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In-silico human electro-mechanical ventricular modelling and simulation for drug-induced pro-arrhythmia and inotropic risk assessment.
Margara, F, Wang, ZJ, Levrero-Florencio, F, Santiago, A, Vázquez, M, Bueno-Orovio, A, Rodriguez, B
Progress in biophysics and molecular biology. 2021;:58-74
Abstract
Human-based computational modelling and simulation are powerful tools to accelerate the mechanistic understanding of cardiac patho-physiology, and to develop and evaluate therapeutic interventions. The aim of this study is to calibrate and evaluate human ventricular electro-mechanical models for investigations on the effect of the electro-mechanical coupling and pharmacological action on human ventricular electrophysiology, calcium dynamics, and active contraction. The most recent models of human ventricular electrophysiology, excitation-contraction coupling, and active contraction were integrated, and the coupled models were calibrated using human experimental data. Simulations were then conducted using the coupled models to quantify the effects of electro-mechanical coupling and drug exposure on electrophysiology and force generation in virtual human ventricular cardiomyocytes and tissue. The resulting calibrated human electro-mechanical models yielded active tension, action potential, and calcium transient metrics that are in agreement with experiments for endocardial, epicardial, and mid-myocardial human samples. Simulation results correctly predicted the inotropic response of different multichannel action reference compounds and demonstrated that the electro-mechanical coupling improves the robustness of repolarisation under drug exposure compared to electrophysiology-only models. They also generated additional evidence to explain the partial mismatch between in-silico and in-vitro experiments on drug-induced electrophysiology changes. The human calibrated and evaluated modelling and simulation framework constructed in this study opens new avenues for future investigations into the complex interplay between the electrical and mechanical cardiac substrates, its modulation by pharmacological action, and its translation to tissue and organ models of cardiac patho-physiology.
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Alpha and beta myosin isoforms and human atrial and ventricular contraction.
Walklate, J, Ferrantini, C, Johnson, CA, Tesi, C, Poggesi, C, Geeves, MA
Cellular and molecular life sciences : CMLS. 2021;(23):7309-7337
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Abstract
Human atrial and ventricular contractions have distinct mechanical characteristics including speed of contraction, volume of blood delivered and the range of pressure generated. Notably, the ventricle expresses predominantly β-cardiac myosin while the atrium expresses mostly the α-isoform. In recent years exploration of the properties of pure α- & β-myosin isoforms have been possible in solution, in isolated myocytes and myofibrils. This allows us to consider the extent to which the atrial vs ventricular mechanical characteristics are defined by the myosin isoform expressed, and how the isoform properties are matched to their physiological roles. To do this we Outline the essential feature of atrial and ventricular contraction; Explore the molecular structural and functional characteristics of the two myosin isoforms; Describe the contractile behaviour of myocytes and myofibrils expressing a single myosin isoform; Finally we outline the outstanding problems in defining the differences between the atria and ventricles. This allowed us consider what features of contraction can and cannot be ascribed to the myosin isoforms present in the atria and ventricles.
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Quantitative analysis of variability in an integrated model of human ventricular electrophysiology and β-adrenergic signaling.
Gong, JQX, Susilo, ME, Sher, A, Musante, CJ, Sobie, EA
Journal of molecular and cellular cardiology. 2020;:96-106
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Abstract
In ventricular myocytes, stimulation of β-adrenergic receptors activates critical cardiac signaling pathways, leading to shorter action potentials and increased contraction strength during the "fight-or-flight" response. These changes primarily result, at the cellular level, from the coordinated phosphorylation of multiple targets by protein kinase A. Although mathematical models of the intracellular signaling downstream of β-adrenergic receptor activation have previously been described, only a limited number of studies have explored quantitative interactions between intracellular signaling and electrophysiology in human ventricular myocytes. Accordingly, our objective was to develop an integrative mathematical model of β-adrenergic receptor signaling, electrophysiology, and intracellular calcium (Ca2+) handling in the healthy human ventricular myocyte. We combined published mathematical models of intracellular signaling and electrophysiology, then calibrated the model results against voltage clamp data and physiological changes occurring after stimulation of β-adrenergic receptors with isoproterenol. We subsequently: (1) explored how molecular variability in different categories of model parameters translated into phenotypic variability; (2) identified the most important parameters determining physiological cellular outputs in the model before and after β-adrenergic receptor stimulation; and (3) investigated which molecular level alterations can produce a phenotype indicative of heart failure with preserved ejection fraction (HFpEF). Major results included: (1) variability in parameters that controlled intracellular signaling caused qualitatively different behavior than variability in parameters controlling ion transport pathways; (2) the most important model parameters determining action potential duration and intracellular Ca2+ transient amplitude were generally consistent before and after β-adrenergic receptor stimulation, except for a shift in the importance of K+ currents in determining action potential duration; and (3) decreased Ca2+ uptake into the sarcoplasmic reticulum, increased Ca2+ extrusion through Na+/Ca2+ exchanger and decreased Ca2+ leak from the sarcoplasmic reticulum may contribute to HFpEF. Overall, this study provided novel insight into the phenotypic consequences of molecular variability, and our integrated model may be useful in the design and interpretation of future experimental studies of interactions between β-adrenergic signaling and cellular physiology in human ventricular myocytes.
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Pregnancy complications in chronic hypertensive patients are linked to pre-pregnancy maternal cardiac function and structure.
Vasapollo, B, Novelli, GP, Gagliardi, G, Farsetti, D, Valensise, H
American journal of obstetrics and gynecology. 2020;(3):425.e1-425.e13
Abstract
BACKGROUND Chronic hypertension complicates around 3% of all pregnancies and is associated with an increased risk for pregnancy complications such as superimposed preeclampsia, fetal growth restriction, preterm delivery, and stillbirth, reaching a rate of complications of up to 25-28%. OBJECTIVE We performed an echocardiographic study to evaluate pre-pregnancy cardiac geometry and function, along with the hemodynamic features of treated chronic hypertension patients, searching for a possible correlation with the development of feto-maternal complications and with pre-pregnancy therapy. MATERIALS AND METHODS This was a prospective observational cohort study of 192 consecutive patients receiving treatment for chronic hypertension (calcium channel blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, β-blockers, α1-adrenoceptor antagonists, and/or diuretics). Patients underwent echocardiography before pregnancy, assessing left ventricular morphology and function, cardiac output, and total vascular resistance. Pre-pregnancy therapy was noted, patients were shifted to α-methyldopa right before pregnancy, and were followed until delivery, noting major early (<34weeks' gestation) and late (≥34 weeks' gestation) complications. Comparisons among the 3 groups (ie, those with no complications, early complications, and late complications) were performed with 1-way analysis of variance with Student-Newman-Keuls correction for multiple comparisons. The Mann-Whitney U test was used for non-normally distributed data. Comparison of proportions was used as appropriate. Receiver operating characteristic curve analysis was used to identify cutoff values of diastolic dysfunction in this population using the E/e' ratio, and separate cutoff of values for total vascular resistance for the prediction of early and late complications of pregnancy. Binary univariate and multivariate logistic regression as well as Cox proportional hazards regression were used to evaluate the possible correlation among angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and/or calcium channel blocker pre-pregnancy therapy, cardiovascular features, and the risk for subsequent early and late complications of pregnancy. RESULTS Of 192 patients, 141 had no complications, and 51 had a complicated pregnancy (24 had early complications and 27 had late complications). Concentric geometry was more frequent in those women with early versus late and no complications (50% vs 13.5% and 11.1%, respectively; P < .05), whereas eccentric hypertrophy was more represented in women with late versus early and no complications (32% versus 12.5% and 1.4%, respectively; P < .05). The receiver operating characteristic curve showed an E/e' ratio value >7.65 (sensitivity, 59.6%; specificity, 68.6%) as a predictor of subsequent complications of pregnancy, whereas total vascular resistance <1048 (sensitivity, 83.7%; specificity, 55.6%) was predictive for late complications and total vascular resistance >1498 (sensitivity, 87.5%; specificity, 78.0%) for the early complications of pregnancy. Univariate analysis showed that the following parameters were predictive for complications of pregnancy: altered geometry of the left ventricle (odds ratio, 5.94; 95% confidence interval, 2.90-12.19), diastolic dysfunction (odds ratio, 3.22; 95% confidence interval, 1.63-6.37), altered total vascular resistance (odds ratio, 3.52; 95% confidence interval, 1.78-6.97), and pre-pregnancy therapy without calcium channel blockers/angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (odds ratio, 2.73; 95% confidence interval, 1.37-5.42). These parameters, except for altered total vascular resistance, were independent predictors in the multivariate analysis corrected for body mass index, heart rate, parity, and mean arterial pressure. CONCLUSION Chronic hypertension patients with pre-pregnancy cardiac remodeling and dysfunction more often develop early and late complications of pregnancy. Pre-pregnancy therapy for chronic hypertension patients with calcium channel blockers and/or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers may positively influence cardiac profiles and the outcome of a future pregnancy with a reduced rate of complications.
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Effect of Low-Sodium versus Conventional Sodium Dialysate on Left Ventricular Mass in Home and Self-Care Satellite Facility Hemodialysis Patients: A Randomized Clinical Trial.
Marshall, MR, Vandal, AC, de Zoysa, JR, Gabriel, RS, Haloob, IA, Hood, CJ, Irvine, JH, Matheson, PJ, McGregor, DOR, Rabindranath, KS, et al
Journal of the American Society of Nephrology : JASN. 2020;(5):1078-1091
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Abstract
BACKGROUND Fluid overload in patients undergoing hemodialysis contributes to cardiovascular morbidity and mortality. There is a global trend to lower dialysate sodium with the goal of reducing fluid overload. METHODS To investigate whether lower dialysate sodium during hemodialysis reduces left ventricular mass, we conducted a randomized trial in which patients received either low-sodium dialysate (135 mM) or conventional dialysate (140 mM) for 12 months. We included participants who were aged >18 years old, had a predialysis serum sodium ≥135 mM, and were receiving hemodialysis at home or a self-care satellite facility. Exclusion criteria included hemodialysis frequency >3.5 times per week and use of sodium profiling or hemodiafiltration. The main outcome was left ventricular mass index by cardiac magnetic resonance imaging. RESULTS The 99 participants had a median age of 51 years old; 67 were men, 31 had diabetes mellitus, and 59 had left ventricular hypertrophy. Over 12 months of follow-up, relative to control, a dialysate sodium concentration of 135 mmol/L did not change the left ventricular mass index, despite significant reductions at 6 and 12 months in interdialytic weight gain, in extracellular fluid volume, and in plasma B-type natriuretic peptide concentration (ratio of intervention to control). The intervention increased intradialytic hypotension (odds ratio [OR], 7.5; 95% confidence interval [95% CI], 1.1 to 49.8 at 6 months and OR, 3.6; 95% CI, 0.5 to 28.8 at 12 months). Five participants in the intervention arm could not complete the trial because of hypotension. We found no effect on health-related quality of life measures, perceived thirst or xerostomia, or dietary sodium intake. CONCLUSIONS Dialysate sodium of 135 mmol/L did not reduce left ventricular mass relative to control, despite improving fluid status. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER The Australian New Zealand Clinical Trials Registry, ACTRN12611000975998.
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A nutraceutical combination reduces left ventricular mass in subjects with metabolic syndrome and left ventricular hypertrophy: A multicenter, randomized, double-blind, placebo-controlled trial.
Mercurio, V, Pucci, G, Bosso, G, Fazio, V, Battista, F, Iannuzzi, A, Brambilla, N, Vitalini, C, D'Amato, M, Giacovelli, G, et al
Clinical nutrition (Edinburgh, Scotland). 2020;(5):1379-1384
Abstract
BACKGROUND & AIMS Increased left ventricular mass (LVM) is often present in metabolic syndrome (MS), also in the setting of well-controlled blood pressure (BP). Aim of the present study was to evaluate the efficacy of a nutraceutical combination of berberine, red yeast rice extract and policosanol (Armolipid Plus™, AP) in reducing LVM in patients with MS and left ventricular hypertrophy (LVH). METHODS In this multicenter, randomized, double-blind, placebo-controlled trial, 158 patients with MS (IDF criteria) and LVH (LVM > 48 g/m2.7 in men and > 44 g/m2.7 in women), were randomized 1:1 to receive AP or placebo for 24 weeks. Reduction of LVM, regression of LVH, and changes in lipids were analysed. RESULTS One-hundred-and-forty-five patients (AP n = 74, placebo n = 71) completed the study. A significant percentage reduction in LVM was observed in AP group vs baseline (-2.7%, p < 0.0001), and compared to placebo (-4.1%, p < 0.0001), and remained significant after adjustment for age, sex, baseline systolic BP and BMI and their changes during the study period. The proportion of subjects showing LVM reduction was higher in AP group than in the placebo group (57% vs 28%, adjusted p = 0.007). Treatment with AP was associated with improvement of lipid profile. CONCLUSIONS 24-week of treatment with AP is associated with a significant reduction in LVM in subjects with MS and LVH, in addition to favourable effects on lipid profile, and could represent an effective strategy aiming at reducing the associated cardiovascular risk. The trial was registered at clinicaltrials.gov with ID NCT02295176.
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Meta-analysis Assessing the Effect of Sodium-Glucose Co-transporter-2 Inhibitors on Left Ventricular Mass in Patients With Type 2 Diabetes Mellitus.
Patoulias, D, Papadopoulos, C, Katsimardou, A, Kalogirou, MS, Doumas, M
The American journal of cardiology. 2020;:149-152
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Left Ventricular Assist Device Therapy in Older Adults: Addressing Common Clinical Questions.
DeFilippis, EM, Nakagawa, S, Maurer, MS, Topkara, VK
Journal of the American Geriatrics Society. 2019;(11):2410-2419
Abstract
OBJECTIVES To review the literature and summarize the evidence for left ventricular assist device (LVAD) use in older adults (aged >75 years), highlighting patient selection, day-to-day life with an LVAD, age-specific complications, and end-of-life considerations. DESIGN Contemporary review of current literature on LVAD therapy in older adults. RESULTS There is a paucity of data on LVAD use and outcomes in adults older than 75 years and even less commonly are such devices implanted in those older than 80 years. Candidates and recipients of this age often have multiple chronic conditions and extracardiac impairments, which can negatively affect their short-term outcomes and daily experience following LVAD implantation. Therefore, selection prior to implant should incorporate end-organ function, nutritional status, measures of frailty, neurocognitive status, and social support, among others, to determine the patient population most likely to benefit from such therapy. CONCLUSION When LVAD therapy is utilized in an older adult, the needs for multidisciplinary team management and expertise in palliative care are essential. More age-specific outcome data are required to help inform providers, patients, and caregivers. J Am Geriatr Soc 67:2410-2419, 2019.
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A Spatiotemporal Ventricular Myocyte Model Incorporating Mitochondrial Calcium Cycling.
Song, Z, Xie, LH, Weiss, JN, Qu, Z
Biophysical journal. 2019;(12):2349-2360
Abstract
Intracellular calcium (Ca2+) cycling dynamics in cardiac myocytes are spatiotemporally generated by stochastic events arising from a spatially distributed network of coupled Ca2+ release units that interact with an intertwined mitochondrial network. In this study, we developed a spatiotemporal ventricular myocyte model that integrates mitochondria-related Ca2+ cycling components into our previously developed ventricular myocyte model consisting of a three-dimensional Ca2+ release unit network. Mathematical formulations of mitochondrial membrane potential, mitochondrial Ca2+ cycling, mitochondrial permeability transition pore stochastic opening and closing, intracellular reactive oxygen species signaling, and oxidized Ca2+/calmodulin-dependent protein kinase II signaling were incorporated into the model. We then used the model to simulate the effects of mitochondrial depolarization on mitochondrial Ca2+ cycling, Ca2+ spark frequency, and Ca2+ amplitude, which agree well with experimental data. We also simulated the effects of the strength of mitochondrial Ca2+ uniporters and their spatial localization on intracellular Ca2+ cycling properties, which substantially affected diastolic and systolic Ca2+ levels in the mitochondria but exhibited only a small effect on sarcoplasmic reticulum and cytosolic Ca2+ levels under normal conditions. We show that mitochondrial depolarization can cause Ca2+ waves and Ca2+ alternans, which agrees with previous experimental observations. We propose that this new, to our knowledge, spatiotemporal ventricular myocyte model, incorporating properties of mitochondrial Ca2+ cycling and reactive-oxygen-species-dependent signaling, will be useful for investigating the effects of mitochondria on intracellular Ca2+ cycling and action potential dynamics in ventricular myocytes.
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Perioperative Management of the Right and Left Ventricles.
Lampert, BC
Cardiology clinics. 2018;(4):495-506
Abstract
Left ventricular assist devices (LVADs) improve survival in select advanced heart failure patients and rates of LVAD implantation are growing. LVAD support carries significant morbidity and mortality with the greatest risk in the perioperative period. Strategies have evolved to minimize this risk. Medical and mechanical support is used for right and left ventricular optimization. Other strategies emphasize improving nutrition, hematologic abnormalities, infection risk, and renal function. Intraoperative approaches highlight anesthesia-related issues, management of concomitant valve disease, right ventricular failure, and weaning from cardiopulmonary bypass. Postoperative efforts concentrate on augmenting right ventricular function, supporting end-organ recovery, and quickly identifying complications.