Traditional Assessment Tools May Underestimate Cardiovascular Risk in AATD


Patients with AATD had increased cardiovascular risk compared to non-AATD COPD and healthy controls, with results suggesting physiological tests may assess risk more accurately.

Elizabeth Sapey, MBBS, PhD | Credit: University of Birmingham

Elizabeth Sapey, MBBS, PhD

Credit: University of Birmingham

Findings from a recent study are providing evidence supporting a relationship between cardiovascular disease (CVD) and lung disease in alpha 1 antitrypsin deficiency (AATD).1

Results call attention to an increased risk of cardiovascular disease measured by arterial stiffness when adjusted for age and smoking history compared to non-AATD chronic obstructive pulmonary disease (COPD) and healthy controls. Of note, this risk was not captured by QRISK2®, suggesting physiological tests such as aortic pulse wave velocity (aPWV) may be a better tool for screening than traditional risk factors alone.1

An inherited genetic disorder that increases the risk of emphysema, cirrhosis, and panniculitis, AATD affects people who have 2 copies of the SERPINA1 gene that produces an abnormal type of alpha-1 antitrypsin. Although it shares features with COPD, AATD has a greater burden of proteinase-related tissue damage generally associated with CVD.2

“It is unclear whether patients with AATD have a greater risk of CVD compared to usual COPD, how best to screen for this, and whether neutrophil proteinases are implicated in AATD-associated CVD,” Elizabeth Sapey, MBBS, PhD, director of the Institute of Inflammation and Ageing at the University of Birmingham, and colleagues wrote.1

Thus, investigators sought to compare CVD risk in never-augmented AATD patients to non-AATD COPD and healthy controls; to assess relationships between CVD risk and lung physiology; and to determine if neutrophil proteinase activity is associated with CVD risk in AATD. To do so, they conducted an observational study among patients with AATD, patients with COPD but no AATD, and healthy controls.1

Cardiovascular risk was assessed by QRISK2® score and aortic stiffness measurements using aPWV. Additionally, medical history, computed tomography scans, and post-bronchodilator lung function parameters were reviewed and systemic proteinase 3 activity was measured, and participants were followed for 4 years to assess CVD development.1

In total, 228 patients with AATD, 50 with non-AATD COPD, and 51 healthy controls were recruited. Of those with AATD, 221 were PiZ and 7 were Z null genotypes. These participants were matched physiologically to 50 patients with non-AATD COPD. Sex was matched across all groups, and 51 healthy controls were matched for age with the non-AATD COPD group.1

Investigators noted there were no differences between groups in the prevalence of diabetes, chronic kidney disease, atrial fibrillation, rheumatoid arthritis, and treated hypertension. However, there were differences in the ages across the cohorts, with AATD patients being younger than both healthy controls and COPD patients (P <.0001 for both).1

After excluding patients with a previous diagnosis of CVD from QRISK2® calculation, 211 AATD, 41 COPD, and 47 healthy controls were compared for QRISK2® and aPWV. Results showed that in all COPD and healthy control participants, QRISK2® and aPWV gave concordant results, with no COPD patients or healthy controls having a low QRISK2® score and a high aPWV or visa versa.1

However, investigators noted the same was not true for patients with AATD. While 116 patients (55%) had concordant QRISK2® and aPWV results, 95 (45%) had discordant results, suggesting QRISK2® and aPWV were not aligned in this population in the same way as in the non-AATD COPD or healthy control cohorts.1

Further analysis adjusting for age and smoking history (total model P <.0001, Adjusted R2 = 0.23), aPWV was lower in both non-AATD COPD (co-efficient − 0.90; 95% CI, − 1.65 to − 0.14; P = .02) and healthy controls (co-efficient − 1.84; 95% CI, − 2.60 to − 1.11; P <.0001) compared with AATD.1

Investigators pointed out greater aPWV was associated with impairments in lung physiology, the presence of emphysema on CT scan, and proteinase 3 activity following adjustment for age, smoking status, and traditional CVD risk factors using QRISK2® scores in AATD, but there were no such relationships with QRISK2® alone in AATD.1

At 4 years of follow-up, there were 23 AATD, 18 COPD, and 7 healthy control participants with a new diagnosis of CVD. Of note, AATD patients with confirmed CVD had a greater aPWV but not QRISK2® at baseline assessment.1

Investigators outlined several potential limitations to these findings. These included the lack of coronary artery angiograms to definitively diagnose CVD in AATD, the inability to determine whether the degree of neutrophil activity influences the severity of CVD or the timing of its acquisition, and the potential underpowering of certain comparisons in the study.1

“This study suggests relationships between CVD and lung disease in AATD, with a proposed mechanism being proteinase-driven breakdown of elastin fibers in the large arteries and lungs,” investigators concluded.1 “Studies assessing the effects of augmentation therapy or anti-proteinases on CVD in carefully matched AATD patients are now indicated, to test this hypothesis further.”


  1. Sapey E, Crowley LE, Edgar RG, et al. Cardiovascular disease in Alpha 1 antitrypsin deficiency: an observational study assessing the role of neutrophil proteinase activity and the suitability of validated screening tools. Orphanet J Rare Dis 19, 130 (2024).
  2. Cleveland Clinic. Alpha-1 Antitrypsin Deficiency. Diseases & Conditions. October 18, 2022. Accessed May 28, 2024.
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