Clinical Management and Transplant Considerations in Pediatric Pulmonary Hypertension Due to Left Heart Disease: A Scientific Statement From the American Heart Association
Anoikis, Form Of Natural Cell Death, May Help In Diagnosing CTEPH
Anoikis, a form of programmed cell death, is involved in the development of chronic thromboembolic pulmonary hypertension (CTEPH), according to a genetic analysis study.
Researchers identified two anoikis-related genes associated with CTEPH — PLAUR and HMOX1 — which may serve as diagnostic biomarkers or as treatment targets.
Data also suggest that stannsoporfin, a drug that inhibits the protein encoded by HMOX1, may offer a way of treating CTEPH patients, the scientists, all in China, reported.
The study, "Identification of Anoikis-related potential biomarkers and therapeutic drugs in chronic thromboembolic pulmonary hypertension via bioinformatics analysis and in vitro experiment," was published in Nature Scientific Reports.
Activity levels of 2 genes higher in blood of people with CTEPHIn CTEPH, a rare form of pulmonary hypertension, blood clots block the blood vessels that pass through the lungs, increasing blood pressure. This causes various symptoms, including shortness of breath, light-headedness, fainting, chest discomfort, and, in more severe cases, right heart failure.
Early symptoms of CTEPH usually are not obvious, making a prompt diagnosis challenging. In part, this failing also is due to the lack of disease-specific biomarkers helping to predict CTEPH severity and a person's clinical outcomes. A need exists for genetic biomarkers that could shed light on the disease's underlying biology and detect therapeutic targets, the researchers wrote.
Anoikis is a specialized form of programmed cell death, or apoptosis, a biological process that eliminates abnormal or unwanted cells. This form is triggered by the detachment of cells from the extracellular matrix, a three-dimensional network of molecules and proteins that provides structural support to cells.
However, "the precise involvement of anoikis in the progression of CTEPH remains poorly understood," wrote the researchers, who conducted a gene expression (activity) analysis of data from the Gene Expression Omnibus database to identify genes expressed differently between CTEPH patients and people without this disease, serving as controls.
The analysis identified 676 differently expressed genes, or those with higher or lower activity in patients than controls. Of these, 32 were associated with anoikis, mostly related to regulating the apoptotic process. Still, an enrichment in many immune-related genes also was noted.
Researchers then used machine learning, a type of artificial intelligence that uses algorithms to learn from data and identify patterns, to narrow the number of these genes down to five. Using a second dataset as a validation step, two matching genes, PLAUR and HMOX1, stood out.
"This suggests that PLAUR and HMOX1 may be the most important diagnostic markers," the researchers wrote.
In line with these findings, a blood sample analysis found significantly higher expression of both the PLAUR and HMOX1 genes in CTEPH patients than in controls.
Proteins encoded by these genes were also significantly higher in patients. PLAUR encodes the urokinase receptor, a protein tethered to the cell membrane. HMOX1 encodes heme oxygenase 1, an enzyme that breaks down heme, a molecule that enables red blood cells to transport oxygen.
Levels of two types of immune cells seen as possibly affected by diseaseGiven that immune-related genes were previously identified, further analysis suggested that two immune cell types, mast cells and neutrophils, played a role in CTEPH development. Consistently, elevated PLAUR expression significantly correlated with low levels of activated mast cells, while elevated HMOX1 significantly correlated with high neutrophil levels.
Lastly, the researchers searched for drugs that modulate the proteins encoded by PLAUR and HMOX1. Stannsoporfin, which inhibits heme oxygenase 1, was identified, suggesting it may have a therapeutic effect on CTEPH.
"The study demonstrates for the first time that Anoikis may be involved in the [development] of CTEPH," the researchers concluded. "HMOX1 and PLAUR are two powerful and promising diagnostic biomarkers for CTEPH-related Anoikis," they added.
Chronic Thromboembolic Pulmonary Hypertension
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Once CTEPH develops, the most effective cure is a surgical procedure known as pulmonary endarterectomy that reestablishes normal blood flow to the lungs.
This surgery can reverse pulmonary hypertension and reverse damage to the heart and other organs. With surgery, patients can expect excellent long-term survival approaching 90% at five years. Without surgery, patients have substantially reduced long-term survival and quality of life.
Are there non-surgical options for CTEPH?
Medications may be an option for patients with CTEPH to prevent further clot buildup and to relax the wall of the blood vessels.
In addition, patients may be candidates for a minimally invasive procedure called pulmonary balloon angioplasty.
How do you know if you have CTEPH?
CTEPH is a vastly underdiagnosed disease. But some of the symptoms include:
Any patient with a history of blood clot formations should consider seeing a specialist if they are having trouble performing daily activities due to less energy or shortness of breath.
Survivors of acute pulmonary embolism can develop long-term pulmonary hypertension. So any patient with a history of acute pulmonary embolism should undergo an annual echocardiogram to check the function of the heart.
GLP-1 Receptor Agonists May Have Broader Range Of Benefits, Risks
Glucagon-like peptide 1 receptor agonists (GLP-1RAs) may have a wider range of benefits and risks than what the medical community currently understands.
In a discovery study, investigators generated an atlas of associations with GLP-1RA initiation versus use of sulfonylureas, dipeptidyl peptidase 4 (DPP4) inhibitors and sodium-glucose cotransporter-2 (SGLT2) inhibitors. They followed 1,955,135 patients treated for diabetes or obesity within the Veterans Affairs health system for a median 3.68 years. The study population, which had a mean age of 68.26 years, was 94.72% male, 71.19% White, 18.46% Black, and 10.40% other races.
Among 175 health outcomes, GLP-1RAs were linked with various protective effects. GLP-1RA use vs usual care was significantly associated with a reduced risk of substance use and psychotic disorders, seizures, neurocognitive disorders (including Alzheimer disease and dementia), coagulation disorders, cardiometabolic disorders, infectious illnesses and several respiratory conditions, Ziyad Al-Aly, MD, of Washington University in St. Louis, Missouri, and colleagues reported in Nature Medicine. Despite earlier concerns, the findings showed that GLP-1RA use reduced the risk of suicidal ideation, attempt or intentional self-harm. With respect to seizures, emerging data indicate GLP-1RA had anticonvulsant properties. GLP-1RAs also might be a useful a primary or adjuvant therapy for various substance use disorders, psychotic disorders and depressive disorders, the investigators suggested.
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The results provide insights into the benefits and risks of GLP-1RAs and may be useful for informing clinical care and guiding research agendas.
With respect to risks, GLP-1RA use was significantly associated with an increased risk of gastrointestinal disorders, hypotension, syncope, arthritic disorders, drug-induced pancreatitis, and other conditions, Dr Al-Aly's team reported.
Nephrologists in particular should know that GLP-1RAs might increase the risk for kidney stones and interstitial nephritis. In line with practice-changing trial data, GLP-1 RA reduces cardiovascular and renal outcomes, such as risks for heart failure, chronic kidney disease, acute kidney injury, and major adverse cardiovascular events. These agents also lower the risk for urinary tract infection, septicemia, and bacterial infections, the investigators reported. Obesity is a risk factor for thromboembolic disease, whereas GLP-1RAs have shown anti-thromboembolic effects.
GLP-1RA use may raise the risk of hypotension and syncope. According to Dr Al-Aly's team, careful monitoring of blood pressure and adjustment of antihypertensive medications may be needed.
GLP-1 RA use also may reduce the risks for hepatic failure, inflammatory bowel disease, diverticulitis, and obesity-related cancers attributable to their metabolic and anti-inflammatory properties, the investigators reported.
"The results provide insights into the benefits and risks of GLP-1RAs and may be useful for informing clinical care and guiding research agendas," Dr Al-Aly's team wrote.
This article originally appeared on Renal and Urology News
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