Heart Research Articles

Изменения вариабельности сердечного ритма под влиянием сахароснижающей терапии у больных сахарным диабетом 2-го типа

Актуальность. Сахарный диабет (СД) признан Всемирной организацией здравоохранения неинфекционной эпидемией XXI века. Сердечно-сосудистая патология является основной причиной смерти этих пациентов. Цель исследования: изучить показатели вариабельности сердечного ритма (ВСР) у больных СД 2-го типа в зависимости от степени компенсации, а также их динамику после коррекции сахароснижающей терапии. Материалы и методы. Обследовано 53 пациента с СД 2-го типа и 10 практически здоровых людей контрольной группы. Лабораторное исследование включало определение С-пептида, гликированного гемоглобина (HbA1c), креатинина крови и микроальбумина в утренней порции мочи. Всем обследуемым проводилось длительное мониторирование гликемии параллельно с электрокардио­графией по Холтеру в течение 24 часов. Пациенты были разделены на две группы по уровню НbА1с: группа 1 (n = 23) с НbА1с ≤ 7 % и группа 2 (n = 30) с НbА1с > 7 %. Группы были разделены на подгруппы по отсутствию (а) или наличию (б) гипогликемии. Через 6 месяцев после модификации сахароснижающей терапии проводилось повторное обследование пациентов в том же объеме. Результаты. Группы и подгруппы больных СД 2-го типа существенно не отличались между собой по показателям ВСР (p > 0,05) и имели достоверное снижение показателей SDNN сутки, pNN50% сутки, VLF сутки, высокочастотный спектр (HF) ВРС сутки в сравнении с контрольной группой (р < 0,05). Суточные показатели общей мощности спектра (TP) существенно не отличались от контроля только в 1а подгруппе (р > 0,05). Значения низкочастотного спектра (LF) ВРС сутки были достоверно ниже по сравнению с контролем только при анализе всей основной группы больных СД 2-го типа. Показатель LF/HF сутки был достоверно выше контроля во всех подгруппах обеих групп (р < 0,05). Выводы. Пациенты с СД 2-го типа имели достоверно более низкие показатели ВСР, которые преимущественно касались SDNN, TP и VLF, HF и LF/HF. Через 6 месяцев после модификации сахароснижающей терапии получено достоверное увеличение практически всех показателей ВСР, кроме LF. Наибольшая динамика касалась повышения показателей pNN50% сутки (+50 %), pNN50% день (+50 %), RMSSD день (+43,5 %), RMSSD сутки (+28,6 %), HF (+133,1 % — сутки, +172,2 % — день, +57,5 % — ночь) и снижение отношения LF/HF (–42,9 % — сутки, –46,2 % — день, –32,7 % — ночь) (p < 0,05). Полученные результаты наглядно демонстрируют восстановление вагосимпатического баланса сердечно-сосудистой системы под влиянием компенсации углеводного обмена.

Особливості змін згортальної та фібринолітичної активності у пацієнтів з ішемічною хворобою серця із супутнім цукровим діабетом 2-го типу залежно від наявності діабетичних судинних ускладнень

Мета. Вивчення маркерів ендогенної коагуляції/фібринолізу у пацієнтів з ішемічною хворобою серця (ІХС) із супутнім цукровим діабетом (ЦД) 2-го типу та порівняння цих показників стосовно мікросудинних ускладнень. Матеріали та методи. Обстежено 54 пацієнти з ІХС і супутнім ЦД 2-го типу (розподілено на дві групи: з ускладненнями та без них), яких було госпіталізовано в кардіологічне та ендокринологічне відділення Київської клінічної лікарні на залізничному транспорті. Результати. При оцінюванні показників у двох групах (ІХС + ЦД 2-го типу та ІХС + ЦД 2-го типу + діабетичні ускладнення) у згортальній системі було виявлено подовжений протромбіновий час (на 7,64 % у пацієнтів без мікросудинних ускладнень і на 7,49 % — з ускладненнями) та значне підвищення вмісту фібриногену (на 36 та 42 % відповідно), але вірогідних змін між групами не було. Під час дослідження показників антикоагулянтної системи крові встановлено, що активність антитромбіну ІІІ і протеїну С у групі пацієнтів з ІХС і супутнім ЦД 2-го типу та діабетичними ускладненнями була нижчою (на 26 та 19,4 % відповідно) від значень контрольної групи. З боку фібринолітичної системи було виявлено значне пригнічення фібринолітичної активності плазми крові. Висновки. Отримані дані вказують на пригнічення фібринолітичної та антикоагулянтної активності плазми крові, що найбільше проявлялося у пацієнтів з ІХС і супутнім ЦД 2-го типу та мікросудинними ускладненнями. Зв’язок між фібринолізом і судинними захворюваннями залежить від стану судинного русла, що є значним збільшенням ризику розвитку макро- та мікросудинних уражень у пацієнтів з ІХС і супутнім ЦД 2-го типу.

Роль щитоподібної залози при метаболічному синдромі та в поєднанні з хронічною ішемічною хворобою серця та цукровим діабетом 2-го типу

Актуальність. Метаболічний синдром (МС), в основі якого лежать порушення ліпідного, вуглеводного обміну та гормонального статусу, зокрема функціонального стану гіпоталамо-гіпофізарної і тиреоїдної систем, є актуальною проблемою ХХІ століття, виступає як критерій тяжкості перебігу цукрового діабету (ЦД) 2-го типу та ішемічної хвороби серця (ІХС). Функціональний стан щитоподібної залози (ЩЗ) при МС дедалі частіше стає об’єктом досліджень багатьох вчених. Доведено, що в регуляції секреції інсуліну важливе місце посідають гормони ЩЗ, відома концепція гіпотиреозіндукованого МС. Субклінічний гіпотиреоз є незалежним фактором ризику атеросклерозу та гострого коронарного синдрому у жінок старшого віку. З огляду на це важливо приділити значну увагу дослідженню ЩЗ при коморбідній патології. Мета дослідження: вивчення функціонального стану щитоподібної залози при метаболічному синдромі та в поєднанні з хронічною ішемічною хворобою серця та цукровим діабетом 2-го типу в стані компенсації та декомпенсації. Матеріали та методи. Обстежено 319 пацієнтів із МС в поєднанні його з хронічною ІХС і ЦД 2-го типу в стані компенсації та декомпенсації. Залежно від наявності чи відсутності поєднаної патології сформовано шість груп пацієнтів із МС. Першу групу становили пацієнти з МС без ускладнень, другу групу — особи з МС та компенсованим ЦД 2-го типу, третю групу — хворі з МС та декомпенсованим ЦД 2-го типу, четверту групу — особи з МС у поєднанні з хронічною ІХС, п’яту групу — хворі з МС у поєднанні з хронічною ІХС та компенсованим ЦД 2-го типу, шосту групу — пацієнти з МС, хронічною ІХС та декомпенсованим ЦД 2-го типу. Пацієнтам визначали рівні тиреотропного гормону (ТТГ), кортизолу, вільного тироксину (вТ4), а також антитіл до тиреоглобуліну і тиреоїдної пероксидази з метою з’ясування функціонального стану ЩЗ і підтвердження її патогенетичної участі в цій комплексній патології. Результати. Для МС без ускладнень, а також для МС із хронічною ІХС і МС з хронічною ІХС та ЦД в стані компенсації властиве збільшення рівня ТТГ. Ці зміни вказують на наявність субклінічного гіпотиреозу, беручи до уваги нормальні рівні вТ4. Зрушення кортизолу при цьому характерні спочатку в сторону його підвищення при МС без ускладнень, з подальшим його зниженням. При МС з хронічною ІХС та декомпенсованому ЦД рівень ТТГ перебуває на рівні контрольної групи, що вказує на нормалізацію функції ЩЗ, з одночасним підвищенням рівня кортизолу. Висновки. Рівні ТТГ та кортизолу є маркерами тяжкості перебігу поєднаної патології (МС з хронічною ІХС та ЦД 2-го типу).

Localized Pulmonary Vein Scar Promotes Atrial Fibrillation in High Left Atrial Pressure.

BackgroundPulmonary vein (PV) ablation is unsuccessful in atrial fibrillation (AF) patients with high left atrial (LA) pressure. Increased atrial stretch by increased pressure is proarrhythmic for AF, and myocardial scar alters wall deformation. We hypothesized that localized PV scar is proarrhythmic for AF in high LA pressure.MethodsRadiofrequency energy was delivered locally in the right PV of healthy sheep. The sheep recovered for 4 months. Explanted hearts (n = 9 PV scar, n = 9 controls) were perfused with 1:4 blood:Tyrode’s solution in a four-chamber working heart setup. Programmed PV stimulation was performed during low (∼12 mmHg) and high (∼25 mmHg) LA pressure. An AF inducibility index was calculated based on the number of induction attempts and the number of attempts causing AF (run of ≥ 20 premature atrial complexes).ResultsIn high LA pressure, the presence of PV scar increased the AF inducibility index compared with control hearts (0.83 ± 0.20 vs. 0.38 ± 0.40 arb. unit, respectively, p = 0.014). The diastolic stimulation threshold in high LA pressure was higher (108 ± 23 vs. 77 ± 16 mA, respectively, p = 0.006), and its heterogeneity was increased in hearts with PV scar compared with controls. In high LA pressure, the refractory period was shorter in PV scar than in control hearts (178 ± 39 vs. 235 ± 48 ms, p = 0.011).ConclusionLocalized PV scar only in combination with increased LA pressure facilitated the inducibility of AF. This was associated with changes in tissue excitability remote from the PV scar. Localized PV ablation is potentially proarrhythmic in patients with increased LA pressure.

Breath-by-breath analysis of respiratory sinus arrhythmia in dogs

Dogs differ greatly in size, heart (HR) and breathing rates (BR). In addition, they have a clear Respiratory Sinus Arrhythmia (RSA) at rest. Therefore, better than any other mammalian species, dogs offer an opportunity to test whether resting RSA varies with body weight, HR or BR. Sequences of inter-beat-intervals (IBI, ms) a few-minutes long were collected in twenty-three resting dogs of different sizes, together with pneumograms. IBI variability was quantified by standard time-domain criteria. From beat-to-beat instantaneous heart rate (hR, beats/min), RSA was the difference between inspiratory peak (hR-peak) and expiratory trough (hR-trough), in percent of mean HR. RSA averaged 40.1 % ±4.5, or more than three times that of humans, with large inter-animal variability. On average, RSA contributed 38 % of the total IBI variability. RSA did not differ between sexes and did not correlate with body weight. It had modest negative correlations with HR (P < 0.05) and BR (P < 0.05), and a very strong negative correlation with hR-trough (P < 0.001). In two separate dogs, during panting, RSA was absent. In the transition from resting to panting, RSA continued like at rest for several breaths, despite the tachypnea, underlying the importance of central mechanisms in the origin of RSA. In conclusion, RSA in dogs is very large and explains less than half of their sinus arrhythmia. Rather than HR, BR or hR-peak, changes in the vago-sympathetic control, represented by hR-trough, are the most likely source of variability of RSA among subjects.

An integrative multiscale view of early cardiac looping.

The heart is the first organ to form and function during the development of an embryo. Heart development consists of a series of events believed to be highly conserved in vertebrates. Development of heart begins with the formation of the cardiac fields followed by a linear heart tube formation. The straight heart tube then undergoes a ventral bending prior to further bending and helical torsion to form a looped heart. The looping phase is then followed by ballooning, septation, and valve formation giving rise to a four-chambered heart in avians and mammals. The looping phase plays a central role in heart development. Successful looping is essential for proper alignment of the future cardiac chambers and tracts. As aberrant looping results in various congenital heart diseases, the mechanisms of cardiac looping have been studied for several decades by various disciplines. Many groups have studied anatomy, biology, genetics, and mechanical processes during heart looping, and have proposed multiple mechanisms. Computational modeling approaches have been utilized to examine the proposed mechanisms of the looping process. Still, the exact underlying mechanism(s) controlling the looping phase remain poorly understood. Although further experimental measurements are obviously still required, the need for more integrative computational modeling approaches is also apparent in order to make sense of the vast amount of experimental data and the complexity of multiscale developmental systems. Indeed, there needs to be an iterative interaction between experimentation and modeling in order to properly find the gap in the existing data and to validate proposed hypotheses. This article is categorized under: Cardiovascular Diseases > Genetics/Genomics/Epigenetics Cardiovascular Diseases > Computational Models Cardiovascular Diseases > Molecular and Cellular Physiology.

The Clinical Outcome of Patients Undergoing Fontan Surgery; Over 10 Years of Experience in a Single Center

Background: The modified Fontan operation is one of the essential surgical techniques in children with congenital heart diseases. Therefore, we sought to identify the characteristics as well as the early and late outcomes of patients who have undergone Fontan operation during more than 10 years. Methods: This study was conducted with a cross-sectional design. The medical records of 52 patients who underwent modified Fontan operation from March 21th, 2006 to March 20th, 2018, at Tabriz Children's Hospital including the bassline, clinical and surgical data were extracted retrospectively reviewed. Patients were invited for follow up visits and clinical examination and echocardiographic evaluations were conducted. Findings: The most prevalent heart anomaly was tricuspid valve disorders (28 cases, 51.9%). The majority of patients (42 cases, 80.2 %) underwent intracardiac lateral tunnel Fontan. The most prevalent complications were prolonged pleural effusion and neurologic events (each one in 10 cases, 19.2%). The in-hospital mortality rate was 15.3%. The patients were followed for a median 7 years. The survival of those successfully followed was 74.5 percent in 5 years. The most common valvular disorder was mitral valve regurgitation (MR), which was present in 84% of cases. The group of patients with single ventricle had a significantly higher mortality rate than the other groups (P = 0.018). Conclusion: The clinical data of patients who have undergone Fontan surgery was reviewed. Despite acceptable survival, patients remain at risk for morbid events in particular prolonged pleural effusion and neurologic events. Moreover, patients with Fontan circulation should be strictly followed to investigate the development of MR and to timely repair in severe cases to prevent further deterioration. Of note, due to some limitations of our study, further multi-centric studies are warranted to confirm our findings.

B-PO03-023 HIS BUNDLE PACING ACHIEVES BETTER VENTRICULAR SYNCHRONY THAN BIVENTRICULAR PACING IN PATIENTS WITH SCAR IN THE LEFT VENTRICULAR FREE WALL

His bundle pacing (HBP) is a novel pacing strategy for cardiac resynchronization therapy (CRT). HBP has been associated with improved response compared to conventional CRT and biventricular endocardial (BIV-endo) pacing. The effect of HBP in patients with scar has however not yet been studied. To investigate differences in response between HBP and BIV-endo pacing in patients with scar in the left ventricular (LV) free wall. We computed ventricular activation on 24 four-chamber heart meshes with Purkinje networks exhibiting left bundle branch block (LBBB). We mapped a LV free wall scar and border zone geometry from a pre-existing LV mesh [Fig A]. HBP and BIV-endo pacing were simulated in the presence and in the absence of scar. Response from baseline was quantified with LV 95% activation time (LV-AT 95) and biventricular dyssynchronous index (BIV-DI), computed as the standard deviation of ventricular activation times. BIV-DI was significantly reduced during HBP compared to BIV-endo pacing both in the presence (-13±2ms vs -15±2ms, p<0.05) and in the absence (-9±2 ms vs -11±2ms, p<0.05) of scar in the LV lateral wall [Fig B]. LV-AT 95 was also significantly shorter during HBP compared to BIV-endo pacing (scar: -31±8ms vs -54±9ms, p<0.05; no scar: -22±7ms vs -44±7ms, p<0.05) [Fig C]. HBP restores native synchronous activation by recruiting the viable fast-conducting Purkinje system. LBBB patients with lateral scar therefore experience better ventricular resynchronization using HBP compared to BIV-endo pacing.

Causes of altered ventricular mechanics in hypertrophic cardiomyopathy: an in-silico study

BackgroundHypertrophic cardiomyopathy (HCM) is typically caused by mutations in sarcomeric genes leading to cardiomyocyte disarray, replacement fibrosis, impaired contractility, and elevated filling pressures. These varying tissue properties are associated with certain strain patterns that may allow to establish a diagnosis by means of non-invasive imaging without the necessity of harmful myocardial biopsies or contrast agent application. With a numerical study, we aim to answer: how the variability in each of these mechanisms contributes to altered mechanics of the left ventricle (LV) and if the deformation obtained in in-silico experiments is comparable to values reported from clinical measurements.MethodsWe conducted an in-silico sensitivity study on physiological and pathological mechanisms potentially underlying the clinical HCM phenotype. The deformation of the four-chamber heart models was simulated using a finite-element mechanical solver with a sliding boundary condition to mimic the tissue surrounding the heart. Furthermore, a closed-loop circulatory model delivered the pressure values acting on the endocardium. Deformation measures and mechanical behavior of the heart models were evaluated globally and regionally.ResultsHypertrophy of the LV affected the course of strain, strain rate, and wall thickening—the root-mean-squared difference of the wall thickening between control (mean thickness 10 mm) and hypertrophic geometries (17 mm) was >10%. A reduction of active force development by 40% led to less overall deformation: maximal radial strain reduced from 26 to 21%. A fivefold increase in tissue stiffness caused a more homogeneous distribution of the strain values among 17 heart segments. Fiber disarray led to minor changes in the circumferential and radial strain. A combination of pathological mechanisms led to reduced and slower deformation of the LV and halved the longitudinal shortening of the LA.ConclusionsThis study uses a computer model to determine the changes in LV deformation caused by pathological mechanisms that are presumed to underlay HCM. This knowledge can complement imaging-derived information to obtain a more accurate diagnosis of HCM.

Outcomes of hepatitis C virus nucleic acid testing positive donors in aviremic recipients with delayed direct-acting antiviral initiation.

The use of allografts from hepatitis C virus (HCV) Nucleic Acid Testing (NAT)+ donors into HCV NAT- recipients has been reported to be efficacious in a handful of studies. However, these studies have not reflected real-world practice where the initiation of direct-acting antivirals (DAA) is dependent on insurance coverage. A single-center, retrospective chart review of HCV NAT- recipients who underwent solid organ transplantation (SOT) from a HCV NAT+ donor between April 1, 2019 and May 27, 2020 was conducted. Sixty-one HCV NAT- patients underwent SOT with a HCV NAT+ organ, with 59 transplant recipients included for evaluation: 22 kidney (KT), 18 liver (LiT), 10 heart (HT), nine lung (LuT). HCV transmission occurred in 100% of recipients. Average time to DAA initiation was POD 46.3 ± 25 days. SVR12 was achieved in 98% (56/57; two patients ineligible for analysis). Treatment failure occurred in one LuT on glecaprevir/pibrentasvir with P32del and Q80K mutations. No patients developed fibrosing cholestatic hepatitis. Two patients died, secondary to anastomotic complication (LuT) and pulmonary embolism (HT). Clinically significant rejection was diagnosed and treated in two HT (one patient with ACR2 and one with ACR2/pAMR2) and one LiT (RAI 5/9). Six patients (10.2%) had documented adverse effects attributed to DAA therapy, primarily gastrointestinal.

Long-Term Cardiac, Vascular and Hypertensive Safety of Bosutinib in Patients with Philadelphia Chromosome-Positive (Ph+) Leukemia Resistant or Intolerant to Prior Therapy

Long-Term Cardiac, Vascular and Hypertensive Safety of Bosutinib in Patients with Philadelphia Chromosome-Positive (Ph+) Leukemia Resistant or Intolerant to Prior Therapy

Fully Retargeted, Myeloma-Specific Oncolytic Measles Viruses.

We previously reported that attenuated measles viruses have potent anti-tumor activity in primary myeloma cells and myeloma xenograft models. The viruses are selectively oncolytic because they cause extensive cell to cell fusion via CD46, a membrane complement regulatory protein that is more highly expressed on myeloma cells than on normal cells. A phase I clinical trial is planned at Mayo Clinic using an oncolytic measles virus engineered to express the thyroidal sodium iodide symporter gene (MV-NIS). Expected toxicities of MV-NIS include a mild measles-like illness due to residual infection of normal host cells via either of the two natural virus receptors, CD46 and SLAM. To facilitate the development of fully retargeted oncolytic measles viruses we recently developed the pseudoreceptor system “STAR”, which allows rescue and propagation of targeted viruses with modified H proteins that no longer bind to the native measles receptors (Nakamura T. et. al., Nature Biotechnology, 2005). Using the STAR system, we have now generated fully retargeted oncolytic measles viruses against two targets, CD38 or HM1.24 that are highly expressed on the surface of multiple myeloma cells. CD38 is expressed abundantly on myeloma plasma cells but is also expressed in a variety of normal human cells, such as myeloid progenitors and activated T cells. The HM1.24 antigen is highly expressed on terminally differentiated B-cells (including myeloma cells) and is not found on liver, spleen, kidney, or heart. To facilitate evaluation of the receptor specificity of the recombinant viruses, they were each constructed with an additional transgene insert coding for green fluorescent protein (GFP). Efficient viral incorporation of each of the recombinant H proteins was demonstrated by immunoblotting of pelleted virions. CHO cells were transfected with each of the targeted receptors and then infected with each of the targeted viruses. As expected, each virus demonstrated the predicted host range properties and was blind to CD46 and SLAM receptors, but efficiently entered cells through the respective targeted receptor. In addition, these retargeted viruses demonstrated myeloma-specific infection, syncytium formation and cytotoxicity for multiple myeloma cell lines RPIM8226 and KAS-6/1, but not on receptor-negative control cells such as K562 human erythroleukemic cells. These fully retargeted oncolytic measles viruses are promising candidates that may provide the basis for safer and more effective virotherapy in multiple myeloma.

Automated detection of chronic kidney disease using image fusion and graph embedding techniques with ultrasound images

Chronic Kidney disease (CKD) is a progressive disease affecting more than twenty million individuals in the United States. Disease progression is often characterized by complications such as cardiovascular diseases, anemia, hyperlipidemia and metabolic bone diseases etc., Based on estimated GFR values, the disease is categorized in 5 stages which significantly influence patient outcome. Cardiovascular ultrasound (US) (echocardiography) imagery demonstrate significant hemodynamic alterations that are secondary to CKD in the form of volume/ pressure overload. As the CKD pathology directly impacts cardiovascular disease, the US imaging shows structural and hemodynamic adaptation. Hence, the development of a computer-aided diagnosis (CAD) model to predict CKD would be desirable, and can potentially improve treatment. Several prior studies have utilized kidney features for quantitative analysis. In this paper, acquisition of the four-chamber heart US image is employed to predict CKD stage. The method combines image and feature fusion techniques under a graph embedding framework to characterize heart chamber properties. Moreover, a support vector machine is incorporated to classify heart US images. The proposed method achieved 100 % accuracy for a two-class system, and 99.09 % accuracy for a multi-class categorization scenario. Hence, our proposed CAD tool is deployable in both clinic and hospital settings for computer-aided screening of CKD.

Differential Spatio-Temporal Regulation of T-Box Gene Expression by microRNAs during Cardiac Development.

Cardiovascular development is a complex process that starts with the formation of symmetrically located precardiac mesodermal precursors soon after gastrulation and is completed with the formation of a four-chambered heart with distinct inlet and outlet connections. Multiple transcriptional inputs are required to provide adequate regional identity to the forming atrial and ventricular chambers as well as their flanking regions; i.e., inflow tract, atrioventricular canal, and outflow tract. In this context, regional chamber identity is widely governed by regional activation of distinct T-box family members. Over the last decade, novel layers of gene regulatory mechanisms have been discovered with the identification of non-coding RNAs. microRNAs represent the most well-studied subcategory among short non-coding RNAs. In this study, we sought to investigate the functional role of distinct microRNAs that are predicted to target T-box family members. Our data demonstrated a highly dynamic expression of distinct microRNAs and T-box family members during cardiogenesis, revealing a relatively large subset of complementary and similar microRNA–mRNA expression profiles. Over-expression analyses demonstrated that a given microRNA can distinctly regulate the same T-box family member in distinct cardiac regions and within distinct temporal frameworks, supporting the notion of indirect regulatory mechanisms, and dual luciferase assays on Tbx2, Tbx3 and Tbx5 3′ UTR further supported this notion. Overall, our data demonstrated a highly dynamic microRNA and T-box family members expression during cardiogenesis and supported the notion that such microRNAs indirectly regulate the T-box family members in a tissue- and time-dependent manner.

Prenatal alcohol exposure causes structural and functional cardiac defects, which can be prevented with folate supplementation

Increased regurgitant blood flow has been linked to endocardial cushion defects and resultant congenital heart diseases (CHDs). Prenatal alcohol exposure (PAE) has been shown to alter early blood flow resulting in abnormal endocardial cushions and CHDs. Compounds, including folic acid (FA), mitigate PAE effects and prevent CHDs, but few studies have assessed their effects on blood flow. We modeled binge drinking in avian embryos at gastrulation. Embryos were exposed to ethanol alone, FA (3.2 μg/egg) alone, and the two simultaneously. We quantified in cardiac looping stages (equivalent to 4 weeks of human gestation) regurgitant blood flow with Doppler optical coherence tomography (OCT) and endocardial cushion volumes using OCT imaging. Incidences of abnormal body curvature and heart rates were also measured. Embryos exposed to ethanol showed significantly increased regurgitant blood flow compared to controls, while embryos given FA with ethanol had significantly reduced regurgitant blood flow but did not return to control levels. Ethanol exposure led to significantly smaller, abnormal endocardial cushions and the addition of FA improved their size, but they remained smaller than controls. Abnormal body curvatures after PAE were reduced in incidence but not fully prevented by FA. FA supplementation partially alleviated PAE induced abnormal cardiovascular function and morphology. Normal blood flow and endocardial cushions are both required to produce a healthy four-chambered heart. These findings support that FA supplementation should begin early in pregnancy to prevent heart as well as neural tube defects. Investigations into the efficacy of combinations of compounds to prevent PAE-induced defects is warranted.

Linking statistical shape models and simulated function in the healthy adult human heart.

Cardiac anatomy plays a crucial role in determining cardiac function. However, there is a poor understanding of how specific and localised anatomical changes affect different cardiac functional outputs. In this work, we test the hypothesis that in a statistical shape model (SSM), the modes that are most relevant for describing anatomy are also most important for determining the output of cardiac electromechanics simulations. We made patient-specific four-chamber heart meshes (n = 20) from cardiac CT images in asymptomatic subjects and created a SSM from 19 cases. Nine modes captured 90% of the anatomical variation in the SSM. Functional simulation outputs correlated best with modes 2, 3 and 9 on average (R = 0.49 ± 0.17, 0.37 ± 0.23 and 0.34 ± 0.17 respectively). We performed a global sensitivity analysis to identify the different modes responsible for different simulated electrical and mechanical measures of cardiac function. Modes 2 and 9 were the most important for determining simulated left ventricular mechanics and pressure-derived phenotypes. Mode 2 explained 28.56 ± 16.48% and 25.5 ± 20.85, and mode 9 explained 12.1 ± 8.74% and 13.54 ± 16.91% of the variances of mechanics and pressure-derived phenotypes, respectively. Electrophysiological biomarkers were explained by the interaction of 3 ± 1 modes. In the healthy adult human heart, shape modes that explain large portions of anatomical variance do not explain equivalent levels of electromechanical functional variation. As a result, in cardiac models, representing patient anatomy using a limited number of modes of anatomical variation can cause a loss in accuracy of simulated electromechanical function.

Using Chicken Embryo as a Powerful Tool in Assessment of Developmental Cardiotoxicities.

Chicken embryos are a classical model in developmental studies. During the development of chicken embryos, the time window of heart development is well-defined, and it is relatively easy to achieve precise and timely exposure via multiple methods. Moreover, the process of heart development in chicken embryos is similar to mammals, also resulting in a four-chambered heart, making it a valuable alternative model in the assessment of developmental cardiotoxicities. In our lab, the chicken embryo model is routinely used in the assessment of developmental cardiotoxicities following exposure to various environmental pollutants, including per- and polyfluoroalkyl substances (PFAS), particulate matter (PMs), diesel exhaust (DE) and nano materials. The exposure time can be freely selected based on the need, from the beginning of development (embryonic day 0, ED0) all the way to the day prior to hatch. The major exposure methods include air-cell injection, direct microinjection, and air-cell inhalation (originally developed in our lab), and the currently available endpoints include cardiac function (electrocardiography), morphology (histological assessments) and molecular biological assessments (immunohistochemistry, qRT-PCR, western blotting, etc.). Of course, the chicken embryo model has its own limitations, such as limited availability of antibodies. Nevertheless, with more laboratories starting to utilize this model, it can be used to make significant contributions to the study of developmental cardiotoxicities.

Epidemiology of Infections in Adult Heart and Lung Transplant Recipients: A Single Center Experience

<h3>Purpose</h3> Infectious complications are a common cause of morbidity and mortality among solid organ transplant (SOT) recipients. Understanding their epidemiology and outcomes is vital when planning preventative strategies. <h3>Methods</h3> We conducted a retrospective study of selected infections diagnosed in patients receiving heart (HT) or lung transplantation (LT) from January 2013 to June 2018. We examined the incidence of infections and outcomes one-year post-transplant. <h3>Results</h3> We reviewed 217 patients that underwent heart or lung transplantation (109 HT, 108 LT) at our center over a five-year period. Median follow-up was 2.5 years, median age was 51, 68% were males, and 75%-white. Indication for transplant in HT recipients was predominantly idiopathic dilated cardiomyopathy (22%) and ischemic dilated cardiomyopathy (11%). Indications for lung transplants included idiopathic pulmonary fibrosis (19%), chronic obstructive pulmonary disease (9%), and cystic fibrosis (7%). Within the first year post-transplant, 46% of transplant recipients had defined infections (56% LT, 35% HT)(Table). In the HT group, CMV (14%) respiratory viruses (9%), aspergillosis (6%), and <i>Clostridioides difficile</i> infection (6%) were most common. In the LT group, respiratory viruses (39%), aspergillosis (21%), <i>Clostridioides difficile</i> (14%), and extended-spectrum beta-lactamase producing bacteria (9%) were most common. All-cause mortality at one year was 5% and 10% in the HT and LT recipients, respectively. There was no infection-related mortality at one year in both groups. <h3>Conclusion</h3> Despite standard infection prevention strategies, nearly half of all HT and LT recipients had identified infections at the end of one year. The most frequent infectious process was respiratory viral infections, particularly in the LT group. Further studies identifying associated risk factors and additional preventative measures may be needed to reduce these infections.

Impact of Transplanting Hepatitis C Nucleic Acid Testing Positive (NAT+) Donors to Hepatitis C Virus NAT- Cardiothoracic Recipients

<h3>Purpose</h3> The purpose of this study is to assess the clinical impact of utilizing HCV NAT+ donors in aviremic heart (HT) and lung (LT) transplant recipients. <h3>Methods</h3> A single-center, retrospective chart review was conducted on patients who received a HT or LT between 4/1/19-5/27/20. HCV antibody - and NAT- recipients of a HCV NAT+ graft were included in the analysis. <h3>Results</h3> Nineteen HCV NAT- patients underwent cardiothoracic transplantation (CT) with a HCV NAT+ organ (10 HT and 9 LT) and were included for evaluation; 47.4% male, average age 58 ± 7.9 years, 73.7% white. HCV transmission occurred in 100% of recipients. Average time to direct acting antiviral (DAA) initiation was 46 ± 20.7 days after transplant. SVR12 was achieved in 93.3% (14/15; 4 patients have not completed 12-week follow up post DAA completion). Treatment failure occurred in 1 LT patient with P32del mutation on glecaprevir/pibrentasvir, requiring alternative therapy (sofosbuvir/velpatasvir/voxilaprevir and ribavirin). 84.2% of patients developed post-transplant liver dysfunction. No patients developed fibrosing cholestatic hepatitis. Two patients died, 1 due to anastomotic complication (LT) and 1 due to pulmonary embolism (HT). De novo donor specific antibodies were present in 1 HT and 2 LT recipients, developing 4 days and a median of 137.5 (56-219) days post-transplant, respectively. Clinically significant rejection was identified and treated in 1 HT patient (ACR2). No episodes of rejection were identified in LT recipients. Five patients (26.3%) had documented DAA related adverse effects, including gastrointestinal, fatigue, orthostatic hypotension, and nail discoloration. <h3>Conclusion</h3> A high SVR12 rate was achieved in HCV NAT donor +/recipient - CT, who were initiated on DAA therapy after insurance approval. These results are reflective of real-word experience for patients not included in clinical trials. Few reported clinically significant episodes of rejection or DAA adverse effects occurred.

Immunosuppressive Treatment Does Not Prevent Humoral and Cellular Virus-Specific Immunity in Heart or Lung Recipients with SARS-CoV-2 Pneumonia

PurposeClinical characteristics of SARS-CoV-2 infection and virus-specific humoral and cellular response were analyzed in 4 heart (HR) and 3 lung (LR) Tx recipients in standard triple immunosuppressive regimen.MethodsSARS-CoV-2 infection was diagnosed by real-time PCR on naso-pharingeal swabs (NPS). T-cell response to structural antigens Spike (S), Envelope (E), Membrane (M) and Nucleocapsid (N) was evaluated by PBMC stimulation with overlapping peptides spanning the entire viral proteins and subsequent detection of cell activation markers CD137 and CD25. Serum IgG antibody to S and N, and IgA antibody to S were determined by ELISA.ResultsThree patients developed SARS-CoV-2 infection early (<3 months) and four patients late (>3 years) after Tx. One HR was asymptomatic, one LR presented only gastrointestinal symptoms, and five patients developed dyspnea with radiologic signs of interstitial pneumonia (in one HR ICU admittance was necessary. All patients recovered from SARS-CoV-2 infection, with viral clearance from NPS within 3 weeks. However, two HR (one early and one late HR) died at 6 and 4 months after infection because of multi-organ failure and sudden death. Both deaths were considered as unrelated to SARS-CoV2 infection. Patients who had no lung involvement did not develop specific antibody response, while all the other five patients developed IgG and IgA antibodies to S, and IgG antibody to N, within 2 months after infection. All the symptomatic patients developed a detectable CD4+ T-cell response to two or more antigens. Four patients were subsequently examined >3 months after infection, showing the persistence of IgG and IgA antibodies to S and a decline of IgG antibody to N, while CD4+ T-cell response to N was maintained. Timing of Tx did not affect the occurrence of virus specific immunity.ConclusionAlthough this series is small, the data indicate that immunosuppression does not prevent the development of a specific humoral and cellular anti-SARS-CoV-2 response, more likely in patients who have experienced clinically relevant pneumonia. These preliminary data encourage the maintenance of regular follow-up to monitor the persistence of immune response and the potential occurrence of SARS-CoV-2-related sequelae in heart and lung recipients.