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.

scholarly journals Computational Investigation of Transmural Differences in Left Ventricular Contractility

2016 ◽  
Vol 138 (11) ◽  
Author(s):  
Hua Wang ◽  
Xiaoyan Zhang ◽  
Shauna M. Dorsey ◽  
Jeremy R. McGarvey ◽  
Kenneth S. Campbell ◽  
...  
Keyword(s):  
Myocardial Contractility ◽  
Ex Vivo ◽  
Experimental Studies ◽  
Contractile Force ◽  
Left Ventricular ◽  
Lv Function ◽  
Fe Model ◽  
Myocardial Layers ◽  
Best Fit

Myocardial contractility of the left ventricle (LV) plays an essential role in maintaining normal pump function. A recent ex vivo experimental study showed that cardiomyocyte force generation varies across the three myocardial layers of the LV wall. However, the in vivo distribution of myocardial contractile force is still unclear. The current study was designed to investigate the in vivo transmural distribution of myocardial contractility using a noninvasive computational approach. For this purpose, four cases with different transmural distributions of maximum isometric tension (Tmax) and/or reference sarcomere length (lR) were tested with animal-specific finite element (FE) models, in combination with magnetic resonance imaging (MRI), pressure catheterization, and numerical optimization. Results of the current study showed that the best fit with in vivo MRI-derived deformation was obtained when Tmax assumed different values in the subendocardium, midmyocardium, and subepicardium with transmurally varying lR. These results are consistent with recent ex vivo experimental studies, which showed that the midmyocardium produces more contractile force than the other transmural layers. The systolic strain calculated from the best-fit FE model was in good agreement with MRI data. Therefore, the proposed noninvasive approach has the capability to predict the transmural distribution of myocardial contractility. Moreover, FE models with a nonuniform distribution of myocardial contractility could provide a better representation of LV function and be used to investigate the effects of transmural changes due to heart disease.

scholarly journals Proteases: History, discovery, and roles in health and disease

2019 ◽  
Vol 294 (5) ◽  
pp. 1643-1651 ◽  
Author(s):  
Judith S. Bond
Keyword(s):  
Proteolytic Enzymes ◽  
Structural Characteristics ◽  
Research Area ◽  
History Of ◽  
Health And Disease ◽  
Regulation Mechanisms ◽  
American Society ◽  
Kinetics Of

The Journal of Biological Chemistry (JBC) has been a major vehicle for disseminating and recording the discovery and characterization of proteolytic enzymes. The pace of discovery in the protease field accelerated during the 1971–2010 period that Dr. Herb Tabor served as the JBC's editor-in-chief. When he began his tenure, the fine structure and kinetics of only a few proteases were known; now thousands of proteases have been characterized, and over 600 genes for proteases have been identified in the human genome. In this review, besides reflecting on Dr. Tabor's invaluable contributions to the JBC and the American Society for Biochemistry and Molecular Biology (ASBMB), I endeavor to provide an overview of the extensive history of protease research, highlighting a few discoveries and roles of proteases in vivo. In addition, metalloproteinases, particularly meprins of the astacin family, will be discussed with regard to structural characteristics, regulation, mechanisms of action, and roles in health and disease. Proteases and protein degradation play crucial roles in living systems, and I briefly address future directions in this highly diverse and thriving research area.

scholarly journals Impact of heart rate on cross-bridge cycling kinetics in failing and nonfailing human myocardium

2019 ◽  
Vol 317 (3) ◽  
pp. H640-H647
Author(s):  
Jae-Hoon Chung ◽  
Nima Milani-Nejad ◽  
Jonathan P. Davis ◽  
Noah Weisleder ◽  
Bryan A. Whitson ◽  
...  
Keyword(s):  
Heart Failure ◽  
Heart Rate ◽  
Human Myocardium ◽  
Force Frequency ◽  
Human Heart Failure ◽  
Relaxation Kinetics ◽  
Heart Rates ◽  
Cross Bridge ◽  
Maximal Activation

The force-frequency relationship (FFR) is an important regulatory mechanism that increases the force-generating capacity as well as the contraction and relaxation kinetics in human cardiac muscle as the heart rate increases. In human heart failure, the normally positive FFR often becomes flat, or even negative. The rate of cross-bridge cycling, which has been reported to affect cardiac output, could be potentially dysregulated and contribute to blunted or negative FFR in heart failure. We recently developed and herein use a novel method for measuring the rate of tension redevelopment. This method allows us to obtain an index of the rate of cross-bridge cycling in intact contracting cardiac trabeculae at physiological temperature and assess physiological properties of cardiac muscles while preserving posttranslational modifications representative of those that occur in vivo. We observed that trabeculae from failing human hearts indeed exhibit an impaired FFR and a reduced speed of relaxation kinetics. However, stimulation frequencies in the lower spectrum did not majorly affect cross-bridge cycling kinetics in nonfailing and failing trabeculae when assessed at maximal activation. Trabeculae from failing human hearts had slightly slower cross-bridge kinetics at 3 Hz as well as reduced capacity to generate force upon K+ contracture at this frequency. We conclude that cross-bridge kinetics at maximal activation in the prevailing in vivo heart rates are not majorly impacted by frequency and are not majorly impacted by disease. NEW & NOTEWORTHY In this study, we confirm that cardiac relaxation kinetics are impaired in filing human myocardium and that cross-bridge cycling rate at resting heart rates does not contribute to this impaired relaxation. At high heart rates, failing myocardium cross-bridge rates are slower than in nonfailing myocardium.

Argon Exposure Induces Postconditioning in Myocardial Ischemia–Reperfusion

2017 ◽  
Vol 22 (6) ◽  
pp. 564-573 ◽  
Author(s):  
Sandrine Lemoine ◽  
Katrien Blanchart ◽  
Mathieu Souplis ◽  
Adrien Lemaitre ◽  
Damien Legallois ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ischemia Reperfusion ◽  
Contractile Force ◽  
Left Ventricular ◽  
Border Zone ◽  
Left Ventricular Ejection ◽  
Human Atrial Appendages ◽  
Hypoxia Reoxygenation

Background and Purpose: Cardioprotection against ischemia–reperfusion (I/R) damages remains a major concern during prehospital management of acute myocardial infarction. Noble gases have shown beneficial effects in preconditioning studies. Because emergency proceedings in the context of myocardial infarction require postconditioning strategies, we evaluated the effects of argon in such protocols on mammalian cardiac tissue. Experimental Approaches: In rat, cardiac I/R was induced in vivo by transient coronary artery ligature and cardiac functions were evaluated by magnetic resonance imaging. Hypoxia–reoxygenation (H/R)-induced arrhythmias were evaluated in vitro using intracellular microelectrodes on both rat-isolated ventricle and a model of border zone in guinea pig ventricle. Hypoxia–reoxygenation loss of contractile force was assessed in human atrial appendages. In those models, postconditioning was induced by 5 minutes application of argon at the time of reperfusion. Key Results: In the in vivo model, I/R produced left ventricular ejection fraction decrease (24%) and wall motion score increase (36%) which was prevented when argon was applied in postconditioning. In vitro, argon postconditioning abolished H/R-induced arrhythmias such as early after depolarizations, conduction blocks, and reentries. Recovery of contractile force in human atrial appendages after H/R was enhanced in the argon group, increasing from 51% ± 2% in the nonconditioned group to 83% ± 7% in the argon-treated group ( P < .001). This effect of argon was abolished in the presence of wortmannin and PD98059 which inhibit prosurvival phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) and MEK/extracellular receptor kinase 1/2 (ERK 1/2), respectively, or in the presence of the mitochondrial permeability transition pore opener atractyloside, suggesting the involvement of the reperfusion injury salvage kinase pathway. Conclusion and Implications: Argon has strong cardioprotective properties when applied in conditions of postconditioning and thus appears as a potential therapeutic tool in I/R situations.

scholarly journals Sacubitril/valsartan is well tolerated in patients with longstanding heart failure and history of cancer and improves ventricular function: real-world data

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Maria Klara Frey ◽  
Henrike Arfsten ◽  
Noemi Pavo ◽  
Emilie Han ◽  
Stefan Kastl ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Lv Function ◽  
Real World Data ◽  
Ventricular Ejection Fraction ◽  
History Of ◽  
History Of Cancer

Abstract Background Sacubitril/valsartan has been shown to significantly reduce cardiovascular mortality and hospitalizations due to heart failure in patients with reduced ejection fraction (HFrEF) when compared to enalapril. Data about sacubitril/valsartan in patients with a history of cancer are scarce, as these patients were excluded from the pivotal trial, PARADIGM-HF. The aim of the current study was to assess tolerability of sacubitril/valsartan in patients with a history of cancer. Methods We identified 225 patients at our heart failure out-patient unit who fulfilled the indication criteria to receive sacubitril/valsartan. Out of these, 9.3% (n = 21) had a history of histologically confirmed cancer. Oncologic surgery was performed in 16 (76.2%) patients, 11 (52.4%) patients received previous antineoplastic therapy and 9 patients (42.9%) radiation. Results Sacubitril/valsartan was withdrawn in 3 of 21 patients (14.3%) because of dizziness (n = 2) or pruritus (n = 1). After a median follow-up of 12 months (range 1–34 months), NYHA functional class improved significantly from NYHA 3 to NYHA 2 (mean -0.6, p = 0.006) and left ventricular ejection fraction as assessed by echocardiography increased significantly from 26.8 ± 5.4% to 39.2 ± 10% (mean + 12%, CI 95% [8.4–16.4], p = 0.0004). NT-proBNP was significantly reduced (baseline median 2774 pg/ml, range 1441 – 12,982 vs follow-up 1266 pg/ml, range 199–6324, p = 0.009). There was no significant change in creatinine levels (1.18 ± 0.4 vs 1.22 ± 0.4 mg/dl; mean + 0.005 mg/dl, CI 95% [-0.21- 0.12], p = 0.566). Conclusions In our pilot study we show that sacubitril/valsartan is generally well tolerated in patients with HFrEF and history of cancer. Importantly, even patients with long-standing cardiotoxicity induced heart failure can be treated and up-titrated with sacubitril/valsartan to usual target dosages, leading to improvement in LV function and biomarkers. Larger studies are needed to confirm these findings in cancer patients with cardiotoxicity.

scholarly journals 131 Cancer and takotsubo syndrome: clinical features, outcome, and inflammatory patterns. Results from a multicentre prospective registry

2021 ◽  
Vol 23 (Supplement_G) ◽  
Author(s):  
Enrica Vitale ◽  
Francesco Santoro ◽  
Alessandra Leopizza ◽  
Adriana Mallardi ◽  
Massimo Iacoviello ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Clinical Features ◽  
Left Ventricular ◽  
Takotsubo Syndrome ◽  
Patients With Cancer ◽  
History Of ◽  
Inflammatory Pattern ◽  
History Of Cancer ◽  
Long Term Mortality

Abstract Aims Cancer represents one of the major determinants of prognosis in patients with Takotsubo Syndrome (TTS). Aim of this study was therefore to compare clinical features, short- and long-term outcome and inflammatory pattern among TTS patients with history of cancer. Methods and results 412 consecutive patients with TTS were enrolled in a multicentre prospective registry from July 2007 to February 2021. Clinical features, in and out of hospital MACE, laboratory and imaging data were collected. A sub-analysis evaluating serum interleukins levels among 12 patients with cancer vs. a propensity score matched cohort was performed. Prevalence of history of cancer was 12% (N = 51 pts). Patients with history of cancer were older (77 vs. 72 years, P = 0.01), with a higher percentage of male (23.5% vs. 8.8%, P = 0.01). Diabetes, dyslipidemia, and obesity were more prevalent in patients with cancer (29% vs. 22%, 49% vs. 42%, 25.5% vs. 18.5%, P = 0.01 respectively), while a similar prevalence was found for hypertension and smoke. Left ventricular ejection fraction (LVEF) at admission and discharge was lower in patients with history of cancer (33% vs. 37%, 44% vs. 50%. P = 0.03 respectively). Patients with cancer showed higher incidence of in hospital events (41% vs. 33%, P = 0.01) mainly driven by cardiogenic shock (21.5% vs. 8.5% P = 0.01), in hospital death (13.7% vs. 4.7%, P = 0.01), left ventricular thrombi (9.8% vs. 3.3%, P = 0.01) and ventricular arrhythmias (13.7% vs. 7.4%, P = 0.01). The long-term mortality was higher in patients with history of cancer (31.3% vs. 11.3%, P = 0.01). A distinct inflammatory pattern was found in cancer patients: at admission there were higher levels of IL 2 and VEGF levels (IL-2 3.3 vs. 0.7 pg/ml, P = 0.05, VEGF 476.3 vs. 249.5 pg/ml, P = 0.03); at discharge IL-4 was lower (1.17 pg/ml vs. 2.49 pg/ml, P = 0.04) while VEGF remained higher in subjects with TTS and cancer (406 vs. 128 pg/ml, P = 0.03). Conclusions Cancer patients with TTS are characterized by different clinical features, epidemiological characteristics, worse prognosis and higher long-term mortality when compared to patients with TTS without history of malignancy. A distinct inflammatory pattern can be found in this subset of TTS patients.

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

Beneficial effects of the Ca2+ sensitizer levosimendan in human myocardium

2002 ◽  
Vol 282 (1) ◽  
pp. H131-H137 ◽  
Author(s):  
Klara Brixius ◽  
Sebastian Reicke ◽  
Robert H. G. Schwinger
Keyword(s):  
Heart Failure ◽  
Contractile Force ◽  
Left Ventricular ◽  
Human Myocardium ◽  
Force Frequency ◽  
Heart Failure Patients ◽  
Beneficial Effects ◽  
Intracellular Ca ◽  
Frequency Relationship ◽  
Contraction Kinetics

Levosimendan has been reported to increase cardiac Ca2+ sensitivity, thereby not enhancing intracellular Ca2+ or diastolic tension. This may be advantageous for the treatment of heart failure patients. Therefore, the present study investigates the mode of action of levosimendan in both failing and nonfailing (NF) human myocardium. The effects of levosimendan on contractile force, Ca2+ transient (fura 2), and the force-frequency relationship (0.5–3 Hz) were studied in left ventricular terminally failing [dilated cardiomyopathy (DCM; n = 18)] and nonfailing (NF) myocardium (donor hearts, n = 6). Levosimendan (0.03–10 μmol/l) increased contractile force in NF (EC50: 0.38 μmol/l). In left ventricular failing myocardium, levosimendan only increased force after prestimulation with isoprenaline (0.1 μmol/l, EC50levosimendan: 0.062 μmol/l) or after elevation of the extracellular Ca2+ concentration from 1.8 to 3.2 mmol/l. After application of isoprenaline, levosimendan shortened relaxation and contraction kinetics. Levosimendan did not change the systolic Ca2+ transient but it improved the force-frequency relationship in DCM. In conclusion, levosimendan improves contraction in failing human myocardium under conditions with already increased intracellular Ca2+.

Effect of pH and inhibitors on beta-amyloid fibril assembly

1996 ◽  
Vol 54 ◽  
pp. 752-753
Author(s):  
Beverly E. Maleeff ◽  
Timothy K. Hart ◽  
Stephen J. Wood ◽  
Ronald Wetzel
Keyword(s):  
Amyloid Fibril ◽  
Peptide Fragment ◽  
Hydrophobic Peptides ◽  
Amyloid Fibril Formation ◽  
Effects Of Ph ◽  
Severity Of The Disease ◽  
Kinetics Of ◽  
The Brain

Alzheimer's disease is characterized post-mortem in part by abnormal extracellular neuritic plaques found in brain tissue. There appears to be a correlation between the severity of Alzheimer's dementia in vivo and the number of plaques found in particular areas of the brain. These plaques are known to be the deposition sites of fibrils of the protein β-amyloid. It is thought that if the assembly of these plaques could be inhibited, the severity of the disease would be decreased. The peptide fragment Aβ, a precursor of the p-amyloid protein, has a 40 amino acid sequence, and has been shown to be toxic to neuronal cells in culture after an aging process of several days. This toxicity corresponds to the kinetics of in vitro amyloid fibril formation. In this study, we report the biochemical and ultrastructural effects of pH and the inhibitory agent hexadecyl-N-methylpiperidinium (HMP) bromide, one of a class of ionic micellar detergents known to be capable of solubilizing hydrophobic peptides, on the in vitro assembly of the peptide fragment Aβ.

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
Sign in / Sign up

Export Citation Format

Share Document