Impact of etiology on force and kinetics of left ventricular end-stage failing human myocardium

2021 ◽  
Vol 156 ◽  
pp. 7-19
Author(s):  
Mohammed A. Mashali ◽  
Nancy S. Saad ◽  
Benjamin D. Canan ◽  
Mohammad T. Elnakish ◽  
Nima Milani-Nejad ◽  
...  
Keyword(s):  
Left Ventricular ◽  
Human Myocardium ◽  
End Stage ◽  
Kinetics Of

scholarly journals Gene expression of adrenomedullin in failing myocardium: comparison to atrial natriuretic peptide

2002 ◽  
Vol 92 (3) ◽  
pp. 1058-1063 ◽  
Author(s):  
Anselm T. Bäumer ◽  
Christina Schumann ◽  
Bodo Cremers ◽  
Gabi Itter ◽  
Wolfgang Linz ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Normal Subjects ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Human Myocardium ◽  
Idiopathic Dilated Cardiomyopathy ◽  
Left Ventricular Myocardium ◽  
End Stage ◽  
Atrial Natriuretic

The expression of adrenomedullin (AM) and atrial natriuretic factor (ANF) were investigated in the myocardium of a rat model of chronic ischemic heart failure (CHF) compared with sham-operated controls. In addition, human myocardium of patients with end-stage heart failure due to idiopathic dilated cardiomyopathy compared with myocardium of normal subjects (NF) was studied. In CHF, similar AM levels but increased ANF expression were observed in left ventricular myocardium, as assessed by semiquantitative PCR. Functional experiments with freshly excised papillary muscles showed no influence of AM on myocardial contractility. In NF human myocardium, the expression of AM mRNA was threefold higher in atrial compared with ventricular tissue. In analogy, ANF mRNA was increased by ∼15-fold in atrial tissue. In dilated cardiomyopathy, the expression of AM was significantly increased in right and left ventricles compared with NF. In parallel, ventricular ANF expression was enhanced.

Abstract 35: 2-deoxy Adenosine Triphosphate Improves Contraction In Human End-stage Heart Failure

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Farid Moussavi-Harami ◽  
Maria V Razumova ◽  
Yuanhua Cheng ◽  
Alice W Racca ◽  
April Stempien-Otero ◽  
...  
Keyword(s):  
Heart Failure ◽  
Striated Muscle ◽  
Isometric Force ◽  
Heart Tissue ◽  
Left Ventricular ◽  
Human Myocardium ◽  
Ventricular Assist ◽  
Novel Approach ◽  
End Stage Heart Failure ◽  
End Stage

We are developing a novel approach to treat heart failure that involves adeno-associated virus vectors to elevate intracellular 2 deoxy-ATP (dATP) via increased expression of the enzyme Ribonucleotide Reductase. Our studies in rodents have shown that substitution of dATP for ATP as the energy substrate increases contraction in striated muscle. Here we report for the first time the effect of dATP on human cardiac muscle contraction. We measured the contractile properties of demembranated multicellular ventricular wall preparations and isolated myofibrils from adult human heart tissue obtained from twelve patients undergoing surgery for cardiac transplantation or placement of left ventricular-assist device for end-stage heart failure. Isometric force at saturating calcium concentration was increased by about ten percent from 38.6±3.8 mN/mm2 to 42.8±4.2 mN/mm2 when dATP was substituted for ATP (P<0.001). The effect was even greater at physiologic calcium concentrations with an approximate increase of thirty percent. Isometric force increased from 21.2 ± 6.1 mN/mm2 to 26.4± 6.4 mN/mm2 (p<0.001) at pCa=5.6 and from 22.6 ± 5.9 mN/mm2 to 27.5± 6.3 mN/mm2 (p<0.001) at pCa=5.8 with dATP for ATP substitution. The result was an increase in the Ca2+ sensitivity of force as the [Ca2+] required to elicit half maximum force (pCa50) increased by 0.08 units from 5.68±0.03 to 5.79±0.03 (N=24, P< 0.001). The maximum rate of force redevelopment (ktr) in demembranated wall muscle increased (0.82±0.01 s-1 vs. 0.62±0.01 s-1, P< 0.05), as was the rate of contractile activation in isolated myofibrils (0.80±0.06 s-1 vs. 0.57±0.06 s-1, P<0.01) suggesting dATP may increase dP/dT in failing human myocardium. Importantly, there was no slowing of relaxation, as the time to 50% and 90% myofibril relaxation were unchanged. Purified myosin from failing human myocardium showed enhanced NTPase activity with dATP (0.89±0.17 s-1/head) vs. ATP (0.55±0.20 s-1/head, P<0.05). In conclusion, the data strongly suggest dATP increases cross-bridge cycling, compared with ATP in failing human myocardium and shows promise in restoring cardiac pump function. These data support a novel myofilament approach for treating heart failure that warrants further pre-clinical evaluation.

Abstract 13508: Left Ventricular Contractile and Kinetic Changes in Failing Human Myocardium Due to Anthracycline Toxicity

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Mohammed Mashali ◽  
Nancy Saad ◽  
Salome Kiduko ◽  
Kyra Peczkowski ◽  
Amanda Huang ◽  
...  
Keyword(s):  
Contractile Force ◽  
Left Ventricular ◽  
Human Myocardium ◽  
Relaxation Kinetics ◽  
Frequency Dependent ◽  
History Of ◽  
Kinetics Of ◽  
Anthracycline Toxicity ◽  
History Of Cancer

Introduction: Anthracyclines are used effectively to treat many cancers. However, cumulative and irreversible cardiotoxicity can limit anthracyclines’ clinical benefit. Mechanisms of cardiotoxicity have been assessed in murine models, but no studies directly assess human heart contractility. Our objective was to assess left ventricular contractile force, kinetics of contraction and relaxation, and frequency-dependent activation in anthracycline-induced failing human myocardium. Methods: From 2009-2019, we assessed live tissue-level contractile forces and kinetics in isolated left ventricular intact trabeculae from failing and non-failing human hearts. After the trabeculae were transferred to and stabilized in a custom setup, baseline contractile force and kinetic parameters were assessed at 1 Hz (normal resting in vivo heart rate), followed by frequency-dependent activation (0.5-3.0 Hz) under near-physiological conditions. Retrospectively, we analyzed muscles from three cohorts of individuals: (1) with non-ischemic cardiomyopathy due to anthracycline toxicity (NICM-AC; n =14), (2) with NICM and history of cancer without anthracycline or known cardiotoxic treatments (NICM; n =14), and (3) with non-failing myocardium and no history of cancer (NF; n =14). Results: At stimulation of 1 Hz, active developed force (Fdev) of NICM-AC trabeculae was significantly lower than NF and NICM trabeculae. NICM-AC trabeculae exhibited prolonged 90% relaxation time (RT90), significantly slower maximal rate of force decay (-dF/dt), and slower maximal kinetic rate of relaxation (-dF/dt/Fdev). In addition, frequency-dependent activation and relaxation were markedly impaired in both failing groups. Conclusions: Human myocardium failing due to anthracycline toxicity had significantly decreased force and slower relaxation kinetics compared to non-ischemic failing myocardium. With increase in stimulation frequency, anthracycline treated myocardium exhibited impaired activation and relaxation kinetics. These findings suggest that cardio-protection strategies should aim to improve not only contractile force, but also kinetics of relaxation.

Passive force in left ventricular human myocardium is not passive

2009 ◽  
Vol 56 (S 01) ◽  
Author(s):  
I Karliova ◽  
L Hakami ◽  
AA Peivandi ◽  
N Kayhan ◽  
U Mehlhorn ◽  
...  
Keyword(s):  
Left Ventricular ◽  
Human Myocardium ◽  
Passive Force

SURVEY OF CARDIOVASCULAR RISK FACTORS AND ELECTROCARDIGRAPHIC, ECHOCARDIOGRAPHIC ABNORMALITIES IN PATIENTS ON WAITING LIST FOR RENAL TRANSPLANTATION

2014 ◽  
pp. 26-30
Author(s):  
Huu Thinh Nguyen ◽  
Thi Thuy Hang Nguyen ◽  
Bui Bao Hoang
Keyword(s):  
Risk Factors ◽  
Cardiovascular Risk ◽  
Renal Transplantation ◽  
Left Ventricular Hypertrophy ◽  
Cardiovascular Risk Factors ◽  
Ventricular Hypertrophy ◽  
Left Ventricular ◽  
Valve Insufficiency ◽  
Transplant Candidates ◽  
End Stage

Background: Cardiovascular disease is the major cause of death in dialysis patients, as well as in kidney transplant patients. Assessment of cardiovascular risks of renal transplant candidates to prevent or slow the progression of cardiovascular abệnh nhânormalities. Aim: 1) Evaluating cardiovascular risk factors, electrocardiographic and echocardiographic abnormalities in renal transplant candidates. 2) Identifying the correlation between cardiac morphological parameters with a number of factors involved. Subjects and Methods: We assessed 57 patients (73.7% male, mean age 32.4±8.8) with end-stage renal disease waiting for renal transplantation at Cho Ray Hospital between Jan 2012 and Jan 2013. All patients received a physical examination, blood pressure measurement, Hb, blood glucose test, lipid profile, ECG, echocardiography. Results: The percentage of hypertension was 98.2%, smoking (69.2%), dyslipidemia 40.4% and diabetes 12.3%. All patients had sinus rhythm, left ventricular hypertrophy 61.4% in ECG. Pericardial effusion 5.3%, mitral valve insufficiency 56.1%, aortic valve insufficiency 12.3%, left ventricular hypertrophy 94.7% in echocardiography. IVSd, LVPWd, LVMI positively correlated with kidney failure time (p <0.01, p<0.001), with DBP and SBP (p <0.05) and the degree of anemia (p <0.05). Percentage the degree of hypertension associated with proportion of left ventricular hypertrophy (p <0.05). Conclusions: Identification of cardiovascular risk factors for the prevention or intervention to reduce mortality in renal transplantation. Keywords: Cardiovascular risk factors, end-stage chronic renal failure, renal transplantation.

AIM2-driven inflammasome activation in chronic heart failure

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Ruppert ◽  
Z.S Onodi ◽  
P Leszek ◽  
V.E Toth ◽  
G Koncsos ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Animal Models ◽  
Left Ventricular ◽  
Inflammasome Activation ◽  
Coronary Artery Ligation ◽  
Funding Source ◽  
Human Cardiomyocytes ◽  
Pannexin 1 ◽  
End Stage

Abstract Background Inflammation and cytokine release have been implicated in the pathogenesis of chronic heart failure (CHF). Of particular interest, Canakinumab, a monoclonal antibody against interleukin-1b (IL-1β), had provided benefit against cardiovascular events, suggesting that blockade of IL-1β secretion and signaling might be a promising new therapeutic target. Although, recent studies have provided evidence that inflammasome activation is the main contributor to IL-1β maturation, the role of inflammasome activation in CHF remains unknown. Objective Therefore, we aimed to assess inflammasome activation in myocardial samples from end-stage failing hearts. Methods Inflammasome activation was assessed by immunoblotting in left ventricular myocardial specimens harvested from patients with end-stage CHF. Furthermore, immunoblot measurements were also performed on translational animal models of CHF (e.g. rat models of permanent coronary artery ligation and transverse aortic constriction). Left ventricular monocyte and macrophage infiltration was detected by immunohistochemistry. To investigate the molecular background of inflammasome activation, a series of cell culture experiments were performed on AC16 human cardiomyocytes and THP-1 human monocytic cell lines. Results Out of the 4 major inflammasome sensors tested, expression of the inflammasome protein absent in melanoma 2 (AIM2) and NLR family CARD domain-containing protein 4 (NLRC4) increased in human CHF while the NLRP1 and NLRP3 (NLR family, pyrin domain containing 1 and 3) inflammasome showed no change. A similar expression pattern in AIM2 and NLRC4 was also noted in CHF animal models. Furthermore, robust infiltration of Iba1+ monocytes/macrophages was observed in human failing hearts as well as in different animal models of CHF. In vitro AIM2 inflammasome activation, as induced by transfection with double-stranded DNA [poly(deoxyadenylic-deoxythymidylic)] was reduced significantly by the pharmacological blockade of pannexin-1 channels. Conclusions AIM2 and NLRC4 inflammasome activation might contribute to chronic inflammation in CHF. Our findings suggest that pannexin-1 channels might be a promising novel target to reduce inflammasome activation. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): NVKP_16-1-2016-0017

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