Blood protein levels of TSP2 may be biomarker in PH, study finds

High TSP2 levels linked to right heart changes across PH types

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by Andrea Lobo |

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An illustration showing a heart in front of a pair of lungs.

Blood levels of a protein called thrombospondin-2 (TSP2) — related to clinically identifiable measures of right heart structure and function — are consistently increased across patients with different types of pulmonary hypertension (PH), a study in Germany suggests.

According to the researchers, these data indicate “that plasma [blood] TSP2 levels inform on the presence of PH” and may be a biomarker for disease progression among people with the chronic rare disorder.

The study, “Clinical phenotyping of plasma thrombospondin-2 reveals relationship to right ventricular structure and function in pulmonary hypertension,” was published in the journal ERJ Open Research.

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Higher TSP2 blood protein levels found in PH patients versus controls

PH can be associated with chronic heart and lung conditions, be heritable, or lack an identifiable cause — when pulmonary arterial hypertension (PAH) is called idiopathic.

PAH is caused by the narrowing of the pulmonary arteries, which restricts blood flow in the lungs and causes high blood pressure. This makes the heart work harder to pump blood.

If left untreated, PH is associated with high morbidity and mortality, meaning an increased risk of disease or death. Therefore, a blood biomarker might be useful for early diagnosis, treatment selection and response, and for the development of new medications.

In previous studies, TSP2, a protein secreted by cells lining blood vessels, emerged as a likely disease-related blood marker. While its levels were increased in PAH patients compared with healthy people, a genetic variant that leads to higher TSP2 levels could reduce the risk of developing PAH.

Now, researchers in Germany analyzed TSP2 levels in 196 patients with different forms of PH and 16 controls — individuals with suspected PH but normal resting pulmonary blood flow. All were recruited at the University Medical Centre Hamburg-Eppendorf between January 2021 and January 2022 (NCT04654650).

The participants had a median age of 67, and about two-thirds were women. Most patients had PAH (60%).

TSP2 blood levels in PH patients were significantly higher than in controls — median levels of 29.59 nanograms(ng)/mL vs. 19.45 ng/mL — and could effectively distinguish the two groups. In fact, its ability to do so was superior to that of high levels of NT-proBNP, a known marker of heart failure.

“In current clinical management, elevated levels of BNP/NT-proBNP, a marker of cardiac origin that is affected by comorbidities [co-existing conditions], is used to rule-in diagnosis and to assess disease severity in PH. More data are required to establish whether measurements of TSP2 in patients with PH might affect clinical decision-making above that of BNP/NT-proBNP,” the researchers wrote.

Blood levels of TSP2 were consistently elevated in people with different types of PH, including PAH, PH due to lung diseases, and PH caused by left heart disease, compared with control participants.

TSP2 levels also were increased in those with PAH caused by connective tissue or congenital heart diseases, and in those with PH due to chronic obstructive pulmonary disease (COPD) and interstitial lung diseases — disorders collectively characterized by inflammation and scarring in the lungs.

In contrast, participants with chronic thromboembolic PH (CTEPH) did not have increased levels of TSP2 relative to controls.

Next, the team found that high TSP2 levels were associated with 12 clinical measures in testing with 152 variables. Nine of these measures directly related to right heart structure and function, including right atrial pressure, or the filling pressure of the right heart, TAPSE — a measurement obtained by imaging of the heart, called echocardiography, that reflects the health of the right ventricle — and stroke volume, which is the amount of blood ejected from the ventricle with each cardiac cycle.

Among participants with PAH, TSP2 blood levels were increased in the patients with maladaptive changes in the right ventricle, and could distinguish these patients from those with adaptive right ventricle changes. Maladaptive right ventricle alterations were defined based on structural and functional criteria, the team noted, and are associated with reduced cardiac output.

Activity of the THBS2 gene, which codes for the TSP2 protein, also was increased in right ventricle tissue from patients with maladaptive changes compared with those with adaptive right ventricle adaptations, or controls.

Further research is needed to establish diagnostic accuracy for TSP2 regarding detection of PH and monitoring of [right ventricle] functionality, and to define the molecular mechanisms responsible.

TSP2 blood levels also were found to successively increase with exercise intolerance, a consequence of right ventricle maladaptation.

“We present observational evidence from a contemporary cohort [group] that TSP2 levels as measured in plasma samples are consistently increased across the spectrum of PH and that TSP2 can identify phenotypically distinct and clinical meaningful RV [right ventricle] responses,” the researchers wrote, adding, “Further research is needed to establish diagnostic accuracy for TSP2 regarding detection of PH and monitoring of RV functionality, and to define the molecular mechanisms responsible.”

Overall, these findings suggest [email protected] as a potential blood biomarker in PH.

“Converging evidence promotes thrombospondin-2 as a biomarker in pulmonary hypertension, that informs on the presence and progression of the disease,” the team wrote.

A Conversation With Rare Disease Advocates