Evaluation and Management of Pulmonary Hypertension in Noncardiac Surgery: A Scientific Statement From the American Heart Association | Circulation



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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:

  • Chest pain
  • Shortness of breath
  • Fainting
  • Fatigue
  • Pounding in your chest
  • Dizziness
  • Swelling of legs, neck or abdomen
  • 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. 


    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 CTEPH

    In 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 disease

    Given 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.


    Advanced Therapies, Medicines Bring New Hope For Pulmonary Hypertension Patients: Dr Manisha Mendiratta

    Dr Manisha Mendiratta, associate director & head - pulmonology, Sarvodaya Hospital, Faridabad emphasizes the importance of early detection and the integration of advanced treatment modalities to enhance patient outcomes. "Timely intervention with innovative therapies and a multidisciplinary approach can significantly improve the quality of life for PHTN patients," she states while highlighting emerging treatments for pulmonary hypertension (PHTN).

    PHTN is a debilitating condition characterized by high blood pressure in the arteries of the lungs, leading to severe complications if left untreated. Defined by a mean pulmonary arterial pressure greater than 20 mmHg at rest or over 30 mmHg during exercise, PHTN can result from various causes, including left-sided heart disease, chronic lung conditions such as COPD and interstitial lung disease, or pulmonary embolism. In many cases, its origin remains unknown, leading to idiopathic pulmonary arterial hypertension.

    Dr Mendiratta informed that the emerging pharmacological advancements include inhaled prostacyclin like Treprostinil (available in oral, inhaled, subcutaneous, and intravenous forms). It enhances exercise capacity and mitigates lung disease exacerbations. Iloprost (inhaled) improves exercise tolerance and functional class and Non-Prostanoid Prostaglandin Receptor Agonist: Selexipag (oral) demonstrates significant improvement in functional class and exercise tolerance.

    Several interventional procedures have been developed to alleviate the pressure on the heart and lungs, albeit with certain risks like balloon atrial septostomy. It creates a controlled opening between the heart chambers to ease pressure build-up.

    Transcatheter Potts Shunt connects the left pulmonary artery to the descending aorta, reducing strain on the right heart. Balloon pulmonary angioplasty (BPA) helps to open blocked pulmonary arteries. Pulmonary artery denervation reduces nerve signals responsible for constricting blood vessels. Pulmonary endarterectomy is a surgical option for chronic thromboembolic pulmonary hypertension (CTEPH) in eligible patients.

    Dr Mendiratta further informed that innovative emerging therapies include recombinant fusion protein like Sotatercept. It modifies growth signals to prevent abnormal blood vessel growth, a promising approach for disease modification. Future directions in PHTN treatment include aldosterone blockers. Medications such as eplerenone and spironolactone reduce heart muscle thickening. Kinase inhibitors target the growth factor pathways responsible for vascular remodelling. Imatinib - a tyrosine kinase inhibitor that interrupts harmful signalling in idiopathic pulmonary arterial hypertension.

    Current standard medications for pulmonary arterial hypertension (PAH) management include endothelin receptor antagonists which promote relaxation of pulmonary blood vessels. Examples: Bosentan, Ambrisentan and Macitentan. It also includes Phosphodiesterase Inhibitors to induce vasodilation by relaxing lung blood vessels. Examples: sildenafil, tadalafil. Prostacyclin analogues mimic natural substances to dilate blood vessels and inhibit clotting. Example: Epoprostenol. Guanylate Cyclase Stimulators stimulate pathways that relax blood vessels. Example: Riociguat.

    Dr Mendiratta underscores the significance of early diagnosis, lifestyle modifications, and prompt specialist intervention in managing PHTN effectively. She concluded, "As medical advancements progress, we continue to witness improved patient outcomes. The key lies in a comprehensive approach that combines pharmacological, interventional, and lifestyle strategies."

    With continuous research and the advent of groundbreaking therapies, there is renewed hope for PHTN patients to lead healthier and more fulfilling lives. The integration of these innovative treatments into clinical practice marks a significant step forward in the fight against pulmonary hypertension.






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