Blood proteins that predict right ventricle failure in PH identified

They may serve as biomarkers of disease progression, therapeutic targets

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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A scientist looks at samples through a microscope in a lab, with vials on the countertop nearby.

Researchers have identified three proteins — NID1, C1QTNF1, and CRTAC1 — in the bloodstream of people with pulmonary hypertension (PH) whose presence accurately predicted the failure of the heart’s right ventricle (RV) and related outcomes, a study reports.

The proteins may serve as biomarkers to assess disease progression and severity or as potential therapeutic targets for heart failure in PH patients.

The study “Transcriptional profiling unveils molecular subgroups of adaptive and maladaptive right ventricular remodeling in pulmonary hypertension,” was published in Nature Cardiovascular Research.

People with PH have elevated blood pressure in their pulmonary arteries, which carry oxygen-poor blood pumped from the right side of the heart into the lungs to be oxygenated. With pushback from high blood pressure, the RV must work harder to pump blood, which can strain and weaken heart muscles over time.

The RV’s muscle walls are relatively thin and flexible, allowing for large changes in blood volume. They can also compensate for increasing pulmonary blood pressure by thickening and strengthening contractions, a process called adaptive remodeling.

With PH, these compensatory mechanisms become insufficient over time and the RV muscle progressively weakens, called maladaptive remodeling. The RV’s failure to pump blood is the primary cause of death among PH patients.

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What proteins contribute to right ventricle failure?

Understanding the molecular players involved in transitioning from adaptive remodeling to RV dysfunction could help identify outcome markers and possible therapeutic targets to slow or halt these changes, leading a team of researchers in Germany, Canada, and the U.K. to compare gene activity in RV tissue from three stages of this transition — normal (control), early adaptive remodeling, and late maladaptive remodeling.

Determining which genes are turned on or off at each stage, also called differential gene expression (DEG), can reveal both distinct and shared biological processes and associated molecules. Tissues were collected from 40 people and two animal models, and were classified into transitional groups, based on RV function and other standard tests.

Compared with control human samples, those with RV dysfunction showed altered expression of 2,027 genes and 260 DEGs between adaptive and maladaptive samples. No differences were seen between the adaptive and control samples.

DEGs in dysfunctional RV tissue were associated with greater activity of genes associated with pro-inflammatory signaling proteins and the extracellular matrix (ECM), a three-dimensional network of molecules and proteins, including collagen, that provides structural support to cells. The ECM plays a key role in tissue remodeling.

Genes with lower expression were associated with energy metabolism and heart muscle contraction in maladaptive samples, while adaptive samples had higher expression among these same genes.

Rat models of PH were either induced with the chemical monocrotaline or by physically restricting pulmonary blood flow. The researchers detected 259 genes commonly altered in dysfunctional samples in both rat models and human samples that were associated with ECM, pro-inflammatory signaling proteins, and blood vessels’ widening and constriction.

In human female samples, no changes were detected between control and early adaptive remodeling. Major changes were associated with dysfunctional samples similar to the DEG analysis of the entire group.

In male samples, 739 genes were dysregulated in the adaptive group and 38 genes were dysregulated in the maladaptive group, suggesting “male participants may develop maladaptive hypertrophy earlier than females.”  Sex-specific differences in RV adaptation were associated with fatty acid metabolism and estrogen response.

Blood proteins identified

Five ECM proteins commonly altered in human and rat samples were identified as significant. NID1 and C1QTNF1 were elevated in maladaptive samples, while CRTAC1, SPARCL1, and MEGF9 were higher in adaptive remodeling tissues.

Bloodstream levels of these proteins were measured in two independent groups of people with pulmonary arterial hypertension (PAH), a type of PH caused by narrowing of the pulmonary arteries.

Elevated blood levels of NID1 and C1QTNF1 significantly correlated with increased mean pulmonary artery pressure (mPAP) and proBNP levels, a marker of heart failure. Decreased MEGF9 levels were strongly associated with high proBNP levels, worse cardiac index, a measure of heart function, and elevated resistance to blood flow in the pulmonary arteries.

All five proteins could significantly differentiate between adaptive and maladaptive groups of PAH patients. NID1, C1QTNF1, and CRTAC1 best predicted the development of a maladaptive RV state and worse outcomes. NID1 and C1QTNF1 could distinguish early and late RV dysfunction changes.

“Our study provides a resource for subphenotyping [subcharacterizing] RV states, identifying state-specific biomarkers, and potential therapeutic targets for RV dysfunction,” the researchers wrote.

A Conversation With Rare Disease Advocates