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ASAIO Journal (American Society For... Jun 2024The development of new right ventricular (RV) dysfunction after cannulation to venovenous (VV) extracorporeal membrane oxygenation (ECMO) and its association with worse...
The development of new right ventricular (RV) dysfunction after cannulation to venovenous (VV) extracorporeal membrane oxygenation (ECMO) and its association with worse outcomes is increasingly recognized in adult patients, however, no studies have evaluated this phenomenon in pediatric patients. We report results of a single-center retrospective cohort study at a large academic children's hospital. New RV systolic dysfunction was present in 48% (12/25) of pediatric patients on VV ECMO for acute respiratory distress syndrome (ARDS). There was no statistically significant difference in survival, duration of mechanical ventilation, or hospital length of stay between those with and without RV dysfunction. Over half (5/9, 56%) of survivors with RV dysfunction on ECMO had RV dilation or RV hypertrophy on post-ECMO echocardiograms, and in two patients the RV dysfunction persisted for months following decannulation. Cardiac catheterization and autopsy reports suggested that echocardiographic assessment of RV systolic function alone may not be sufficient to diagnose clinically relevant RV injury. This is the first study to report the prevalence of RV dysfunction on VV ECMO for pediatric ARDS. Future multicenter collaboration is needed to create a clinically relevant definition of pediatric "RV injury" and to further evaluate risk factors and outcomes of RV dysfunction.
PubMed: 38896850
DOI: 10.1097/MAT.0000000000002257 -
Current Protocols Jun 2024Fabry disease (FD) is a lysosomal storage disorder caused by variants in the GLA gene encoding α-galactosidase A, an enzyme required for catabolism of...
Fabry disease (FD) is a lysosomal storage disorder caused by variants in the GLA gene encoding α-galactosidase A, an enzyme required for catabolism of globotriaosylceramide (Gb). Accumulation of Gb in patients' cells, tissues, and biological fluids causes clinical manifestations including ventricular hypertrophy, renal insufficiency, and strokes. This protocol describes a methodology to analyze urinary Gb and creatinine. Samples are diluted with an internal standard solution containing Gb(C17:0) and creatinine-D, centrifuged, and directly analyzed by ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) using an 8.7-min method. Eight Gb isoforms [C16:0, C18:0, C20:0, C22:1, C22:0, C24:1, C24:0, and (C24:0)OH] are analyzed and the total is normalized to creatinine. Confirmation ions are monitored to detect potential interferences. The Gb limit of quantification is 0.023 µg/ml. Its interday coefficients of variation (3 concentrations measured) are ≤15.4%. This method minimizes matrix effects (≤6.5%) and prevents adsorption or precipitation of Gb. Urine samples are stable (bias <15%) for 2 days at 21°C, 7 days at 4°C, and 4 freeze/thaw cycles, whereas prepared samples are stable for 5 days at 21°C, and 14 days at 4°C. The Gb/creatinine age-related upper reference limits (mean + 2 standard deviations) are 29 mg/mol creatinine (<7 years) and 14 mg/mol creatinine (≥7 years). This simple, robust protocol has been fully validated (ISO 15189) and provides a valuable tool for diagnosis and monitoring of FD patients. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Analysis of urinary globotriaosylceramide (Gb) and creatinine by UHPLC-MS/MS Support Protocol 1: Preparation of the urinary quality controls Support Protocol 2: Preparation of the urine matrix used for the Gb calibration curve Support Protocol 3: Preparation of the Gb calibrators Support Protocol 4: Preparation of the working solution containing the internal standards Support Protocol 5: Preparation of the creatinine calibrators Support Protocol 6: Preparation of the UHPLC solutions and mobile phases.
Topics: Humans; Tandem Mass Spectrometry; Trihexosylceramides; Chromatography, High Pressure Liquid; Fabry Disease; Creatinine
PubMed: 38896100
DOI: 10.1002/cpz1.1087 -
BioRxiv : the Preprint Server For... Jun 2024Heart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis is poorly understood. The ability to assess genetic and pharmacologic...
UNLABELLED
Heart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis is poorly understood. The ability to assess genetic and pharmacologic interventions is hampered by the lack of robust preclinical mouse models of HFpEF. We have developed a novel "2-hit" model, which combines obesity and insulin resistance with chronic pressure overload to recapitulate clinical features of HFpEF. C57BL6/NJ mice fed a high fat diet for >10 weeks were administered an AAV8-driven vector resulting in constitutive overexpression of mouse . Control mice, HFD only, Renin only and HFD-Renin (aka "HFpEF") littermates underwent a battery of cardiac and extracardiac phenotyping. HFD-Renin mice demonstrated obesity and insulin resistance, a 2-3-fold increase in circulating renin levels that resulted in 30-40% increase in left ventricular hypertrophy, preserved systolic function, and diastolic dysfunction indicated by altered E/e', IVRT, and strain measurements; increased left atrial mass; elevated natriuretic peptides; and exercise intolerance. Transcriptomic and metabolomic profiling of HFD-Renin myocardium demonstrated upregulation of pro-fibrotic pathways and downregulation of metabolic pathways, in particular branched chain amino acid catabolism, similar to findings in human HFpEF. Treatment of these mice with the sodium-glucose cotransporter 2 inhibitor empagliflozin, an effective but incompletely understood HFpEF therapy, improved exercise tolerance, left heart enlargement, and insulin homeostasis. The HFD-Renin mouse model recapitulates key features of human HFpEF and will enable studies dissecting the contribution of individual pathogenic drivers to this complex syndrome. Addition of HFD-Renin mice to the preclinical HFpEF model platform allows for orthogonal studies to increase validity in assessment of interventions.
NEW & NOTEWORTHY
Heart failure with preserved ejection fraction (HFpEF) is a complex disease to study due to limited preclinical models. We rigorously characterize a new two-hit HFpEF mouse model, which allows for dissecting individual contributions and synergy of major pathogenic drivers, hypertension and diet-induced obesity. The results are consistent and reproducible in two independent laboratories. This high-fidelity pre-clinical model increases the available, orthogonal models needed to improve our understanding of the causes and assessment treatments for HFpEF.
PubMed: 38895483
DOI: 10.1101/2024.06.06.597821 -
Therapeutic Apheresis and Dialysis :... Jun 2024This study aims to examine the relationship between fluid overload, Vascular Endothelial Growth Factor C (VEGF-C), plasma Angiotensinogen (pAGT), and echocardiography...
INTRODUCTION
This study aims to examine the relationship between fluid overload, Vascular Endothelial Growth Factor C (VEGF-C), plasma Angiotensinogen (pAGT), and echocardiography findings in hemodialysis patients.
METHODS
This was a single-center, cross-sectional study. Patients were divided into two groups according to mid-week inter-dialytic weight gain (mIDWG): (1) mIDWG ≤3% and (2) mIDW >3%.
RESULTS
A total of 55 patients were enrolled in this study. While the mean pAGT and left ventricular mass index were significantly higher in patients with mIDWG >3% compared to patients with mIDWG ≤3%, VEGF-C was similar between groups. pAGT ≥76.8 mcg/L, VEGF-C ≤175.5 pg/ML, and pAGT /VEGF-C ≥0.45 were significant cut-offs for the prediction of left ventricular hypertrophy(LVH). Univariate logistic regression analysis revealed that these cut-off values were significantly associated with LVH.
CONCLUSION
Renin-angiotensin-aldosterone system activation may persist in hemodialysis patients with excessive IDWG. Additionally, pAGT and VEGF-C could be risk factors for the development of LVH.
PubMed: 38894556
DOI: 10.1111/1744-9987.14178 -
International Journal of Molecular... Jun 2024Increased mitochondrial reactive oxygen species (ROS) formation is important for the development of right ventricular (RV) hypertrophy (RVH) and failure (RVF) during...
Does Cell-Type-Specific Silencing of Monoamine Oxidase B Interfere with the Development of Right Ventricle (RV) Hypertrophy or Right Ventricle Failure in Pulmonary Hypertension?
Increased mitochondrial reactive oxygen species (ROS) formation is important for the development of right ventricular (RV) hypertrophy (RVH) and failure (RVF) during pulmonary hypertension (PH). ROS molecules are produced in different compartments within the cell, with mitochondria known to produce the strongest ROS signal. Among ROS-forming mitochondrial proteins, outer-mitochondrial-membrane-located monoamine oxidases (MAOs, type A or B) are capable of degrading neurotransmitters, thereby producing large amounts of ROS. In mice, MAO-B is the dominant isoform, which is present in almost all cell types within the heart. We analyzed the effect of an inducible cardiomyocyte-specific knockout of MAO-B (cmMAO-B KO) for the development of RVH and RVF in mice. Right ventricular hypertrophy was induced by pulmonary artery banding (PAB). RV dimensions and function were measured through echocardiography. ROS production (dihydroethidium staining), protein kinase activity (PamStation device), and systemic hemodynamics (in vivo catheterization) were assessed. A significant decrease in ROS formation was measured in cmMAO-B KO mice during PAB compared to Cre-negative littermates, which was associated with reduced activity of protein kinases involved in hypertrophic growth. In contrast to littermates in which the RV was dilated and hypertrophied following PAB, RV dimensions were unaffected in response to PAB in cmMAO-B KO mice, and no decline in RV systolic function otherwise seen in littermates during PAB was measured in cmMAO-B KO mice. In conclusion, cmMAO-B KO mice are protected against RV dilatation, hypertrophy, and dysfunction following RV pressure overload compared to littermates. These results support the hypothesis that cmMAO-B is a key player in causing RV hypertrophy and failure during PH.
Topics: Animals; Hypertrophy, Right Ventricular; Monoamine Oxidase; Hypertension, Pulmonary; Mice; Mice, Knockout; Reactive Oxygen Species; Myocytes, Cardiac; Heart Failure; Male; Disease Models, Animal; Heart Ventricles; Ventricular Dysfunction, Right
PubMed: 38892401
DOI: 10.3390/ijms25116212 -
International Journal of Molecular... May 2024The association between vitamin D deficiency and cardiovascular disease remains a controversial issue. This study aimed to further elucidate the role of vitamin D...
Ablation of Vitamin D Signaling in Cardiomyocytes Leads to Functional Impairment and Stimulation of Pro-Inflammatory and Pro-Fibrotic Gene Regulatory Networks in a Left Ventricular Hypertrophy Model in Mice.
The association between vitamin D deficiency and cardiovascular disease remains a controversial issue. This study aimed to further elucidate the role of vitamin D signaling in the development of left ventricular (LV) hypertrophy and dysfunction. To ablate the vitamin D receptor (VDR) specifically in cardiomyocytes, VDR mice were crossed with Mlcv2-Cre mice. To induce LV hypertrophy experimentally by increasing cardiac afterload, transverse aortic constriction (TAC) was employed. Sham or TAC surgery was performed in 4-month-old, male, wild-type, VDR, Mlcv2-Cre, and cardiomyocyte-specific VDR knockout (VDR) mice. As expected, TAC induced profound LV hypertrophy and dysfunction, evidenced by echocardiography, aortic and cardiac catheterization, cardiac histology, and LV expression profiling 4 weeks post-surgery. Sham-operated mice showed no differences between genotypes. However, TAC VDR mice, while having comparable cardiomyocyte size and LV fibrosis to TAC VDR controls, exhibited reduced fractional shortening and ejection fraction as measured by echocardiography. Spatial transcriptomics of heart cryosections revealed more pronounced pro-inflammatory and pro-fibrotic gene regulatory networks in the stressed cardiac tissue niches of TAC VDR compared to VDR mice. Hence, our study supports the notion that vitamin D signaling in cardiomyocytes plays a protective role in the stressed heart.
Topics: Animals; Myocytes, Cardiac; Mice; Hypertrophy, Left Ventricular; Receptors, Calcitriol; Vitamin D; Gene Regulatory Networks; Fibrosis; Signal Transduction; Male; Disease Models, Animal; Mice, Knockout; Inflammation
PubMed: 38892126
DOI: 10.3390/ijms25115929 -
Animals : An Open Access Journal From... Jun 2024Primary hyperthyroidism is a rarely diagnosed endocrinopathy in equids and there have been no previous reports of structural and functional cardiac changes associated...
Primary hyperthyroidism is a rarely diagnosed endocrinopathy in equids and there have been no previous reports of structural and functional cardiac changes associated with hyperthyroidism in these species. This case report investigates a 20-year-old mule gelding that presented for a three-month history of thin body condition despite polyphagia, with a heart murmur and elevated free and total thyroid hormone concentrations. On presentation, physical exam revealed a body condition score of two out of nine, persistent tachycardia, pansystolic heart murmur and firm bilateral ventral proximal cervical masses. Bloodwork confirmed markedly elevated free T4, total T4 and T3 concentrations. Echocardiogram demonstrated left ventricular concentric hypertrophy with increased ventricular and atrial systolic function. Bilateral thyroidectomy was performed under standing sedation without complications. Histopathology demonstrated adenocarcinoma of the left thyroid gland and multiple adenomas with osseous metaplasia within the right thyroid. The mule was supplemented with levothyroxine sodium two weeks post-op after a thyroid panel demonstrated undetectable concentrations. Polyphagia resolved following surgery and the mule began gaining weight. Echocardiographic changes improved but did not resolve at two years post-operative. Continued bi-annual follow up and monitoring of thyroid levels was recommended. This case represents the first documentation of hemodynamically relevant cardiac remodeling in an equid associated with primary hyperthyroidism.
PubMed: 38891707
DOI: 10.3390/ani14111660 -
Scientific Reports Jun 2024Pulmonary arterial hypertension (PAH) is a progressive disease characterized by pulmonary vascular remolding and occlusion, leading to the elevated pulmonary arterial...
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by pulmonary vascular remolding and occlusion, leading to the elevated pulmonary arterial pressures, right ventricular hypertrophy, and eventual heart failure if left untreated. Understanding the molecular mechanisms underlying the development and progression of pulmonary hypertension (PH) is crucial for devising efficient therapeutic approaches for the disease. Lung homogenates were collected weekly and underwent RNA-sequencing in the monocrotaline (MCT)-induced PH rat model to explore genes associated with PH progression. Statistical analyses revealed 1038, 1244, and 3125 significantly altered genes (P < 0.05, abs (logfold change) > log1.5) between control and MCT-exposed rats during the first, second, and third week, respectively. Pathway enrichment analyses revealed involvement of cell cycle and innate immune system for the upregulated genes, GPCR and VEGF signaling for the downregulated genes. Furthermore, qRT-PCR validated upregulation of representative genes associated with cell cycle including Cdc25c (cell division cycle 25C), Cdc45, Top2a (topoisomerase IIα), Ccna2 (cyclin A2) and Ccnb1 (cyclin B1). Western blot and immunofluorescence analysis confirmed increases in PCNA, Ccna2, Top2a, along with other proliferation markers in the lung tissue of MCT-treated rats. In summary, RNA sequencing data highlights the significance of cell proliferation in progression of rodent PH.
Topics: Animals; Cell Proliferation; Rats; Hypertension, Pulmonary; Gene Expression Profiling; Disease Progression; Monocrotaline; Disease Models, Animal; Male; Rats, Sprague-Dawley; Transcriptome; Lung
PubMed: 38890390
DOI: 10.1038/s41598-024-64251-w -
Frontiers in Cardiovascular Medicine 2024Hypertrophic cardiomyopathy (HCM) is a very prevalent inherited disease with a wide global distribution and a prevalence rate of approximately 0.2% in the general... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is a very prevalent inherited disease with a wide global distribution and a prevalence rate of approximately 0.2% in the general population. Left ventricular hypertrophy (LVH) caused by sarcomere mutation is the primary reason of HCM. The histopathology feature is that cardiomyocyte hypertrophy, myocyte disorder and myocardial fibrosis lead to diminished diastolic function, left ventricular outflow tract obstruction (LVOTO) and arrhythmia, all of which result in serious cardiac complications. Previously, HCM was considered a malignant disease that was almost untreatable. With the improvement of medical standards and increasing awareness of HCM, it has become a highly treatable disease in contemporary times, with a significant decrease in mortality rates. However, there are still significant unmet requirements in the therapy of HCM. This paper draws on more than 100 references from the past four decades and summarizes current advances in the treatment of HCM. The article will review the pathogenesis and types, recent development in pharmacotherapy, invasive treatments and gene therapies, as well as dilemma and future development of HCM.
PubMed: 38887447
DOI: 10.3389/fcvm.2024.1387596 -
European Heart Journal. Case Reports May 2024Hypertrophic cardiomyopathy (HCM) is a genetic heart disease that can lead to heart failure, atrial fibrillation, and ischaemic symptoms. Managing patients with HCM and...
BACKGROUND
Hypertrophic cardiomyopathy (HCM) is a genetic heart disease that can lead to heart failure, atrial fibrillation, and ischaemic symptoms. Managing patients with HCM and ischaemic symptoms is challenging, and several treatment options have been proposed.
CASE SUMMARY
A 30-year-old male patient presented with severe chest pain that had been ongoing for more than 30 min at rest. He was diagnosed with HCM and had periodic chest pain since the age of 14. He underwent two separate ethyl alcohol ablations of the first septal branches of the left anterior descending and posterior descending arteries, which relieved his symptoms.
DISCUSSION
This case report highlights the challenges in managing patients with HCM and ischaemic symptoms. In this patient, the use of ethyl alcohol ablation was effective in reducing left ventricular outflow tract obstruction and improving symptoms. Ethyl alcohol ablation is a minimally invasive procedure that has been shown to be effective in symptomatic patients with HCM. Overall, this case report emphasizes the importance of individualized treatment for patients with HCM and the potential benefits of alcohol ablation in this population.
PubMed: 38887220
DOI: 10.1093/ehjcr/ytae213