translational repression by tumor suppressor menin also contributed to JunD downregulation. Indeed, menin was significantly upregulated in DB hearts and co-immunoprecipitation experiments confirmed the binding of menin to JunD. Furthermore, rat ventricular myocytes exposed to high glucose (HG) showed increased menin expression. We found that miR-673 targeting menin was downregulated in hearts of DB mice. Reprogramming miR-673 in HG-treated myocytes was able to restore both menin and JunD expression to control levels. Conclusions Our findings show that downregulation of AP-1 transcription factor JunD contributes to diabetes-induced myocardial dysfunction and miR-673/menin/JunD represents a novel molecular axis involved in hyperglycemia-induced ROS-driven cardiac damage. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): European Society of Cardiology (ESC) Research Grant 2017

scholarly journals Assessment of left ventricular mechanics in right ventricular overload using in silico rat models

2021 ◽  
Vol 2 (4) ◽  
Author(s):  
H Martinez-Navarro ◽  
E K S Espe ◽  
O O Odeigah ◽  
I Sjaastad ◽  
J Sundnes
Keyword(s):  
Cardiac Function ◽  
Circumferential Strain ◽  
Radial Strain ◽  
Left Ventricular ◽  
Public Institution ◽  
Lv Function ◽  
Passive Stiffness ◽  
Ventricular Mechanics ◽  
Longitudinal Strains ◽  
Rv Function

Abstract Background To preserve cardiac function in overload conditions, the RV adapts by developing muscular hypertrophy through progressive tissue remodelling. This process may lead to a vicious cycle with detrimental effects on RV diastolic and systolic function, as seen in pulmonary arterial hypertension (PAH) patients [1]. However, how RV overload affects LV function and remodelling remains an open question [2]. Computational models of cardiac physiology offer an opportunity for investigating mechanisms difficult or impossible to analyse otherwise due to the existence of overlapping factors and technical limitations. Aim This study aims to assess the acute effects of RV overload and increased myocardial passive stiffness on the LV mechanical properties in an anatomically-based computational model of healthy rat heart. Methods A computational simulation pipeline of cardiac mechanics based on the Holzapfel-Ogden model has been implemented using MR images from a healthy rat. Whereas LV function was modelled realistically using catheter measurements conducted on the same subject than the MR imaging, RV function was based on representative literature values for healthy and PAH rats with RV overload. The following cases were defined (Fig. 1): CTRL, with normal RV function; PAH1, with 30% increase in RV ESV (end-systolic volume) and 15% increase in RV ESP (end-systolic pressure) in comparison to CTRL; and PAH2, with 60% increase in RV ESV and 30% increase in RV ESP compared to CTRL. The cardiac cycle was simulated for all cases whilst fitting the experimentally measured LV pressure and volume values from a healthy rat, which allowed quantifying the effects of RV overload on LV function. Results The increase of average circumferential strain in the LV correlated with the degree of RV overload simulated (CTRL: −8.7%, PAH1: −8.9%, PAH2: −9.2%), whilst average radial (CTRL: 35.2%, PAH1: 34.8%, PAH2: 30.3%) and longitudinal strains decreased (CTRL: −7.7%, PAH1: −7.4%, PAH2: −6.6%), as seen in Fig.2. However, regional differences in strain were significant: under RV overload conditions, circumferential strain increased in the septum (−3.5% difference in PAH2 vs. CTRL) but lower values were observed in the lateral wall (+1.7% difference in PAH2 vs. CTRL). Cardiac function of case PAH2 was simulated also with increased myocardial passive stiffness (2.67 kPa instead of 1.34 kPa) which presented a mild strain increase in the mid LV ventricle in comparison to PAH2 with normal stiffness (circumferential strain: −0.8%, radial strain: +0.5%, longitudinal strain: −0.2%). Conclusion Our study provides mechanistic evidence on how RV overload and increased passive myocardial stiffness causes a redistribution of strain and fibre stress in the LV, which may play a significant role in LV remodelling and function. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): K.G. Jebsen Center for Cardiac Research Figure 1. Pressure – volume loops  Figure 2. Mean mid-LV strains

The value of 3D-speckle tracking longitudinal strain for the assessment of left ventricular function recovery in ischemic heart failure patients undergoing surgical remodeling:the RECOVERY-IN study

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Castelvecchio ◽  
M Frigelli ◽  
F Sturla ◽  
M Citarella ◽  
O.A Pappalardo ◽  
...  
Keyword(s):  
Heart Failure ◽  
Speckle Tracking ◽  
Longitudinal Strain ◽  
Left Ventricular ◽  
Ischemic Heart ◽  
Lv Function ◽  
Funding Source ◽  
Basal Region ◽  
Ischemic Heart Failure ◽  
Segmental Analysis

Abstract Background Three-dimensional (3D) speckle-tracking echocardiography is largely employed to evaluate left ventricle (LV) morphology and function. Purpose To investigate LV function before and after surgical ventricular reconstruction (SVR) through the analysis of global (GLS) and segmental (SLS) longitudinal strain, and the derived mechanical dispersion (MD). Methods Twenty patients eligible for SVR, with previous LV remodelling and ischemic heart failure (HF), received 3D echocardiographic evaluation before SVR and at 6-months follow-up; 15 normal controls, matched by age and BSA, were enrolled. Standard off-line GLS analysis was performed with 4D LV-ANALYSIS©; advanced segmental analysis was accomplished automatically through in-house numerical post-processing. Results Before SVR, GLS deteriorated compared to normal subjects (−6.7% vs. −19.6%, P<0.0001) as confirmed by SLS at each LV segment basal, mid and apical level (P<0.0001); MD was higher than in controls (P<0.001) and markedly increased from basal to apical LV segment. After SVR, GLS significantly improved from −6.7% to −11.3% (P<0.0001). Analysis of variance showed that SLS recovery was higher in the basal region (7.25%) than in both mid (4.06%, P=0.001) and apical (1.92%, P<0.0001) segments, respectively, with adjustment for baseline values. Conclusions After SVR, LV longitudinal strain mostly improves in the basal segments, outlining the role of the remote myocardium in enhancing LV function through an extensive volume reduction; post-surgical MD reduction indicates a more homogeneous myocardial contraction. Heath map of longitudinal strain (%) Funding Acknowledgement Type of funding source: Private hospital(s). Main funding source(s): IRCCS Policlinico San Donato is a clinical research hospital partially funded by the Italian Ministry of Health.

scholarly journals Metformin exerts cardioprotection via attenuating mitochondrial fission in cardiac ischaemia-reperfusion injury in rats

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Palee ◽  
L Higgins ◽  
T Leech ◽  
S.C Chattipakorn ◽  
N Chattipakorn
Keyword(s):  
Infarct Size ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Left Ventricular ◽  
Control Group ◽  
Lv Function ◽  
Funding Source ◽  
Cardiac Ischaemia

Abstract Background Cardiac ischemia/reperfusion (I/R) injury following myocardial infarction reperfusion therapy is a phenomenon that results in further cardiomyocytes death and impaired cardiac contractility. Although metformin has been shown to exert cardioprotection in addition to glycemic control, its effect on cardiac I/R injury are still controversy, and the comparative doses of metformin in cardiac I/R injury have never been investigated. Purpose We hypothesized that metformin given acutely prior to cardiac ischaemia exerts cardioprotection in rats with cardiac I/R injury via attenuating cardiac mitochondrial dysfunction, leading to improved left ventricular (LV) function. Methods Forty Male Wistar rats were subjected to cardiac I/R injury. Four treatment groups were investigated. The first group received saline as a control group. The second to the fourth groups received metformin at 100, 200, and 400 mg/kg intravenously, respectively. During the I/R protocols, the LV function, arrhythmia score, and mortality rate were determined. At the end, the hearts were rapidly removed to determine infarct size, cardiac mitochondrial function, cardiac mitochondrial dynamics, and cardiac apoptosis. Results Metformin 200 mg/kg exerted the highest level of cardioprotection through the attenuated incidence of arrhythmia, decreased infarct size (Fig. 1), improved cardiac mitochondrial function, and decreased mitochondrial fission (Fig. 1) and cardiac apoptotic markers, leading to improved cardiac function during I/R injury. Although Metformin at all doses effectively decreased infarct size, improved cardiac mitochondrial function and LV function, Metformin at 200 mg/kg exerted the best efficacy (Fig. 1). Conclusions Metformin exerts cardioprotection by attenuating mitochondrial dysfunction and decreased mitochondrial fission, leading to decreased infarct size and ultimately improved LV function after acute cardiac I/R injury in rats. These findings also indicate the potential biphasic effects of metformin on infarct size which are dose-dependent. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Science and Technology Development Agency Thailand (NC), and Thailand Research Fund (SCC)

Irregular beat-to-beat hemodynamic properties determine left ventricular function during atrial fibrillation

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Lyon ◽  
M.J.W Van Mourik ◽  
D.K Linz ◽  
L Cruts ◽  
J Heijman ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Cycle Length ◽  
Longitudinal Strain ◽  
Computational Study ◽  
Systolic Function ◽  
Image Plane ◽  
Left Ventricular ◽  
Lv Function ◽  
Funding Source ◽  
Physiological Mechanisms

Abstract Background The rapid irregular atrial electrical activity during atrial fibrillation (AF) is associated with an irregular and variable left ventricular (LV) systolic pump function. The effects of cycle length (CL) variations on LV function during AF remain incompletely understood. Purpose To elucidate the physiological mechanisms by which beat-to-beat changes in cycle length affect LV function during AF. We hypothesize that changes in LV preload and afterload cause a large part of the beat-to-beat variability of LV function during AF. Methods Beat-to-beat speckle-tracking echocardiography was performed in 10 patients with persistent AF. In each patient, a hundred consecutive beats were imaged during AF and we evaluated the relation between longitudinal strain in the image plane (4-chamber view) and (pre-)preceding CL in these patients. We used the CircAdapt cardiovascular system model to simulate cardiac mechanics and hemodynamics during AF for each individual patient 1) by imposing the exact irregular sequence of CLs as measured in the patient and 2) by making the atrial myocardium non-contractile. We also simulated generic (i.e. artificially defined) CL sequences (e.g. irregular long CL, irregular short CL) to better understand the determinants of beat-to-beat variations of LV systolic function during AF. Results Generic simulations uncovered the hemodynamic effects of a sudden irregular long or short beat on LV function during the following beat (top). A short beat led to lower LV function in the following beat because of smaller preload, while a longer beat led to larger LV function by Frank-Starling law of contractile myocardium. This CL dependency of LV function was confirmed when analysing clinical data of AF patients (bottom, left). A negative non-linear relation between preceding CL and longitudinal strain was observed (bottom, right). Increased longitudinal strain at high preceding CL (purple box) was explained by a higher preceding EDV (higher preload) (p<0.002). At a given preceding CL, variability in longitudinal strain was explained by the afterload of the preceding beat, with a lower preceding afterload (systolic aortic pressure) leading to higher longitudinal strain (yellow box, p<0.002), but not by changes in preceding preload (non-significant). Conclusions Irregularity in preceding CL leads to changes in LV function through preload and afterload changes. Indeed, as observed in patients during AF, longitudinal LV strain depends non-linearly on the preceding CL. Beat-to-beat changes in preload contribute to variable LV function but changes in afterload also are a key determinant of LV function variability at same preceding CL. Our combined clinical-computational study highlights the variability in longitudinal strain measurement during AF and provides new insight into the physiological mechanisms determining LV function in AF patients. Determinants of LV function in AF Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): NWO-ZonMw, VIDI grant 016.176.340

Cardioprotection using strain-guided management of potentially cardiotoxic cancer therapy: 1 year results of the SUCCOUR trial

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
T Negishi ◽  
P Thavendiranathan ◽  
M Penicka ◽  
J Lemieux ◽  
S Aakhus ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Global Longitudinal Strain ◽  
Measurement Development ◽  
Lv Function ◽  
Relative Reduction ◽  
Funding Source ◽  
Medical Systems ◽  
Private Company ◽  
Lv Dysfunction

Abstract Background Conventional criteria for diagnosis of chemotherapy-related cardiac dysfunction (CTRCD) are dependent on the recognition of heart failure (HF) symptoms and/or changes in LVEF. However, the low sensitivity of EF for minor changes in LV function may delay initiation of cardio-protective therapy (CPT). Global longitudinal strain (GLS) is a robust and sensitive marker of LV dysfunction (LVD), but existing observational data are insufficient to justify changing the diagnostic criteria for CTRCD. Purpose To identify whether GLS guidance of CPT would improve cardiac function of at risk patients undergoing potentially cardiotoxic chemotherapy, compared with usual care. Methods In this international multicenter prospective randomized controlled trial, 331 pts from 23 international sites taking anthracyclines with another risk factor for HF were randomly allocated into 166 undergoing GLS-guided (CPT for >12% relative reduction in GLS using Echopac software) and 165 EF-guided (CPT for >10% absolute reduction of EF). Pts were followed over 1 year for the primary end-point (ΔEF) with 3D echo (3DE); 2D echo (2DE) was used when 3D images were unsuitable for measurement. Development of CTRCD (EF reduction of 10% to <55%) was a secondary endpoint. Results Of 331 randomized patients, 24 withdrew before follow-up imaging was performed (2 died, and rest withdrew or were lost to follow-up). Among 307 patients (age 54±12 years, 94% women) with follow-up 1.0±0.2 years, 277 had breast cancer, 30 had lymphoma/leukemia. HF risk factors were prevalent: 89 (29%) had hypertension and 39 (13%) had diabetes mellitus. The most common chemotherapy regimen during this study was the combination of anthracycline and trastuzumab. The baseline 3D LVEF was 61±5%, and GLS was −20.8±3.2%. At 1 year follow-up, 31 (10%) met CTRCD and was reduced in the GLS-guided arm (Table 1), although new LV dysfunction (EF<55%) and change of EF were not different. Conclusion In this international multicentre trial, the incidence of CTRCD was reduced by strain-guided cardioprotection. Although the final EF and the number of pts developing EF <55% was not altered by strain-guided therapy, this reduces meaningful reduction of EF to the abnormal range. The results support the use of GLS in surveillance for CTRCD. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): General Electric Medical Systems

Sign in / Sign up

Export Citation Format

Share Document