The Utility of Leadless Atrioventricular Synchronous Pacemaker Implantation as a Novel Alternative to a Traditional Pacemaker During Pregnancy.

The Micra™ leadless pacemaker (Medtronic, Minneapolis, MN, USA) is indicated for the management of symptomatic bradycardia and advanced heart block. However, the safety of this procedure during pregnancy has not been studied. Here, we present a unique case of Micra™ leadless pacemaker implantation (MLP) in a 31 weeks pregnant patient with intermittent complete heart block who presented with multiple syncopal episodes. The patient underwent an MLP implantation with <40 mGy radiation exposure (about 0.6 min of total fluoroscopy time), which is deemed a negligible dose of radiation exposure during pregnancy. Her subsequent hospital course was uneventful, and she was safely discharged home and was able to continue her pregnancy and delivery without further syncopal episodes or incidence of heart block.

Bradycardia, Renal Failure, Atrioventricular Nodal Blockade, Shock and Hyperkalaemia Syndrome Involving Digoxin Toxicity: A Case Report.

Bradycardia, renal failure, atrioventricular nodal blockade, shock and hyperkalemia (BRASH) syndrome is named after the pentad of symptoms experienced by patients with this clinical entity, and is propagated via a synergistic mechanism. Herein, we describe a case of an 81-year-old male who presented with bradycardia, dyspnoea on exertion, and confusion. He was also initially found to be in cardiogenic shock. In a setting of elevated digoxin levels, acute renal failure and hyperkalemia, he was diagnosed with BRASH syndrome. Prompt interventions of continuous renal replacement therapy and digoxin antibody administration were performed to treat this patient. His renal function improved and his hyperkalemia and bradycardia resolved over the course of 4 days, and the patient was discharged to a subacute rehabilitation facility after stabilization. BRASH syndrome is a clinical entity requiring prompt diagnosis for life-saving treatment, including renal replacement therapy, vasoactive medications, transvenous pacing, and reversing agents, when appropriate.

Transcatheter Aortic Valve Replacement for Aortic Valve Infective Endocarditis: A Systematic Review and Call for Action.

We aimed to systematically analyze the literature on the use of transcatheter aortic valve replacement (TAVR) to treat active aortic valve infective endocarditis (AV-IE). Surgery is declined in one-third of patients with IE who meet indications because of prohibitive surgical risk. TAVR might be an alternative for selected patients with AV-IE as a bridge-to-surgery or stand-alone therapy. PubMed/MEDLINE, Embase, and Cochrane databases were searched (2002-2022) for studies on TAVR use in active AV-IE. Of 450 identified reports, six met inclusion criteria (all men, mean age 71 ± 12 years, median Society of Thoracic Surgeons (STS) score 27, EuroSCORE 56). All patients were prohibitive surgical risk candidates. Five out of six patients had severe, and one patient had moderate aortic regurgitation on presentation. Five out of six patients had prosthetic valve endocarditis after surgical valve replacement 13 years before (median), and one patient had TAVR a year before hospitalization. All patients had cardiogenic shock as the indication for TAVR. Four patients received balloon-expanding, and two patients received self-expanding TAVR after a median of 19 (IQR 9-25) days from diagnosis of IE. No death or myocardial infarction occurred, but one patient had a stroke within the first 30 days. The median event-free time was 9 (IQR 6-14) months including no death, reinfection, relapse IE, or valve-related rehospitalization. Our review suggests that TAVR can be considered as an adjuvant therapy to medical treatment for selected patients in whom surgery is indicated for treatment of acute heart failure due to aortic valve destruction and incompetence caused by infective endocarditis, but who have a prohibitive surgical risk. Nonetheless, a well-designed prospective registry is urgently needed to investigate the outcomes of TAVR for this off-label indication. No evidence exists for using the TAVR to treat infection-related surgical indications such as uncontrolled infection or control of septic embolization.

PLAAT1 Exhibits Phosphatidylcholine:Monolysocardiolipin Transacylase Activity.

Tissue-specific cardiolipin fatty acyl profiles are achieved by remodeling of de novo synthesized cardiolipin, and four remodeling enzymes have thus far been identified. We studied the enzyme phospholipase A and acyltransferase 1 (PLAAT1), and we report the discovery that it has phosphatidylcholine (PC):monolysocardiolipin (MLCL) transacylase activity. Subcellular localization was analyzed by differential centrifugation and immunoblotting. Total levels of major phospholipids, and the fatty acyl profile of cardiolipin, were analyzed in HEK293 cells expressing murine PLAAT1 using gas chromatography. Apparent enzyme kinetics of affinity-purified PLAAT1 were calculated using radiochemical enzyme assays. This enzyme was found to localize predominantly to the endoplasmic reticulum (ER) but was detected at low levels in the mitochondria-associated ER matrix. Cells expressing PLAAT1 had higher levels of total cardiolipin, but not other phospholipids, and it was primarily enriched in the saturated fatty acids myristate, palmitate, and stearate, with quantitatively smaller increases in the n-3 polyunsaturated fatty acids linolenate, eicosatrienoate, and eicosapentanoate and the monounsaturated fatty acid erucate. Affinity-purified PLAAT1 did not catalyze the transacylation of MLCL using 1-palmitoyl-2-[14C]-linoleoyl-PC as an acyl donor. However, PLAAT1 had an apparent Vmax of 1.61 µmol/min/mg protein and Km of 126 µM using [9,10-3H]-distearoyl-PC as an acyl donor, and 0.61 µmol/min/mg protein and Km of 16 µM using [9,10-3H]-dioleoyl-PC. PLAAT1 is therefore a novel PC:MLCL transacylase.

N-oleoylethanolamide treatment of lymphoblasts deficient in Tafazzin improves cell growth and mitochondrial morphology and dynamics.

Barth syndrome (BTHS) is caused by mutations in the TAZ gene encoding the cardiolipin remodeling enzyme, Tafazzin. The study objective was to quantitatively examine growth characteristics and mitochondrial morphology of transformed lymphoblast cell lines derived from five patients with BTHS relative to five healthy controls, as well as the therapeutic potential of oleoylethanolamide (OEA) and linoleoylethanolamide (LEA). These bioactive lipids both activate PPARα, which may be therapeutic. BTHS lymphoblasts grew more slowly than controls, suggesting lymphopenia merits clinical investigation. Treatment of BTHS lymphoblasts with OEA, but not LEA, significantly restored mitochondrial membrane potential, as well as colony growth in all BTHS lymphoblast lines, although a full growth rescue was not achieved. Quantification analysis of electron micrographs from three BTHS and healthy lymphoblast donors indicated similar numbers of mitochondria per cell, but lower average cristae length per mitochondrion, and higher mitochondrial density. Additionally, BTHS lymphoblasts had larger mitochondria, and a higher percentage of abnormally large mitochondria (> 1 µm2) than healthy controls. Notably, OEA treatment significantly restored mitochondrial size, without affecting density or cristae lengths. Cardiolipin total content, relative linoleic acid content and monolysocardiolipin:cardiolipin ratios were not improved by OEA, indicating that effects on growth, and mitochondrial morphology and function, occurred without resolving this deficit. However, immunoblotting showed higher levels of OPA1, a biomarker for mitochondrial fusion, in BTHS lymphoblasts, which was attenuated by OEA treatment, implicating altered mitochondrial dynamics in the pathology and treatment of BTHS.

Transcription factor CREB3 is a potent regulator of high-fat diet-induced obesity and energy metabolism.

BACKGROUND: The endoplasmic reticulum senses alterations to cellular homeostasis that activates the unfolded protein response (UPR). UPR proteins are known to aid in regulating glucose and lipid metabolism. CREB3 is a UPR-associated transcription factor whose potential role in regulating energy metabolism remains unclear. METHODS: Eight-week-old wild-type (WT) and Creb3+/- mice were placed on control and high-fat diets (HFD) for 8 weeks, and metabolic phenotypes characterized by weekly weighing, indirect calorimetry, body composition scans, glucose tolerance tests, plasma analysis, tissue lipid quantifications and gene/protein expression analysis. RESULTS: HFD weight gain in Creb3+/- males was reduced by 34% (p < 0.0001) and females by 39.5% (p = 0.014) from their WT counterparts. No differences were found in HFD food intake or total fecal lipids between genotypes. Creb3+/- mice had increased energy expenditure and respiratory exchange ratios (p = 0.002) relative to WT. Creb3+/- mice had significant reductions in absolute fat and lean tissue, while Creb3+/- females had significant reductions in body fat% and increased lean% composition (p < 0.0001) compared to WT females. Creb3+/- mice were protected from HFD-induced basal hyperglycemia (males p < 0.0001; females p = 0.0181). Creb3+/- males resisted HFD-induced hepatic lipid accumulation (p = 0.025) and glucose intolerance compared to WT (p < 0.0001) while Creb3+/- females were protected from lipid accumulation in skeletal muscle (p = 0.001). Despite the metabolic differences of Creb3+/- mice on HFD, lipid plasma profiles did not significantly differ from WT. Fasted Creb3+/- mice additionally revealed upregulation of hepatic energy expenditure and gluconeogenic genes such as Pgc-1a and Gr (glucocorticoid receptor) (p < 0.05), respectively. CONCLUSIONS: Reduced expression of CREB3 increased energy expenditure and the respiratory exchange ratio, and protected mice from HFD-induced weight gain, basal hyperglycemia, and sex-specific tissue lipid accumulation. We postulate that CREB3 is a novel key regulator of diet-induced obesity and energy metabolism that warrants further investigation as a potential therapeutic target in metabolic disorders.

A preliminary study on the radiation dose reduction during catheterization procedures using simple partial patient shielding.

Reduction in X-ray exposure during cardiac catheterization is important to reduce radiation risks to operators and personnel. Reducing scattered radiation from the patient can achieve this goal. The goal of this study was to evaluate the reduction in radiation using simple partial shielding of patients undergoing cardiac catheterization. By putting a lead-based apron on the lower extremities of patients undergoing cardiac catheterization, we analyzed the reduction in total radiation dose with and without this shielding. One hundred and twelve patients were divided into two groups. In one group, the protective lead-based apron was put on the lower extremities of patients. Another group did not have any shielding. Total duration of angiography was 332 minutes and 45 seconds in the first group and 269 minutes and 10 seconds in the second group. The total radiation exposure was 33 µGy in the first group vs 606 µGy in the second group. Despite higher exposure time, total radiation dose was 22 times lower in the simple shielded group. Our simple method without any additional cost can significantly reduce radiation exposure in the cardiac catheterization laboratory.

A rare presentation of an elderly patient with acute lymphocytic leukemia and platelet count of zero associated with ST-elevation myocardial infarction, pulmonary thromboembolism in the setting of SARS-CoV 2: a case report.

BACKGROUND: Novel coronavirus disease 2019 (COVID-19) is known to lead not only to severe acute respiratory syndrome, but also can result in thromboembolic events in both the venous and the arterial circulation by inducing coagulation disorders. The potential causes of coagulopathy are inflammation, platelet activation, endothelial dysfunction, and stasis. The thrombotic events including pulmonary embolism, deep venous thrombosis as well as intracatheter thrombosis are more likely to develop in patients infected with severe form of SARS-CoV-2 who are admitted to ICU. Furthermore, these events contribute to multi-organ failure. CASE PRESENTATION: Herein, we report a case of an immunocompromised COVID-19 elderly patient with acute lymphocytic leukemia who developed myocardial infarction with ST elevation in the setting of acute pulmonary thromboembolism in the presence of zero platelet count. Despite successful urgent coronary revascularization and platelet transfusion, the patient eventually died after failed resuscitation efforts. CONCLUSION: Patients with COVID-19 infection are at a greater risk of developing cardiovascular complications, but their appropriate management can decrease the risk of fatal events. Coronary thrombosis associated with pulmonary thromboembolism in the setting of thrombocytopenia is a rare and a complex to manage condition. Significance of single antiplatelet agent in STEMI with thrombocytopenia merits further studies. According to expert opinions and literature reviews, we must avoid dual antiplatelet therapy in these patients and keep platelet transfusion as a standard therapy to avoid drastic bleeding complications.

Novel Product for the Management of Coronary Ruptures Happening during Percutaneous Coronary Interventions.

Coronary artery perforation during percutaneous coronary interventions is a rare but dreaded complication. One of the treatment methods for this complication is the injection of an obliterating material into the ruptured vessel. We will introduce a novel material named "Spongostan" for embolization with significant advantages over available treatment options.

Blood pressure components and incident cardiovascular disease and mortality events among Iranian adults with chronic kidney disease during over a decade long follow-up: a prospective cohort study.

BACKGROUND: To explore the association between systolic and diastolic blood pressure (SBP and DBP respectively) and pulse pressure (PP) with cardiovascular disease (CVD) and mortality events among Iranian patients with prevalent CKD. METHODS: Patients [n = 1448, mean age: 60.9 (9.9) years] defined as those with estimated glomerular filtration rate < 60 ml/min/1.73 m2, were followed from 31 January 1999 to 20 March 2014. Multivariable Cox proportional hazard models were applied to examine the associations between different components of BP with outcomes. RESULTS: During a median follow-up of 13.9 years, 305 all-cause mortality and 317 (100 fatal) CVD events (among those free from CVD, n = 1232) occurred. For CVD and CV-mortality, SBP and PP showed a linear relationship, while a U-shaped relationship for DBP was observed with all outcomes. Considering 120 ≤ SBP < 130 as reference, SBP ≥ 140 mmHg was associated with the highest hazard ratio (HR) for CVD [1.68 (1.2-2.34)], all-cause [1.72 (1.19-2.48)], and CV-mortality events [2.21 (1.16-4.22)]. Regarding DBP, compared with 80 ≤ DBP < 85 as reference, the level of ≥ 85 mmHg increased risk of CVD and all-cause mortality events; furthermore, DBP < 80 mmHg was associated with significant HR for CVD events [1.55 (1.08-2.24)], all-cause [1.68 (1.13-2.5)] and CV-mortality events [3.0 (1.17-7.7)]. Considering PP, the highest HR was seen in participants in the 4th quartile for all outcomes of interest; HRs for CVD events [1.92 (1.33-2.78)], all-cause [1.71 (1.11-2.63)] and CV-mortality events [2.22 (1.06-4.64)]. CONCLUSIONS: Among patients with CKD, the lowest risk of all-cause and CV-mortality as well as incident CVD was observed in those with SBP < 140, 80 ≤ DBP < 85 and PP < 64 mmHg.

Lpaatδ/Agpat4 deficiency impairs maximal force contractility in soleus and alters fibre type in extensor digitorum longus muscle.

Lysophosphatidic acid acyltransferase (LPAAT) δ/acylglycerophosphate acyltransferase 4 is a mitochondrial enzyme and one of five homologues that catalyze the acyl-CoA-dependent synthesis of phosphatidic acid (PA) from lysophosphatidic acid. We studied skeletal muscle LPAATδ and found highest levels in soleus, a red oxidative fibre-type that is rich in mitochondria, and lower levels in extensor digitorum longus (EDL) (white glycolytic) and gastrocnemius (mixed fibre-type). Using Lpaatδ-deficient mice, we found no change in soleus or EDL mass, or in treadmill time-to-exhaustion compared to wildtype littermates. There was, however, a significant reduction in the proportion of type I and type IIA fibres in EDL but, surprisingly, not soleus, where these fibre-types predominate. Also unexpectedly, there was no impairment in force generation by EDL, but a significant reduction by soleus. Oxidative phosphorylation and activity of complexes I, I + II, III, and IV in soleus mitochondria was unchanged and therefore could not explain this effect. However, pyruvate dehydrogenase activity was significantly reduced in Lpaatδ-/- soleus and EDL. Analysis of cellular lipids indicated no difference in soleus triacylglycerol, but specific elevations in soleus PA and phosphatidylethanolamine levels, likely due to a compensatory upregulation of Lpaatß and Lpaatε in Lpaatδ-/- mice. An anabolic effect for PA as an activator of skeletal muscle mTOR has been reported, but we found no change in serine 2448 phosphorylation, indicating reduced soleus force generation is unlikely due to the loss of mTOR activation by a specific pool of LPAATδ-derived PA. Our results identify an important role for LPAATδ in soleus and EDL.

Janus kinase (JAK) inhibitors for the treatment of skin and hair disorders: a review of literature.

Janus kinase family (JAKs) has recently attracted the attention of many researchers, and several JAK inhibitor drugs have been developed targeting different members of the JAK family. Tofacitinib and ruxolitinib are US FDA approved drugs in this family for rheumatoid arthritis and myeloproliferative diseases, respectively. Dysregulation of JAK/STAT pathway is also involved in many skin diseases, specifically inflammatory disorders. The JAK/STAT signaling pathway and its involvement in skin diseases are overviewed in this study. We also review clinical studies of JAK inhibitors in field of dermatology, including psoriasis, atopic dermatitis, alopecia areata and vitiligo. Although the available evidence shows promising results, it is still too early to draw a firm conclusion about the place of these drugs in dermatological treatment.

Probiotics in early life: a preventative and treatment approach.

Microbial colonization of the infant gut plays a key role in immunological and metabolic pathways impacting human health. Since the maturation of the gut microbiota coincides with early life development, failure to develop a health compatible microbiota composition may result in pathology and disease in later life. Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. Maternal transfer of microorganisms is possible during pregnancy and lactation, and the mother's diet and microbiota can influence that of her offspring. Furthermore, pre-term birth, Caesarean section birth, formula feeding, antibiotic use, and malnutrition have been linked to dysbiosis, which in turn is associated with several pathologies such as necrotizing enterocolitis, inflammatory bowel diseases, antibiotic associated diarrhea, colic, and allergies. Thus, early life should represent a preferred stage of life for probiotic interventions. In this context, they could be regarded as a means to 'program' the individual for health maintenance, in order to prevent pathologies associated with dysbiosis. In order to elucidate the mechanisms underlying the benefits of probiotic administration, pre-clinical studies have been conducted and found an array of positive results such as improved microbial composition, intestinal maturation, decreased pathogenic load and infections, and improved immune response. Moreover, specific probiotic strains administered during the perinatal period have shown promise in attenuating severity of necrotizing enterocolitis. The mechanisms elucidated suggest that probiotic interventions in early life can be envisaged for disease prevention in both healthy offspring and offspring at risk of chronic disease.

Microglial cell activation increases saturated and decreases monounsaturated fatty acid content, but both lipid species are proinflammatory.

Neuroinflammation is a component of age-related neurodegenerative diseases and cognitive decline. Saturated (SFA) and monounsaturated (MUFA) fatty acids are bioactive molecules that may play different extrinsic and intrinsic roles in neuroinflammation, serving as exogenous ligands for cellular receptors, or endogenous components of cell structural, energetic and signaling pathways. We determined the fatty acyl profile of BV2 microglial cells before and after acute activation with lipopolysaccharide (LPS). We also investigated the effect of SFA and MUFA pretreatment on the production of an invasive, neurotoxic phenotype in BV2 cells. Acute activation of BV2 microglia resulted in an increase in the relative content of SFA (12:0, 16:0, 18:0, 20:0, 22:0, and 24:0 increased significantly), and a relative decrease in the content of MUFA (16:1n7, 18:1n7, 18:1n9, 20:1n9, 24:1n9 decreased significantly). In agreement, the major stearoyl-CoA desaturase (SCD) isoform in BV2 cells, SCD2, was significantly down-regulated by LPS. We next treated cells with SFA (16:0 or 18:0) or MUFA (16:1n7 or 18:1n9), and found that levels of secreted IL6 were increased, as was secreted MMP9-mediated proteolytic activity. To test the functional significance, we treated SH-SY5Y neuronal cells with conditioned medium from BV2 cells pretreated with fatty acids, and found a small but significant induction of cell death. Our findings suggest differential intrinsic roles for SFA and MUFA in activated microglial cells, but similar extrinsic roles for these fatty acid species in inducing activation. Expansion of SFA is important during microglial cell activation, but either supplemental SFA or MUFA may contribute to chronic low-grade neuroinflammation.