Review on Kidney-Liver Crosstalk: Pathophysiology of Their Disorders.

Kidney-liver crosstalk plays a crucial role in normal and certain pathological conditions. In pathologic states, both renal-induced liver damage and liver-induced kidney diseases may happen through these kidney-liver interactions. This bidirectional crosstalk takes place through the systemic conditions that mutually influence both the liver and kidneys. Ischemia and reperfusion, cytokine release and pro-inflammatory signaling pathways, metabolic acidosis, oxidative stress, and altered enzyme activity and metabolic pathways establish the base of this interaction between the kidneys and liver. In these concomitant kidney-liver diseases, the survival rates strongly correlate with early intervention and treatment of organ dysfunction. Proper care of a nephrologist and hepatologist and the identification of pathological conditions using biomarkers at early stages are necessary to prevent the complications induced by this complex and potentially vicious cycle. Therefore, understanding the characteristics of this crosstalk is essential for better management. In this review, we discussed the available literature concerning the detrimental effects of kidney failure on liver functions and liver-induced kidney diseases.

Hypertension in COVID-19, A Risk Factor for Infection or A Late Consequence?

There are a lot of data about the correlation of SARS-CoV-2 infection and hypertension (HTN), but most of them are in the increased risk of morbidity and mortality in patients with HTN. SARS-CoV-2 can interfere with host cells through the renin-angiotensin system (RAS) via the angiotensin-converting enzyme 2 (ACE2) receptor. RAS activation is associated with pro-inflammatory effects through the ACE/Ang II/ Angiotensin II type 1 receptor (AT1R) pathway or anti-inflammatory effects through ACE2/Ang1-7/Mas axis. In the current paper, we discuss the pathophysiology of newly diagnosed HTN and its effect on morbidity in patients with coronavirus disease 2019 (COVID-19).

Clinical and laboratory findings following transplantation of allogeneic adipose-derived mesenchymal stromal cells in knee osteoarthritis, a brief report.

BACKGROUND: Mesenchymal stromal cells (MSCs) injection has been proposed as an innovative treatment for knee osteoarthritis (KOA). Since, allogeneic MSCs can be available as off-the-shelf products, they are preferable in regenerative medicine. Among different sources for MSCs, adipose-derived MSCs (AD-MSCs) appear to be more available. METHODS: Three patients with KOA were enrolled in this study. A total number of 100 × 106 AD-MSCs was injected intra-articularly, per affected knee. They were followed up for 6 months by the assessment of clinical outcomes, magnetic resonance imaging (MRI), and serum inflammatory biomarkers. RESULTS: The primary outcome of this study was safety and feasibility of allogeneic AD-MSCs injection during the 6 months follow-up. Fortunately, no serious adverse events (SAEs) were reported. Assessment of secondary outcomes of visual analogue scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and knee osteoarthritis outcome score (KOOS) indicated improvement in all patients. Comparison between baseline and endpoint findings of MRI demonstrated a slight improvement in two patients. In addition, decrease in serum cartilage oligomeric matrix protein (COMP) and hyaluronic acid (HA) indicated the possibility of reduced cartilage degeneration. Moreover, quantification of serum interleukin-10 (IL-10) and interleukin-6 (IL-6) levels indicated that the host immune system immunomodulated after infusion of AD-MSCs. CONCLUSION: Intra-articular injection of AD-MSCs is safe and could be effective in cartilage regeneration in KOA. Preliminary assessment after six-month follow-up suggests the potential efficacy of this intervention which would need to be confirmed in randomized controlled trials on a larger population. TRIAL REGISTRATION: This study was registered in the Iranian registry of clinical trials (https://en.irct.ir/trial/46) in 24 April 2018 with identifier IRCT20080728001031N23.

A Novel Missense Variant in Actin Binding Domain of MYH7 Is Associated With Left Ventricular Noncompaction.

Cardiomyopathies are a group of common heart disorders that affect numerous people worldwide. Left ventricular non-compaction (LVNC) is a structural disorder of the ventricular wall, categorized as a type of cardiomyopathy that mostly caused by genetic disorders. Genetic variations are underlying causes of developmental deformation of the heart wall and the resultant contractile insufficiency. Here, we investigated a family with several affected members exhibiting LVNC phenotype. By whole-exome sequencing (WES) of three affected members, we identified a novel heterozygous missense variant (c.1963C>A:p.Leu655Met) in the gene encoding myosin heavy chain 7 (MYH7). This gene is evolutionary conserved among different organisms. We identified MYH7 as a highly enriched myosin, compared to other types of myosin heavy chains, in skeletal and cardiac muscles. Furthermore, MYH7 was among a few classes of MYH in mouse heart that highly expresses from early embryonic to adult stages. In silico predictions showed an altered actin-myosin binding, resulting in weaker binding energy that can cause LVNC. Moreover, CRISPR/Cas9 mediated MYH7 knockout in zebrafish caused impaired cardiovascular development. Altogether, these findings provide the first evidence for involvement of p.Leu655Met missense variant in the incidence of LVNC, most probably through actin-myosin binding defects during ventricular wall morphogenesis.

State-of-the-art modalities in cardio-oncology: insight from a nuclear medicine approach.

Cancer and cardiovascular disease are the most significant causes of morbidity and mortality worldwide. Although the cancer survival rate has increased due to improved treatment approaches, especially targeted therapy, some side effects such as cardiotoxicity decrease the efficiency of the clinical outcome. Radiation therapy and chemotherapy have a long-established history of potential cardiotoxic effects. A new multi-disciplinary and translational field known as cardio-oncology has been developed for the identification, prevention, and treatment of cardiovascular dysfunctions associated with cancer treatment approaches. One of the important tools for detecting and monitoring cardiotoxic effects is non-invasive nuclear cardiac imaging techniques. Cardiac nuclear imaging modalities especially recent findings positron emission tomography (PET) tracers have a quintessential role in the early detection of cardiovascular disorders. Moreover, comprehensive studies are required to investigate novel nuclear medicine treatment approaches such as peptide receptor radionuclide therapy (PRRT), fibroblast activation protein (FAP), and chemokine receptor (CXCR) targeting probes for possible cardiac side effects that play important roles in the treatment of malignancies.

A Novel Insight into Endothelial and Cardiac Cells Phenotype in Systemic Sclerosis Using Patient-Derived Induced Pluripotent Stem Cell.

OBJECTIVE: Systemic sclerosis (SSc) is a connective tissue disease associated with vascular damage and multi organ fibrotic changes with unknown pathogenesis. Most SSc patients suffer from defective angiogenesis/vasculogenesis and cardiac conditions leading to high mortality rates. We aimed to investigate the cardiovascular phenotype of SSc by cardiogenic differentiation of SSc induced pluripotent stem cells (iPSC). MATERIALS AND METHODS: In this experimental study, we generated iPSC from two diffuse SSc patients, followed by successful differentiation into endothelial cells (ECs) and cardiomyocytes (CMs). RESULTS: SSc-derived EC (SSc-EC) expressed KDR, a nearly EC marker, similar to healthy control-EC (C1-EC). After sorting and culturing KDR+ cells, the resulting EC expressed CD31, a late endothelial marker, but vascular endothelial (VE)-cadherin expression markedly dropped resulting in a functional defect as reflected in tube formation failure of SSc-EC. Interestingly, upregulation of SNAI1 (snail family transcriptional repressor 1) was observed in SSc-EC which might underlie VE-cadherin downregulation. Furthermore, SSc-derived CM (SSc-CM) successfully expressed cardiacspecific markers including ion channels, resulting in normal physiological behavior and responsiveness to cardioactive drugs. CONCLUSION: This study provides an insight into impaired angiogenesis observed in SSc patients by evaluating in vitro cardiovascular differentiation of SSc iPSC.

Oxygen-rich Environment Ameliorates Cell Therapy Outcomes of Cardiac Progenitor Cells for Myocardial Infarction.

To some extent, cell therapy for myocardial infarction (MI) has supported the idea of cardiac repair; however, further optimizations are inevitable. Combined approaches that comprise suitable cell sources and supporting molecules considerably improved its effect. Here, we devised a strategy of simultaneous transplantation of human cardiac progenitor cells (CPCs) and an optimized oxygen generating microparticles (MPs) embedded in fibrin hydrogel, which was injected into a left anterior descending artery (LAD) ligating-based rat model of acute myocardial infarction (AMI). Functional parameters of the heart, particularly left ventricular systolic function, markedly improved and reached pre-AMI levels. This functional restoration was well correlated with substantially lower fibrotic tissue formation and greater vascular density in the infarct area. Our novel approach promoted CPCs retention and differentiation into cardiovascular lineages. We propose this novel co-transplantation strategy for more efficient cell therapy of AMI which may function by providing an oxygen-rich microenvironment, and thus regulate cell survival and differentiation.

Heart Repair Induced by Cardiac Progenitor Cell Delivery within Polypyrrole-Loaded Cardiogel Post-ischemia.

Myocardial infarction (MI) irreversibly injures the heart tissue. Cardiovascular tissue engineering has been developed as a promising therapeutic approach for post-MI repair. Previously, we discovered the ability of a polypyrrole (PPy)-incorporated cardiogel (CG) for improvement of maturity and functional synchrony of rat neonatal cardiomyocytes. Here, we used the cross-linked form of PPy-incorporated CG (CG-PPy), in order to improve electromechanical properties of scaffold, for application in cardiac progenitor cell (CPC) transplantation on post-MI rat hearts. Improved mechanical property and electrical conductivity (sixfold) were evident in the cross-linked CG-PPy (P1) compared to cross-linked CG (C1) scaffolds. Transplantation of CPC-loaded P1 (P1-CPC) resulted in substantial improvement of cardiac functional properties. Furthermore, lower fibrotic tissue and higher CPC retention were observed. The grafted cells showed cardiomyocyte characteristics when stained with human cardiac troponin T and connexin43 antibodies, while neovessel formation was similarly prominent. These findings highlight the therapeutic promise of the P1 scaffold as a CPC carrier for functional restoration of the heart post-MI.

Vascular endothelial growth factor sustained delivery augmented cell therapy outcomes of cardiac progenitor cells for myocardial infarction.

Cell therapy has become a novel promising approach for improvement of cardiac functional capacity in the instances of ventricular remodeling and fibrosis caused by episodes of coronary artery occlusion and hypoxia. The challenge toward enhancing cell engraftment as well as formation of functional tissue, however, necessitated combinatorial approaches. Here, we complemented human embryonic stem cell-derived cardiac progenitor cell (hESC-CPC) therapy by heparin-conjugated, vascular endothelial growth factor (VEGF)-loaded fibrin hydrogel as VEGF delivery system. Transplantation of these cardiac committed cells along with sustained VEGF release could surpass the cardiac repair effects of each constituent alone in a rat model of acute myocardial infarction. The histological sections of rat hearts revealed improved vascularization as well as inclusion of hESC-CPC-derived cardiomyocytes, endothelial, and smooth muscle cells in host myocardium. Thus, co-transplantation of hESC-CPC and proangiogenic factor by a suitable delivery rate may resolve the shortcomings of conventional cell therapy.

A Cell-Free SDKP-Conjugated Self-Assembling Peptide Hydrogel Sufficient for Improvement of Myocardial Infarction.

Biomaterials in conjunction with stem cell therapy have recently attracted attention as a new therapeutic approach for myocardial infarction (MI), with the aim to solve the delivery challenges that exist with transplanted cells. Self-assembling peptide (SAP) hydrogels comprise a promising class of synthetic biomaterials with cardiac-compatible properties such as mild gelation, injectability, rehealing ability, and potential for sequence modification. Herein, we developed an SAP hydrogel composed of a self-assembling gel-forming core sequence (RADA) modified with SDKP motif with pro-angiogenic and anti-fibrotic activity to be used as a cardioprotective scaffold. The RADA-SDKP hydrogel was intramyocardially injected into the infarct border zone of a rat model of MI induced by left anterior descending artery (LAD) ligation as a cell-free or a cell-delivering scaffold for bone marrow mesenchymal stem cells (BM-MSCs). The left ventricular ejection fraction (LVEF) was markedly improved after transplantation of either free hydrogel or cell-laden hydrogel. This cardiac functional repair coincided very well with substantially lower fibrotic tissue formation, expanded microvasculature, and lower inflammatory response in the infarct area. Interestingly, BM-MSCs alone or in combination with hydrogel could not surpass the cardiac repair effects of the SDKP-modified SAP hydrogel. Taken together, we suggest that the RADA-SDKP hydrogel can be a promising cell-free construct that has the capability for functional restoration in the instances of acute myocardial infarction (AMI) that might minimize the safety concerns of cardiac cell therapy and facilitate clinical extrapolation.

Mesenchymal stem cell-derived extracellular vesicles alone or in conjunction with a SDKP-conjugated self-assembling peptide improve a rat model of myocardial infarction.

PURPOSE: The aim of this study was to investigate the cardiac repair effect of human bone marrow mesenchymal stromal cells-derived extracellular vesicles (MSC-EVs) after intramyocardial injection in free form or encapsulated within a self-assembling peptide hydrogel modified with SDKP motif, in a rat model of myocardial infarction (MI). METHODS: MSC-EVs were isolated by ultracentrifuge and characterized for physical parameters and surface proteins. Furthermore, cellular uptake and cardioprotective effects of MSC-EVs were evaluated in vitro using neonatal mouse cardiomyocytes (NMCMs). In vivo effects of MSC-EVs on cardiac repair were studied in rat MI model by comparing the vehicle group (injected with PBS), EV group (injected with MSC-EVs) and Gel + EV group (injected with MSC-EVs encapsulated in (RADA)4-SDKP hydrogel) with respect to cardiac function and fibrotic area using echocardiography and Masson's trichrome staining, respectively. Histological sections were assessed by α-SMA and CD68 immunostaining to investigate the angiogenic and anti-inflammatory effects of the MSC-EVs. RESULTS: We observed the uptake of MSC-EVs into NMCMs which led to NMCMs protection against H2O2-induced oxidative stress by substantial reduction of apoptosis. In myocardial infarcted rats, cardiac function was improved after myocardial injection of MSC-EVs alone or in conjunction with (RADA)4-SDKP hydrogel. This functional restoration coincided with promotion of angiogenesis and decrement of fibrosis and inflammation. CONCLUSION: These data demonstrated that MSC-EVs can be used alone as a potent therapeutic agent for improvement of myocardial infarction.

The effects of catechin on endothelial function: A systematic review and meta-analysis of randomized controlled trials.

The findings of trials investigating the effect of catechin on endothelial function are controversial. This meta-analysis of randomized controlled trials (RCTs) was performed to summarize the existing evidence and determine the effects of catechin supplementation on endothelial function. Two authors independently searched electronic databases including MEDLINE, EMBASE, Cochrane Library, and Web of Science from inception until March 2019, in order to find relevant RCTs. The quality of selected RCTs was evaluated using the Cochrane Collaboration risk of bias tool. Cochrane's Q test and I-square (I 2) statistic were used to determine the heterogeneity of included trials. Data were pooled using a random-effects model and weighted mean difference (WMD) was considered as the overall effect size. A total of 16 studies with 22 effect sizes were included in this meta-analysis. A significant increase in flow mediated dilation (FMD) in 10 studies was found after catechin supplementation including 13 effect sizes (WMD: 1.53; 95% CI: 0.93, 2.14). The pooled analysis of 7 effect sizes from 4 studies showed a significant reduction in pulse wave velocity (PWV) after catechin supplementation (WMD: -0.32; 95% CI: -0.44, -0.20) and combining 5 effect sizes from 3 studies in augmentation index (AI) (WMD: -3.57; 95% CI: -6.40, -0.74). Catechin supplementation significantly increased FMD, and significantly reduced PWV and AI, but did not affect other markers of endothelial function.

Effects of resistant starch on glycemic control, serum lipoproteins and systemic inflammation in patients with metabolic syndrome and related disorders: A systematic review and meta-analysis of randomized controlled clinical trials.

The aim of this systematic review and meta-analysis was to evaluate the effects of resistant starch (RS) on glycemic status, serum lipoproteins and inflammatory markers in patients with metabolic syndrome (MetS) and related disorders. Two independent authors systematically searched online database including EMBASE, Scopus, PubMed, Cochrane Library, and Web of Science from inception until 30 April 2019. Cochrane Collaboration risk of bias tool was applied to assess the methodological quality of included trials. The heterogeneity among the included studies was assessed using Cochrane's Q test and I-square (I2) statistic. Data were pooled using a random-effects model and weighted mean difference (WMD) was considered as the overall effect size. Nineteen trials were included in this meta-analysis. Administration of RS resulted in significant reduction in fasting plasma glucose (FPG) (14 studies) (WMD: -4.28; 95% CI: -7.01, -1.55), insulin (12 studies) (WMD: -1.95; 95% CI: -3.22, -0.68), and HbA1C (8 studies) (WMD: -0.60; 95% CI: -0.95, -0.24). When pooling data from 13 studies, a significant reduction in total cholesterol levels (WMD: -8.19; 95% CI: -15.38, -1.00) and LDL-cholesterol (WMD: -8.57; 95% CI: -13.48, -3.66) were found as well. Finally, RS administration was associated with a significant decrease in tumor necrosis factor alpha (TNF-α) (WMD: -2.02; 95% CI: -3.14, -0.90). This meta-analysis showed beneficial effects of RS on improving FPG, insulin, HbA1c, total cholesterol, LDL-cholesterol and TNF-α levels in patients with MetS and related disorders, but it did not affect HOMA-IR, triglycerides, HDL-cholesterol, CRP and IL-6 levels.

Expansion of Human Pluripotent Stem Cell-derived Early Cardiovascular Progenitor Cells by a Cocktail of Signaling Factors.

Cardiovascular progenitor cells (CPCs) derived from human pluripotent stem cells (hPSCs) are proposed to be invaluable cell sources for experimental and clinical studies. This wide range of applications necessitates large-scale production of CPCs in an in vitro culture system, which enables both expansion and maintenance of these cells. In this study, we aimed to develop a defined and efficient culture medium that uses signaling factors for large-scale expansion of early CPCs, called cardiogenic mesodermal cells (CMCs), which were derived from hPSCs. Chemical screening resulted in a medium that contained a reproducible combination of three factors (A83-01, bFGF, and CHIR99021) that generated 1014 CMCs after 10 passages without the propensity for tumorigenicity. Expanded CMCs retained their gene expression pattern, chromosomal stability, and differentiation tendency through several passages and showed both the safety and possible cardio-protective potentials when transplanted into the infarcted rat myocardium. These CMCs were efficiently cryopreserved for an extended period of time. This culture medium could be used for both adherent and suspension culture conditions, for which the latter is required for large-scale CMC production. Taken together, hPSC-derived CMCs exhibited self-renewal capacity in our simple, reproducible, and defined medium. These cells might ultimately be potential, promising cell sources for cardiovascular studies.

Factors That Impact Evaluation of Left Ventricular Systolic Parameters in Myocardial Perfusion Gated SPECT with 16 Frame and 8 Frame Acquisition Models.

OBJECTIVE: Evaluating the effects of heart cavity volume, presence and absence of perfusion defect, gender and type of study (stress and rest) on the difference of systolic parameters of myocardial perfusion scan in 16 and 8 framing gated SPECT imaging. METHODS: Cardiac gated SPECT in both 16 and 8 framing simultaneously and both stress and rest phases at one-day protocol was performed for 50 patients. Data have been reconstructed by filter back projection (FBP) method and left ventricular (LV) systolic parameters were calculated by using QGS software. The effect of some factors such as LV cavity volume, presence and absence of perfusion defect, gender and type of study on data difference between 8 and 16 frames were evaluated. RESULTS: The differences in ejection fraction (EF), end-diastolic volume (EDV) and end-systolic volume (ESV) in both stress and rest were statistically significant. Difference in both framing was more in stress for EF and ESV, and was more in rest for EDV. Study type had a significant effect on differences in systolic parameters while gender had a significant effect on differences in EF and ESV in rest between both framings. CONCLUSION: In conclusion, results of this study revealed that difference of both 16 and 8 frames data in systolic phase were statistically significant and it seems that because of better efficiency of 16 frames, it cannot be replaced by 8 frames. Further well-designed studies are required to verify these findings.

Hypertensive Disorders in Pregnant Women Receiving Fertility Treatments.

Hypertensive disorders (HDs) as the most prevalent medical problem during pregnancy, predispose the patient to a lot of comorbidities and may even cause maternal or fetal death. The rate of infertility has been increasing in recent decades. So, we collected and summarized data about the co-existence of these two entities and found that HDs are somewhat more common in women receiving fertility treatments regardless of pathophysiologic correlation of infertility and hypertension or older age and chance of multiple pregnancies.

Bushehr Elderly Health (BEH) Programme, phase I (cardiovascular system).

PURPOSE: The main objective of the Bushehr Elderly Health Programme, in its first phase, is to investigate the prevalence of cardiovascular risk factors and their association with major adverse cardiovascular events. PARTICIPANTS: Between March 2013 and October 2014, a total of 3000 men and women aged ≥ 60 years, residing in Bushehr, Iran, participated in this prospective cohort study (participation rate=90.2%). FINDINGS TO DATE: Baseline data on risk factors, including demographic and socioeconomic status, smoking and medical history, were collected through a modified WHO MONICA questionnaire. Vital signs and anthropometric measures, including systolic and diastolic blood pressure, weight, height, and waist and hip circumference, were also measured. 12-lead electrocardiography and echocardiography were conducted on all participants, and total of 10 cc venous blood was taken, and sera was separated and stored at -80 °C for possible future use. Preliminary data analyses showed a noticeably higher prevalence of risk factors among older women compared to that in men. FUTURE PLANS: Risk factor assessments will be repeated every 5 years, and the participants will be followed during the study to measure the occurrence of major adverse cardiac events. Moreover, the second phase, which includes investigation of bone health and cognition in the elderly, was started in September 2015. Data are available at the Persian Gulf Biomedical Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran, for any collaboration.

Comparison of technetium-99m IgG with technetium-99m red blood cells labeling in cardiac blood-pool scintigraphy: a preliminary study.

This first clinical prospective study was conducted to use of technetium-99m immunoglobulin G ((99m)Tc-IgG) as compared with autologous (99m)Tc-red blood cells (RBC) in gated blood pool ventriculography. We studied 12 patients who referred to us for a possible diagnosis of liver hemangioma or infection. Six patients underwent gated planar blood pool (GPBP) acquisition using (99m)Tc-RBC and 6 GPBP acquisition using (99m)Tc-IgG. The use of (99m)Tc-IgG in cardiac blood pool studies provided comparable images to (99m)Tc-RBC. In conclusion, (99m)Tc-IgG, which is readily available and needs only a single injection, may be an attractive alternative to (99m)Tc-RBC for the estimation of various cardiac function parameters like left ventricular function.