Comparative analysis of ventricular stiffness across species.

Investigating ventricular diastolic properties is crucial for understanding the physiological cardiac functions in organisms and unraveling the pathological mechanisms of cardiovascular disorders. Ventricular stiffness, a fundamental parameter that defines ventricular diastolic functions in chordates, is typically analyzed using the end-diastolic pressure-volume relationship (EDPVR). However, comparing ventricular stiffness accurately across chambers of varying maximum volume capacities has been a long-standing challenge. As one of the solutions to this problem, we propose calculating a relative ventricular stiffness index by applying an exponential approximation formula to the EDPVR plot data of the relationship between ventricular pressure and values of normalized ventricular volume by the ventricular weight. This article reviews the potential, utility, and limitations of using normalized EDPVR analysis in recent studies. Herein, we measured and ranked ventricular stiffness in differently sized and shaped chambers using ex vivo ventricular pressure-volume analysis data from four animals: Wistar rats, red-eared slider turtles, masu salmon, and cherry salmon. Furthermore, we have discussed the mechanical effects of intracellular and extracellular viscoelastic components, Titin (Connectin) filaments, collagens, physiological sarcomere length, and other factors that govern ventricular stiffness. Our review provides insights into the comparison of ventricular stiffness in different-sized ventricles between heterologous and homologous species, including non-model organisms.

Avaliação ecocardiográfica do paciente com choque circulatório: uma abordagem contemporânea / Echocardiographic evaluation of a patient in circulatory shock: a contemporary approach

O choque circulatório é caracterizado por um estado de ineficiência da oferta de oxigênio tecidual e disfunção múltipla de órgãos. Necessita de diagnóstico e terapias rápidas e assertivas para redução de sua alta letalidade. O ecocardiograma já se estabeleceu como método fundamental no manejo do paciente com choque circulatório. Auxilia de forma crucial no diagnóstico etiológico, prognóstico, monitorização hemodinâmica e estimativa volêmica desses pacientes, tendo como potenciais vantagens a portabilidade, ausência de contraste ou radiação, baixo custo e avaliação em tempo real e de forma seriada. Em ambiente de UTI, demonstra alta correlação com formas invasivas (cateter de artéria pulmonar) e minimamente invasivas (termodiluição transpulmonar) de monitorização hemodinâmica. Atualmente, outras técnicas, como ultrassom pulmonar e VExUS score, têm se agregado à avaliação ecocardiográfica, tornando o método mais abrangente e acurado. Essas técnicas acrescentam dados relevantes na estimativa da volemia do paciente crítico, influenciando na decisão probabilística de fluidoresponsividade e agregando informações no raciocínio diagnóstico das causas do choque, otimizando o prognóstico desses pacientes. O point of care ultrasound (POCUS) tem como objetivo tornar mais acessível, ao médico não especialista em radiologia, habilidades para se obter informações a beira leito, por meio do ultrassom, que o ajudem na tomada de decisões. Esse artigo aborda as diversas aplicabilidades do ecocardiograma em pacientes com choque circulatório, incluindo avaliação prognóstica e diagnóstico etiológico por meio dos parâmetros encontrados nas principais causas de choque, além da monitorização hemodinâmica, avaliação de fluido-responsividade e utilização prática do ultrassom pulmonar.(AU)

Circulatory shock is characterized by a state of inefficient tissue oxygen supply and multiple organ dysfunction. Patients with circulatory shock require fast and assertive diagnosis and therapies to reduce its high lethality. Echocardiography has already been established as a fundamental method in managing patients with circulatory shock. It provides crucial assistance in etiological diagnosis, prognosis, hemodynamic monitoring, and volume estimation in these patients; its potential advantages include portability, absence of contrast or radiation, low cost, and real-time serial assessment. In the intensive care unit setting, it demonstrates a high correlation with invasive (pulmonary artery catheter) and minimally invasive (transpulmonary thermodilution) forms of hemodynamic monitoring. Currently, other techniques, such as pulmonary ultrasound and VExUS score, have been added to echocardiographic assessment, making the method more comprehensive and accurate. These techniques add relevant data to blood volume estimation in critical patients, influencing the probabilistic decision of fluid responsiveness and providing additional information in the diagnostic reasoning of the causes of shock, thus optimizing these patients' prognosis. Point of care ultrasound (POCUS) aims to make abilities to obtain information at the bedside more accessible to physicians who are not specialists in radiology, by means of ultrasound, which assists them in decision-making. This article addresses the diverse applications of echocardiography in patients with circulatory shock, including prognostic evaluation and etiological diagnosis by means of the parameters found in the main causes of shock, in addition to hemodynamic monitoring, evaluation of fluid responsiveness, and practical use of pulmonary ultrasound.(AU)

The Impact of Dominant Ventricular Morphology on the Early Postoperative Course After the Glenn Procedure.

The dominant ventricular morphology affects both the early and late outcomes of the Fontan procedure, but its impact on the patients' status immediately following the Glenn procedure is unknown. This study aims to evaluate the effect of the infants' dominant ventricular morphology on the immediate course after undergoing the Glenn procedure. This single-center, retrospective study included all patients who underwent the Glenn procedure between October 2003 and May 2016. The patients were divided into two groups according to their dominant ventricular morphology. Their postoperative records were reviewed and compared. Out of the 89 patients who underwent the Glenn procedure during the study period, 40 (44.9%) had dominant right ventricular morphology and 49 (55.1%) had left ventricular morphology. There were no significant group differences in baseline characteristics or operative data. The maximal postoperative vasoactive-inotropic score was significantly higher and the extent of ventricular dysfunction was significantly more severe in the dominant right ventricle group (P < 0.05). The length of hospitalization was slightly but not significantly longer in the hypoplastic LV group. It is concluded that patients with a dominant LV morphology had a superior ventricular function and required less inotropic support compared to that of a dominant RV morphology in the immediate postoperative course following the Glenn procedure. Survival was not affected by these differences. Further study to determine the pathophysiologic basis for these differences is warranted.

The relationship between vitamin B12 levels and electrocardiographic ventricular repolarization markers / La relación entre los niveles de vitamina B12 y los marcadores electrocardiográficos de repolarización ventricular

Background: it has been shown that vitamin B12 deficiency, which can cause hematological and neuropsychiatric disorders, may also be associated with cardiac autonomic dysfunction, heart rate variability, endothelial dysfunction, and a decrease in myocardial deformation. Aims: the aim of our study is to evaluate the relationship between vitamin B12 levels and electrocardiographic repolarization disorders, which are indicators of arrhythmogenic predisposition in healthy individuals. Methods: our study population consisted of 214 healthy adults. Considering the distribution of vitamin B12 levels and accepting 25 % and 75 % percentiles as the cut-off values, the participants were divided into 3 groups. Laboratory, echocardiography and electrocardiography (ECG) measurements were compared between three groups. ECG measurements were performed manually and Tpeak-Tend (Tp-e), Tp-e corrected (Tp-ec), QT and QT corrected (QTc) intervals were calculated. Results: the patients in Group 1 (vitamin B12 < 253 pg/ml) were found to have significantly higher QT and QTc dispersions, Tp-e interval, Tp-e/QT and Tp-e/QTc ratios when compared to those in Group 2 (253 pg/ml < vitamin B12 > 436 pg/ml) and Group 3 (vitamin B12 > 436 pg/ml). On the other hand, a negative significant correlation was detected between vitamin B12 levels and Tp-e, Tp-e/QT, Tp-e/QTc ratios, QT and QTc dispersions. Conclusion: a low level of vitamin B12 in healthy individuals can be a significant indicator of arrhythmogenic susceptibility. A close follow-up of these subjects in terms of arrhythmogenic predisposition can be useful (AU)

Fundamento: se ha demostrado que la deficiencia de vitamina B12, que puede causar trastornos hematológicos y neuropsiquiátricos, también puede estar asociada con disfunción autonómica cardíaca, variabilidad de la frecuencia cardíaca, disfunción endotelial y disminución de la deformación miocárdica. Objetivos: el objetivo de nuestro estudio es evaluar la relación entre los niveles de vitamina B12 y los trastornos de repolarización electrocardiográfica que son indicadores de predisposición arritmogénica en individuos sanos. Métodos: la población del estudio fue de 214 adultos sanos. Considerando la distribución de los niveles de vitamina B12 y aceptando los percentiles del 25 % y 75 % como valores de corte, los participantes se dividieron en 3 grupos. Se compararon las mediciones de laboratorio, ecocardiografía y electrocardiografía (ECG) entre tres grupos. Las mediciones del ECG se realizaron manualmente y se calcularon los intervalos Tpeak-Tend (Tp-e), Tp-e corregido (Tp-ec), QT y QT corregido (QTc). Resultados: se encontró que los pacientes del grupo 1 (vitamina B12 < 253 pg/ml) tenían dispersiones QT y QTc, intervalo Tp-e, cocientes Tp-e/QT y Tp-e/QTc significativamente más altos cuando se compararon con los del grupo 2 (253 pg/ml < vitamina B12 > 436 pg/ml) y el grupo 3 (vitamina B12 > 436 pg/ml). Por otro lado, se detectó una correlación significativa negativa entre los niveles de vitamina B12 y las relaciones Tp-e, Tp-e/QT, Tp-e/QTc, dispersiones QT y QTc.Conclusión: el bajo nivel de vitamina B12 en los individuos sanos puede ser un indicador significativo de susceptibilidad arritmogénica. Un seguimiento estrecho de estos sujetos en términos de predisposición arritmogénica podría ser útil (AU)

Novel Transcatheter Mitral Prosthesis Designed to Preserve Physiological Ventricular Flow Dynamics.

BACKGROUND: Current mitral bioprostheses are akin to the aortic valve and therefore abolish the left ventricular (LV) physiological vortex. We evaluated the hemodynamic performance and the effects on intraventricular flow dynamics (IFD) of a novel mitral bioprosthesis that presents an innovative design mimicking the native valve. METHODS: A D-shaped self-expandable stent-bovine pericardium monoleaflet valve was designed to provide physiological asymmetric intraventricular flow. Transapical implantation was consecutively performed in 12 juvenile sheep. Postimplant studies using Doppler echocardiography and IFD using echo particle imaging velocimetry were obtained immediately after the implantation and at 3 months to assess the hemodynamic performance of the prostheses. RESULTS: There were 3 deaths during follow-up, 1 due to valve misplacement because of poor imaging visualization and 2 not valve related. The mean transvalvular gradient and effective orifice area were 2.2 ± 1.2 mm Hg and 4.0 ± 1.1 cm2 after implantation and 3.3 ± 1.5 mm Hg and 3.5 ± 0.5 cm2 at 3 months, respectively. LV vortex dimension, orientation, and physiological anticlockwise rotation were preserved compared with preoperative normal LV flow pattern. One animal showed a moderate paravalvular leak, others mild or none. LV outflow tract obstruction, valve thrombosis, and hemolysis were not observed. CONCLUSIONS: Our preclinical in vivo results confirm the good hemodynamic performance of this new transcatheter bioprosthesis with preservation of the physiological IFD. Clinical studies are needed to document whether these characteristics will foster LV recovery and improve the clinical outcome of patients with mitral regurgitation.

Cardiac structure and function in elite female athletes: A systematic review and meta-analysis.

We conducted a meta-analysis to synthesize the best available evidence comparing cardiac biventricular structure and function using cardiac magnetic resonance imaging (CMR) and transthoracic echocardiography (TTE) in elite female athletes and healthy controls (HC). Chronic exposure to exercise may induce cardiac chamber enlargement as a means to augment stroke volume, a condition known as the "athlete's heart." These changes have not been clearly characterized in female athletes. Multiple databases were searched from inception to June 18, 2019. Outcomes of interest included left ventricular (LV) and right ventricular (RV) dimensional, volumetric, mass, and functional assessments in female athletes. Most values were indexed to body surface area. The final search yielded 22 studies, including 1000 female athletes from endurance, strength, and mixed athletic disciplines. CMR-derived LV end-diastolic volume (LVEDV) and RV end-diastolic volume (RVEDV) were greater in endurance athletes (EA) versus HC (17.0% and 18.5%, respectively; both p < 0.001). Similarly, TTE-derived LVEDV and RVEDV were greater in EA versus HC (16.8% and 28.0%, respectively; both p < 0.001). Both LVEF and RVEF were lower in EA versus HC, with the most pronounced difference observed in RVEF via TTE (9%) (p < 0.001). LV stroke volume was greater in EA versus HC via both CMR (18.5%) and TTE (13.2%) (both p < 0.05). Few studies reported data for the mixed athlete (MA) population and even fewer studies reported data for strength athletes (SA), therefore a limited analysis was performed on MA and no analysis was performed on SA. This evidence-synthesis review demonstrates the RV may be more susceptible to ventricular enlargement. General changes in LV and RV structure and function in female EA mirrored changes observed in male counterparts. Further studies are needed to determine if potential adverse outcomes occur secondary to these changes.

Atrioventricular and Ventricular Functional Interdependence in Individuals Without Overt Cardiac Disease.

Background Left atrial (LA) and right ventricular (RV) performance play an integral role in the pathophysiology and prognosis of heart failure. We hypothesized that subclinical left ventricular dysfunction adversely affects LA/RV geometry and function even in a preclinical setting. This study aimed to investigate the atrioventricular and ventricular functional interdependence in a community-based cohort without overt cardiovascular disease. Methods and Results Left ventricular global longitudinal strain (LVGLS), RV free-wall longitudinal strain and LA phasic strain were assessed by speckle-tracking echocardiography in 1080 participants (600 men; 62±12 years) between 2014 and 2018. One hundred and forty-three participants (13.2%) had an abnormal LVGLS (>-18.6%). LA reservoir strain, conduit strain, and RV free-wall longitudinal strain were significantly decreased in abnormal LVGLS group compared with normal LVGLS group (all P<0.001). LA and RV dysfunction (LA reservoir strain<31.4% and RVLS>-19.2%) were present in 18.9% and 19.6% of participants with abnormal LVGLS. Decreased LVGLS was associated with worse LA reservoir strain, conduit strain and RV free-wall longitudinal strain (standardized ß=-0.20, -0.19 and 0.11 respectively, all P<0.01) independent of cardiovascular risk factors. LA and/or RV dysfunction concomitant with abnormal LVGLS carried significantly increased risk of elevated B-type natriuretic peptide levels (>28.6 pg/mL for men and >44.4 pg/mL for women) compared with normal LVGLS (odds ratio, 2.01; P=0.030). Conclusions LA/RV dysfunction was present in 20% individuals with abnormal LVGLS and multi-chamber impairment was associated with elevated B-type natriuretic peptide level, which may provide valuable insights for a better understanding of atrioventricular and ventricular interdependence and possibly heart failure preventive strategies.

Frank-Starling mechanism, fluid responsiveness, and length-dependent activation: Unravelling the multiscale behaviors with an in silico analysis.

The Frank-Starling mechanism is a fundamental regulatory property which underlies the cardiac output adaptation to venous filling. Length-dependent activation is generally assumed to be the cellular origin of this mechanism. At the heart scale, it is commonly admitted that an increase in preload (ventricular filling) leads to an increased cellular force and an increased volume of ejected blood. This explanation also forms the basis for vascular filling therapy. It is actually difficult to unravel the exact nature of the relationship between length-dependent activation and the Frank-Starling mechanism, as three different scales (cellular, ventricular and cardiovascular) are involved. Mathematical models are powerful tools to overcome these limitations. In this study, we use a multiscale model of the cardiovascular system to untangle the three concepts (length-dependent activation, Frank-Starling, and vascular filling). We first show that length-dependent activation is required to observe both the Frank-Starling mechanism and a positive response to high vascular fillings. Our results reveal a dynamical length dependent activation-driven response to changes in preload, which involves interactions between the cellular, ventricular and cardiovascular levels and thus highlights fundamentally multiscale behaviors. We show however that the cellular force increase is not enough to explain the cardiac response to rapid changes in preload. We also show that the absence of fluid responsiveness is not related to a saturating Frank-Starling effect. As it is challenging to study those multiscale phenomena experimentally, this computational approach contributes to a more comprehensive knowledge of the sophisticated length-dependent properties of cardiac muscle.

Alpha and beta myosin isoforms and human atrial and ventricular contraction.

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 ß-cardiac myosin while the atrium expresses mostly the α-isoform. In recent years exploration of the properties of pure α- & ß-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.

A computationally efficient dynamic model of human epicardial tissue.

We present a new phenomenological model of human ventricular epicardial cells and we test its reentry dynamics. The model is derived from the Rogers-McCulloch formulation of the FitzHugh-Nagumo equations and represents the total ionic current divided into three contributions corresponding to the excitatory, recovery and transient outward currents. Our model reproduces the main characteristics of human epicardial tissue, including action potential amplitude and morphology, upstroke velocity, and action potential duration and conduction velocity restitution curves. The reentry dynamics is stable, and the dominant period is about 270 ms, which is comparable to clinical values. The proposed model is the first phenomenological model able to accurately resemble human experimental data by using only 3 state variables and 17 parameters. Indeed, it is more computationally efficient than existing models (i.e., almost two times faster than the minimal ventricular model). Beyond the computational efficiency, the low number of parameters facilitates the process of fitting the model to the experimental data.

Effects of graft preservation conditions on coronary endothelium and cardiac functional recovery in a rat model of donation after circulatory death.

BACKGROUND: Use of cardiac grafts obtained with donation after circulatory death (DCD) could significantly improve donor heart availability. As DCD hearts undergo potentially deleterious warm ischemia and reperfusion, clinical protocols require optimization to ensure graft quality. Thus, we investigated effects of alternative preservation conditions on endothelial and/or vascular and contractile function in comparison with the current clinical standard. METHODS: Using a rat DCD model, we compared currently used graft preservation conditions, St. Thomas n°2 (St. T) at 4°C, with potentially more suitable conditions for DCD hearts, adenosine-lidocaine preservation solution (A-L) at 4°C or 22°C. Following general anesthesia and diaphragm transection, hearts underwent either 0 or 18 min of in-situ warm ischemia, were explanted, flushed and stored for 15 min with either St. T at 4°C or A-L at 4°C or 22°C, and then reperfused under normothermic, aerobic conditions. Endothelial integrity and contractile function were determined. RESULTS: Compared to 4°C preservation, 22°C A-L significantly increased endothelial nitric oxide synthase (eNOS) dimerization and reduced oxidative tissue damage (p < 0.05 for all). Furthermore, A-L at 22°C better preserved the endothelial glycocalyx and coronary flow compared with St. T, tended to reduce tissue calcium overload, and stimulated pro-survival signaling. No significant differences were observed in cardiac function among ischemic groups. CONCLUSIONS: Twenty-two-degree Celsius A-L solution better preserves the coronary endothelium compared to 4°C St. T, which likely results from greater eNOS dimerization, reduced oxidative stress, and activation of the reperfusion injury salvage kinase (RISK) pathway. Improving heart preservation conditions immediately following warm ischemia constitutes a promising approach for the optimization of clinical protocols in DCD heart transplantation.

Electrophysiological Effects of the Transient Receptor Potential Melastatin 4 Channel Inhibitor (4-Chloro-2-(2-chlorophenoxy)acetamido) Benzoic Acid (CBA) in Canine Left Ventricular Cardiomyocytes.

Transient receptor potential melastatin 4 (TRPM4) plays an important role in many tissues, including pacemaker and conductive tissues of the heart, but much less is known about its electrophysiological role in ventricular myocytes. Our earlier results showed the lack of selectivity of 9-phenanthrol, so CBA ((4-chloro-2-(2-chlorophenoxy)acetamido) benzoic acid) was chosen as a new, potentially selective inhibitor. Goal: Our aim was to elucidate the effect and selectivity of CBA in canine left ventricular cardiomyocytes and to study the expression of TRPM4 in the canine heart. Experiments were carried out in enzymatically isolated canine left ventricular cardiomyocytes. Ionic currents were recorded with an action potential (AP) voltage-clamp technique in whole-cell configuration at 37 °C. An amount of 10 mM BAPTA was used in the pipette solution to exclude the potential activation of TRPM4 channels. AP was recorded with conventional sharp microelectrodes. CBA was used in 10 µM concentrations. Expression of TRPM4 protein in the heart was studied by Western blot. TRPM4 protein was expressed in the wall of all four chambers of the canine heart as well as in samples prepared from isolated left ventricular cells. CBA induced an approximately 9% reduction in AP duration measured at 75% and 90% of repolarization and decreased the short-term variability of APD90. Moreover, AP amplitude was increased and the maximal rates of phase 0 and 1 were reduced by the drug. In AP clamp measurements, CBA-sensitive current contained a short, early outward and mainly a long, inward current. Transient outward potassium current (Ito) and late sodium current (INa,L) were reduced by approximately 20% and 47%, respectively, in the presence of CBA, while L-type calcium and inward rectifier potassium currents were not affected. These effects of CBA were largely reversible upon washout. Based on our results, the CBA induced reduction of phase-1 slope and the slight increase of AP amplitude could have been due to the inhibition of Ito. The tendency for AP shortening can be explained by the inhibition of inward currents seen in AP-clamp recordings during the plateau phase. This inward current reduced by CBA is possibly INa,L, therefore, CBA is not entirely selective for TRPM4 channels. As a consequence, similarly to 9-phenanthrol, it cannot be used to test the contribution of TRPM4 channels to cardiac electrophysiology in ventricular cells, or at least caution must be applied.

An Intra-Cycle Optimal Control Framework for Ventricular Assist Devices Based on Atrioventricular Plane Displacement Modeling.

A promising treatment for congestive heart failure is the implementation of a left ventricular assist device (LVAD) that works as a mechanical pump. Modern LVADs work with adjustable constant rotor speed and provide therefore continuous blood flow; however, recently undertaken efforts try to mimic pulsatile blood flow by oscillating the pump speed. This work proposes an algorithmic framework to construct and evaluate optimal pump speed policies with respect to generic objectives. We use a model that captures the atrioventricular plane displacement, which is a physiological indicator for heart failure. We employ mathematical optimization to adapt this model to patient specific data and to find optimal pump speed policies with respect to ventricular unloading and aortic valve opening. To this end, we reformulate the cardiovascular dynamics into a switched system and thereby reduce nonlinearities. We consider system switches that stem from varying the constant pump speed and that are state dependent such as valve opening or closing. As a proof of concept study, we personalize the model to a selected patient with respect to ventricular pressure. The model fitting results in a root-mean-square deviation of about 6 mmHg. The optimization that considers aortic valve opening and ventricular unloading results in speed modulation akin to counterpulsation. These in silico findings demonstrate the potential of personalized hemodynamical optimization for the LVAD therapy.

Heart failure in pregnancy: what is the long-term impact of pregnancy on cardiac function? A tertiary care centre experience and systematic review.

BACKGROUND: Women with cardiomyopathy (CM) are often advised against pregnancy due to risk for major adverse cardiovascular events (MACE). However, the impact of CM subtype on maternal MACE is not understood, and so we sought to evaluate the influence of CM phenotype on maternal outcomes, as well as the effect on immediate and late left ventricular function. METHODS: We evaluated all pregnant women in our high-risk maternal cardiovascular programme (2009-2019). Composite maternal MACE included: death, inotrope use, left ventricular assist device, orthotopic heart transplant and/or escalation in transplant listing status, acute decompensated heart failure and sustained ventricular arrhythmia. RESULTS: Among 875 women followed, 32 had CM (29±7 years old, left ventricular ejection fraction (LVEF) 41%±12%): 3 ischaemic CM (ICM), 10 peripartum CM (PPCM) and 19 non-ICM (NICM). MACE events occurred in 6 (18%) women (PPCM: 2 (33%), NICM: 4 (67%)). There was no difference in LVEF at baseline, however, women with MACE had significantly lower LVEF both early (LVEF: 27±5% vs . 41±2%, p<0.05) and late post partum (LVEF: 28±5% vs . 44±2%, p<0.01). CONCLUSIONS: In this contemporary cohort of women with CM, maternal MACE rates were lower than previously reported, and were less common in PPCM as compared with ICM and NICM. Heart function in women with MACE was negatively impacted immediately after delivery and in late postpartum follow-up, suggesting that pregnancy itself likely has influence on future left ventricular function in women with underlying CM.

Sex-Based Differences in Cardiac Gene Expression and Function in BDNF Val66Met Mice.

Brain-derived neurotrophic factor (BDNF) is a pleiotropic neuronal growth and survival factor that is indispensable in the brain, as well as in multiple other tissues and organs, including the cardiovascular system. In approximately 30% of the general population, BDNF harbors a nonsynonymous single nucleotide polymorphism that may be associated with cardiometabolic disorders, coronary artery disease, and Duchenne muscular dystrophy cardiomyopathy. We recently showed that transgenic mice with the human BDNF rs6265 polymorphism (Val66Met) exhibit altered cardiac function, and that cardiomyocytes isolated from these mice are also less contractile. To identify the underlying mechanisms involved, we compared cardiac function by echocardiography and performed deep sequencing of RNA extracted from whole hearts of all three genotypes (Val/Val, Val/Met, and Met/Met) of both male and female Val66Met mice. We found female-specific cardiac alterations in both heterozygous and homozygous carriers, including increased systolic (26.8%, p = 0.047) and diastolic diameters (14.9%, p = 0.022), increased systolic (57.9%, p = 0.039) and diastolic volumes (32.7%, p = 0.026), and increased stroke volume (25.9%, p = 0.033), with preserved ejection fraction and fractional shortening. Both males and females exhibited lower heart rates, but this change was more pronounced in female mice than in males. Consistent with phenotypic observations, the gene encoding SERCA2 (Atp2a2) was reduced in homozygous Met/Met mice but more profoundly in females compared to males. Enriched functions in females with the Met allele included cardiac hypertrophy in response to stress, with down-regulation of the gene encoding titin (Tcap) and upregulation of BNP (Nppb), in line with altered cardiac functional parameters. Homozygous male mice on the other hand exhibited an inflammatory profile characterized by interferon-γ (IFN-γ)-mediated Th1 immune responses. These results provide evidence for sex-based differences in how the BDNF polymorphism modifies cardiac physiology, including female-specific alterations of cardiac-specific transcripts and male-specific activation of inflammatory targets.

Morphometric analysis of the His bundle (atrioventricular fascicle) in humans and other animal species. Histological and immunohistochemical study.

The His bundle is a part of the specialized electrical conduction system that provides a connection between the atrial and ventricular myocardial compartments in both normal and abnormal hearts. The aim of this study was to perform a morphometric analysis of His bundle characteristics of in humans, dogs, horses and pigs and compare them in these studied species. Histological sections of 5 µm thickness were obtained and stained with hematoxylin-eosin and Masson's trichrome; the desmin and periodic acid-Schiff methods were also used for precise identification of cells. The His bundle was found to be longer in horses (2.85 ± 1.02 mm) and pigs (1.77 ± 0.9 mm) than in dogs (1.53 ± 0.8 mm) or humans, in which it was shortest (1.06 ± 0.6 mm). The area and diameters in His bundle cells, were significantly larger in pigs and horses than in humans (p < 0.001) or dogs (p < 0.001). We found two organizational patterns of His bundle components: group I, with large cells and a high amount of collagen fibers in ungulates (pigs and horses); and group II, with smaller cells and lower abundance of collagen fibers in humans and dogs. Documenting cell size variations in the His bundle allows us not only to identify this bundle by histological or anatomical location but also to differentiate these cells from others such as nodal or Purkinje cells. Our analysis revealed that His bundle cells have discrete identities based on their morphometric and histological characteristics.

Assessment of fetal cardiac diastolic function of gestational diabetes mellitus using dual-gate Doppler.

ABSTRACT: Gestational Diabetes Mellitus (GDM), as a common complication of pregnancy, has an increasing trend globally. GDM leads to maternal complications and fetal complications. Fetal cardiac diastolic dysfunction is strongly associated with GDM. This study aims to assess the ventricular diastolic function of fetuses exposed to GDM by looking into the diagnostic parameters using both conventional method and Dual-gate Doppler method (DD). And to investigate the potential of DD method in early detection of fetal cardiac diastolic dysfunction.56 women diagnosed with GDM and 55 non-GDM pregnant women were enrolled in their 24 to 30 weeks of gestation. Conventional method and DD method were applied to measure mitral and tricuspid inflow velocities E-waves, A-waves on pulsed-wave Doppler, and mitral and tricuspid annular velocities e'-waves, a'-waves on Tissue Doppler imaging. E/A, e'/a' and E/e' ratio was calculated. The difference between GDM and control groups was statistically tested and analysed using one-sample Kolmogorov-Smirnov test, Student t test, Mann-Whitney U test and Kruskal-Wallis test and Bland-Altman plot analysis.Intraobserver intraclass correlation coefficients of E/A, e'/a', and E/e' value of both mitral and tricuspid valve are all greater than 0.80, while interobserver intraclass correlation coefficients are between 0.71 and 0.88. Right (6.35 vs 6.79; P = .001) ventricular function showed significantly lower E/e' ratios in the GDM group compared with control fetuses by conventional method. Both left (6.16 vs 6.59; P = .036) and right (6.28 vs 6.75; P = .01) ventricular function showed significantly lower E/e' ratios in the GDM group compared with control fetuses by DD method.Exposure to high level of maternal blood glucose leads to impaired diastolic function in the fetuses. Fetal right ventricular function is a potential key point to study to enable an early detection for fetal diastolic dysfunction since the alteration and damage are more likely to happen in right ventricular. Measurement of E/e' ratio using DD method is considered as a promising method in fetal cardiac diastolic function assessment. Well or poorly control of the GDM does not have significant influence on the fetal diastolic function thus an early detection of GDM and GDM induced fetal cardiac dysfunction is necessary.

Metalloproteinases and their inhibitors are associated with pulmonary arterial stiffness and ventricular function in pediatric pulmonary hypertension.

Disturbed balance between matrix metalloproteinases (MMPs) and their respective tissue inhibitors (TIMPs) is a well-recognized pathophysiological component of pulmonary arterial hypertension (PAH). Both classes of proteinases have been associated with clinical outcomes as well as with specific pathological features of ventricular dysfunction and pulmonary arterial remodeling. The purpose of this study was to evaluate the circulating levels of MMPs and TIMPs in children with PAH undergoing the same-day cardiac magnetic resonance imaging (MRI) and right heart catheterization. Children with PAH (n = 21) underwent a same-day catheterization, comprehensive cardiac MRI evaluation, and blood sample collection for proteomic analysis. Correlative analysis was performed between protein levels and 1) standard PAH indices from catheterization, 2) cardiac MRI hemodynamics, and 3) pulmonary arterial stiffness. MMP-8 was significantly associated with the right ventricular end-diastolic volume (R = 0.45, P = 0.04). MMP-9 levels were significantly associated with stroke volume (R = -0.49, P = 0.03) and pulmonary vascular resistance (R = 0.49, P = 0.03). MMP-9 was further associated with main pulmonary arterial stiffness evaluated by relative area change (R = -0.79, P < 0.01).TIMP-2 and TIMP-4 levels were further associated with the right pulmonary artery pulse wave velocity (R = 0.51, P = 0.03) and backward compression wave (R = 0.52, P = 0.02), respectively. MMPs and TIMPs warrant further clinically prognostic evaluation in conjunction with the conventional cardiac MRI hemodynamic indices.NEW & NOTEWORTHY Metalloproteinases have been associated with clinical outcomes in pulmonary hypertension and with specific pathological features of ventricular dysfunction and pulmonary arterial remodeling. In this study, we demonstrated that plasma circulating levels of metalloproteinases and their inhibitors are associated with standard cardiac MRI hemodynamic indices and with the markers of proximal pulmonary arterial stiffness. Particularly, MMP-9 and TIMP-2 were associated with several different markers of pulmonary arterial stiffness. These findings suggest the interplay between the extracellular matrix (ECM) remodeling and overall hemodynamic status in children with PAH might be assessed using the peripheral circulating MMP and TIMP levels.

Beneficial effect of voluntary physical exercise in Plakophilin2 transgenic mice.

Arrhythmogenic right ventricular cardiomyopathy is a hereditary, rare disease with an increased risk for sudden cardiac death. The disease-causing mutations are located within the desmosomal complex and the highest incidence is found in plakophilin2. However, there are other factors playing a role for the disease progression unrelated to the genotype such as inflammation or exercise. Competitive sports have been identified as risk factor, but the type and extend of physical activity as cofactor for arrhythmogenesis remains under debate. We thus studied the effect of light voluntary exercise on cardiac health in a mouse model. Mice with a heterozygous PKP2 loss-of-function mutation were given the option to exercise in a running wheel which was monitored 24 h/d. We analyzed structural and functional development in vivo by echocardiography which revealed that neither the genotype nor the exercise caused any significant structural changes. Ejection fraction and fractional shortening were not influenced by the genotype itself, but exercise did cause a drop in both parameters after 8 weeks, which returned to normal after 16 weeks of training. The electrophysiological analysis revealed that the arrhythmogenic potential was slightly higher in heterozygous animals (50% vs 18% in wt littermates) and that an additional stressor (isoprenaline) did not lead to an increase of arrhythmogenic events pre run or after 8 weeks of running but the vulnerability was increased after 16 weeks. Exercise-induced alterations in Ca handling and contractility of isolated myocytes were mostly abolished in heterozygous animals. No fibrofatty replacements or rearrangement of gap junctions could be observed. Taken together we could show that light voluntary exercise can cause a transient aggravation of the mutation-induced phenotype which is abolished after long term exercise indicating a beneficial effect of long term light exercise.

Mechanisms of phase-3 early afterdepolarizations and triggered activities in ventricular myocyte models.

Early afterdepolarizations (EADs) are abnormal depolarizations during the repolarizing phase of the action potential, which are associated with cardiac arrhythmogenesis. EADs are classified into phase-2 and phase-3 EADs. Phase-2 EADs occur during phase 2 of the action potential, with takeoff potentials typically above -40 mV. Phase-3 EADs occur during phase 3 of the action potential, with takeoff potential between -70 and -50 mV. Since the amplitude of phase-3 EADs can be as large as that of a regular action potential, they are also called triggered activities (TAs). This also makes phase-3 EADs and TAs much more arrhythmogenic than phase-2 EADs since they can propagate easily in tissue. Although phase-2 EADs have been widely observed, phase-3 EADs and TAs have been rarely demonstrated in isolated ventricular myocytes. Here we carry out computer simulations of three widely used ventricular action potential models to investigate the mechanisms of phase-3 EADs and TAs. We show that when the T-type Ca2+ current (ICa,T ) is absent (e.g., in normal ventricular myocytes), besides the requirement of increasing inward currents and reducing outward currents as for phase-2 EADs, the occurrence of phase-3 EADs and TAs requires a substantially large increase of the L-type Ca2+ current and the slow component of the delayed rectifier K+ current. The presence of ICa,T (e.g., in neonatal and failing ventricular myocytes) can greatly reduce the thresholds of these two currents for phase-3 EADs and TAs. This implies that ICa,T may play an important role in arrhythmogenesis in cardiac diseases.