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PAH Clinical Worsening Associated With Fewer Fingernail Capillaries
Having fewer very fine blood vessels in the fold of skin at the base of the fingernails appears to be linked to an increased risk of clinical worsening in pulmonary arterial hypertension (PAH), a study in the Netherlands suggests.
People with chronic thromboembolic pulmonary hypertension (CTEPH) also had fewer fine blood vessels, called capillaries, in their nail folds than healthy people, but this didn't change after a surgical procedure to relieve high blood pressure in their lungs.
This suggests a loss of capillaries isn't unique to PAH or directly caused by how the disease affects blood flow. Instead, shared mechanisms may cause changes to both the pulmonary arteries that supply the lungs and the capillaries throughout the body. The study, "Low nailfold capillary density in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: biomarker of clinical outcome?" was published in Scientific Reports.
PAH occurs when small blood vessels in the lungs become narrower, resulting in high blood pressure in the pulmonary arteries. The disease can result from inherited genetic mutations, where it's called heritable PAH, or when the cause of the narrowing is unknown, called idiopathic PAH.
Usually regarded as a disease that only affects the lungs, PAH often occurs in people with fewer capillaries in the folds of their fingernails, suggesting microangiopathy, that is, a disease of the small blood vessels. This has led the researchers to ask whether loss of capillaries is unique to PAH or is a result of high blood pressure in the lungs in general.
Counting the capillaries at the fingernailsTo investigate this, they used a technique called nail fold capillaroscopy to count the number of capillaries in fingernail folds and see how narrow they were. The study included 30 people with PAH (23 with idiopathic PAH, seven with heritable PAH), 17 people with CTEPH, and 48 healthy people, who served as controls. CTEPH is a type of pulmonary hypertension that occurs when blood clots deposit in the pulmonary arteries, limiting or blocking blood flow. Unlike PAH, CTEPH can be treated with pulmonary endarterectomy (PEA) to remove the clots or balloon pulmonary angioplasty (BPA) to open the narrowed arteries.
Compared to controls, who had an average 10.3 capillaries per mm of their nail folds, capillary density was significantly lower in PAH (7.5 capillaries/mm) and CTEPH (8.4 capillaries/mm). There was no difference in capillary density between idiopathic and heritable PAH (7.5 vs. 7.6 capillaries/mm).
"The current study confirms that patients with [idiopathic PAH] and CTEPH are characterized by increased capillary dimensions and reduced capillary density, but extends these findings to patients with confirmed [heritable PAH]," the researchers wrote.
In PAH, the endothelial cells, smooth muscle cells, and fibroblasts that line the blood vessels grow out of control. As a result, the walls of the blood vessels thicken, narrowing the lumen, or opening, where the blood flows.
The researchers also measured the capillaries' diameter, which on average was significantly larger in people with PAH or CTEPH than controls, indicating both fewer capillaries and changes in their structure. The researchers also looked at whether the number of capillaries was related to how severe the disease was or if it could predict how the disease may get worse. Fewer capillaries were linked to an increased risk of disease worsening in PAH.
Over a median 3.7 years, 11 of the 30 people with PAH worsened and required either additional treatment or a lung transplant, or died. Each loss of one capillary per mm doubled the risk of clinical worsening, even when adjusted for age.
Fifteen people with CTEPH underwent a surgical procedure, eight had PEA and seven had BPA. Eleven had normal mean pulmonary arterial after surgery, while four had residual high blood pressure. For seven patients who had repeat measurements, capillary density remained unchanged even after a median of 3.3 years.
"Although capillary density was associated with time to clinical worsening in patients with PAH, capillary density did not normalize after recovery of pulmonary hemodynamics [blood flow] in patients with CTEPH," the researchers wrote. "Our findings indicate that a loss of peripheral capillaries is not specific to PAH and is not related to the hemodynamic disturbance per se, but that shared mechanisms may account for a simultaneous development of a systemic [body-wide] microangiopathy and pulmonary vascular remodeling."
Biomarkers Show Promise To Improve Risk Evaluation In PAH
Photo Credit: ArtemisDiana
Researchers identified several inflammatory circulating proteins that could be useful biomarkers for predicting outcomes in pulmonary arterial hypertension.
Several inflammation-related circulating proteins appear to predict the risk of lung transplantation or death in patients with pulmonary arterial hypertension (PAH), according to a study published in the Journal of the American Heart Association.
"Pulmonary arterial hypertension ultimately leads to right ventricular failure and premature death," wrote corresponding author Steeve Provencher, MD, MSc, and coauthors. "The identification of circulating biomarkers with prognostic utility is considered a priority."
The study focused on inflammation-related circulating proteins because chronic inflammation is considered a pathogenic driver of PAH. Specifically, researchers measured plasma levels of 384 inflammatory proteins in 60 patients with PAH and 28 control subjects with normal hemodynamics.
According to the study, the results identified 51 circulating proteins that were significantly overexpressed in the plasma of patients with PAH compared with control subjects. Among them, 17 were initially linked with lung transplantation or death in patients with PAH.
However, after adjustment for the 2015 European Society of Cardiology/European Respiratory Society guidelines, the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) 2.0 risk scores, and the refined 4-strata risk assessment, only six proteins remained independently associated with lung transplantation or death at the time of diagnosis with PAH:
Four of the six—namely, CRIM1, PLAUR, FSTL3, and SPON1—showed incremental prognostic value on top of the 2015 European Society of Cardiology/European Respiratory Society guidelines, REVEAL 2.0 risk scores, and the refined 4‐strata risk assessment predictive models.
Western blot analysis revealed that FSTL3 and SPON1 were markedly upregulated in the right ventricle of patients with PAH and in PAH animal models. The finding suggests the stressed right ventricle is a source of circulating FSTL3 and SPON1 in patients with PAH.
"The present study, using high‐throughput proteomic technologies, enabled us to identify potential novel immune‐related plasma biomarkers, which may help improve outcome prediction in PAH if externally confirmed in future studies," Dr. Provencher and colleagues concluded.
Cancer Drugs Spark Surprising Improvement In PAH Symptoms
New anecdotal evidence suggests some chemoimmunotherapy treatments may improve pulmonary arterial hypertension symptoms, but the overall evidence remains murky.
A case report of a patient whose pulmonary arterial hypertension (PAH) symptoms improved while receiving treatment for metastatic lung adenocarcinoma is raising questions about whether — and why — chemotherapy and immunotherapy might have a positive influence on the efficacy of PAH drugs.
Zeenat Safdar, M.D., M.S.
Zeenat Safdar, M.D., M.S., of Houston Methodist Hospital, and colleagues described the case in the journal Pulmonary Circulation.
The patient was a 52-year-old woman with a medical history of connective tissue disease-associated PAH, CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome, interstitial lung disease and ulcerative colitis. She sought care after experiencing shortness of breath, fatigue and bone pain. Subsequent CT and PET imaging led to a diagnosis of stage 4 lung adenocarcinoma with 5% of tumor cells expressing programmed death-ligand 1 (PD-L1). She was negative for EGFR/ALK gene alterations.
At the time, the patient was taking triple therapy for PAH: Uptravi (selexipag), Opsumit (macitentan), and Adempas (riociguat).
For her cancer, she was started on carboplatin and Alimta (pemetrexed) and after, one cycle, immunotherapy with Keytruda (pembrolizumab) was added. Her cancer treatments were successful, although the adverse effects of chemotherapy later led her doctors to switch to single-agent therapy with Keytruda. When she discontinued cancer therapy about seven months after initiation, there was no evidence of active malignancy. For an additional 18 months of follow-up she appeared to be free of cancer.
Her cancer was not the only disease that improved.
After a month on both neoplastic and PAH therapy, the patient showed signs of improved PAH symptoms, including improvement in her six-minute walking distance (6MWD) and functional class I symptoms. The improvement allowed her to return to work as a teacher, Safdar and colleagues reported. Her symptoms continued to improve, and echocardiograms showed improved cardiac output/cardiac index, a normal right atrium size and mild depressed right ventricular function.
Things changed, though, when her immunotherapy was stopped. Despite continuing PAH triple therapy, the patient's condition worsened according to multiple PAH parameters. Eventually, doctors replaced Adempas with Viagra (sildenafil) and later administered intravenous Flolan (epoprostenol). She died in September 2022, a little more than two years after starting her cancer therapy, from respiratory failure with severe right-sided heart failure.
Safdar told Managed Healthcare Executive that when clinicians were first deciding how to treat the patient's cancer, her underlying PAH was an influential consideration.
"Antineoplastic drugs with less cardiovascular side effects were chosen," she said.
Yet, rather than exacerbate the patient's PAH, Safdar and colleagues said they now believe the patient's cancer therapy "may have a positive effect on the vascular remodeling seen in PAH."
One possible reason, they said, is that chemotherapy and immunotherapy increases expression of the FOXO1 transcription factor in pulmonary arterial smooth muscle cells (PAMSCs), which they said may modulate "reverse remodeling" in the PAMSCs.
"In various cancer models, FOXO1 has been shown to inhibit TGFβ‐induced epithelial‐to‐mesenchymal transition (EMT), rendering enhanced epithelization of cancer cells, reduced metastatic capacity, and likely increased chemosensitivity," Safdar and colleagues wrote. "We theorize that this reverse remodeling modulated by FOXO that is exhibited in cancer cells may be present in PASMCs."
Although there have been some reports suggesting chemoimmunotherapy may influence remodeling, the researchers wrote taht it was not possible to know for certain what influence the patient's cancer drugs had on her PAH.
Safdar told Managed Healthcare Executive, however, that Gleevec (imatinib) has been investigated as a therapy for PAH. It was found to be efficacious, she said, but has serious side effects. More recently, she said, an inhaled version of imatinib was studied in PAH, but the study was halted after interim results demonstrated a lack of efficacy.
"Other than that, there is no convincing data on the use of antineoplastic meds as therapy for PAH in humans," she said.
Ironically, one drug from the same class as imatinib, Sprycel (dasatinib) has PAH listed as a possible cardiotoxicity on its label.
Still, Safdar said overall there is conflicting data on antineoplastic medications in PAH. She said more investigation will be needed to clarify what benefits, if any, come from cancer therapies in patients with PAH.
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