New study links ALDH2 enzyme to PH-LHD in heart failure patients

Findings suggest ALDH2 as treatment target for PH due to left heart disease

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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A heart-shaped image is seen on a human heart shown in front of a pair of lungs.

A variant in the gene encoding the ALDH2 enzyme — fully known as aldehyde dehydrogenase 2 — was linked to an increased risk of pulmonary hypertension due to left heart disease (PH-LHD) among heart failure patients, a study in China found.

Also called a polymorphism, meaning it involves one of two or more variants of a particular DNA sequence, the variant is associated with lower activity of the enzyme and a higher risk of cardiovascular conditions in the general population.

Simply put, according to the researchers, the new study shows it’s a predictor of pulmonary hypertension due to left heart disease.

The team further believes the findings altogether position ALDH2 as “a new target for clinical treatment of PH-LHD.”

The study, “Aldehyde Dehydrogenase 2 (ALDH2) rs671 Polymorphism is a Predictor of Pulmonary Hypertension Due to Left Heart Disease,” was published in Heart, Lung and Circulation.

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All forms of pulmonary hypertension (PH) are characterized by elevated pressure in the pulmonary arteries, which pump blood from the heart to the lungs. The most common type is PH-LHD, where this elevated pressure is caused by left heart disease.

Normally, the lungs send oxygenated blood into the left side of heart, which then pumps it out to the rest of the body. When the left side of the heart isn’t functioning properly, blood can’t be moved out of the lungs as effectively, leading to elevated pressure.

The most common cause of PH-LHD is heart failure, and the presence of PH-LHD in heart failure patients is linked to a worse prognosis and higher risk of death. Still, appropriate treatments are lacking. A better understanding of disease mechanisms is needed in order to develop better therapies, according to the authors.

ALDH2 is an antioxidant enzyme that’s known to help reduce cardiac cell death and to have a protective effect on the heart. In a preclinical model of pulmonary arterial hypertension, another form of PH, it has shown to be protective.

Given the shared mechanisms between types of PH, this raises the possibility that ALDH2 also may be involved in PH-LHD.

A known polymorphism in a specific part of the gene that encodes ALDH2, called rs671, is linked to lower ALDH2 function and a higher cardiovascular disease risk in the general population. A polymorphism on its own doesn’t typically cause disease, but it could be a risk factor for certain health problems.

While the main, or wild-type, version of the rs671 site holds a specific DNA building block, G, the variant version instead contains one known as A. This produces a version of ALDH2 with significantly less enzyme activity.

Given that, the scientists aimed to investigate whether the ALDH2 polymorphism is a risk factor for the development of PH-LHD. Their study involved 178 heart failure patients hospitalized at a center in China.

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More patients with PH-LHD had variant in gene encoding the ALDH2 enzyme

Among the patients, 76 people developed PH-LHD and 102 did not. A number of clinical features differed between these two groups. For example, those with PH-LHD were older, with more significant symptoms of heart failure than those who did not develop the condition. A number of laboratory measures related to cardiovascular function and blood flow also differed between the two groups.

A significantly higher proportion of patients with PH-LHD had at least one copy of variant ALDH2 (42.1%) compared with patients without PH-LHD (25.5%).

Additional clinical and laboratory factors were statistically linked to PH-LHD. After controlling for these factors, final statistical analyses indicated that variant ALDH2 was a significant independent risk factor for the development of PH-LHD in heart failure patients.

Further analyses showed that this risk was maintained regardless of age, sex, heart failure type, and the presence of atrial fibrillation — a heart condition marked by an irregular heartbeat. While variant ALDH2 was a risk factor among patients who did not drink alcohol, it was not among those who did.

That finding may be related to the fact that ALDH2 is involved in alcohol metabolism, and thus, the variant may influence alcohol tolerance, according to the researchers.

Variant ALDH2 may be an independent risk factor for [heart failure] combined with PH-LHD.


Among the 76 people with PH-LHD, 44 had wild-type ALDH2 and 32 had a variant version. While most clinical and laboratory factors did not differ between these two groups, those with variant ALDH2 had greater stiffness in the pulmonary arteries.

“Variant ALDH2 may increase the risk of PH-LHD in HF patients by participating in vascular remodeling of pulmonary arteries,” the researchers wrote. Vascular remodeling refers to alterations in the structure of blood vessels that’s implicated in PH progression.

While the findings altogether implicated ALDH2 in PH-LHD, the team noted that larger studies with more extensive tests of cardiac function are still needed to better understand the relationship.

According to the scientists, “follow-on studies are currently being conducted to address these deficiencies.”

Overall, the team concluded, “this study found that the incidence of variant ALDH2 was higher in the HF [heart failure] with PH-LHD group than the HF without PH-LHD group, and variant ALDH2 may be an independent risk factor for HF combined with PH-LHD.”

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