Patients with monoclonal gammopathy of undetermined significance (MGUS) are at a higher risk for a variety of cardiovascular diseases compared with controls, according to a study published in JACC Cardio-Oncology. With 8,189 patients with MGUS and 81,890 controls, the findings from this large sample size highlight the wide-ranging risks that come with MGUS, aside from its risk of progressing to cancer, and signal the importance of monitoring for cardiovascular issues in patients with MGUS, the researchers said.
Every patient in the Danish National Patient Registry who was diagnosed with MGUS between 1995 and 2018 – but not multiple myeloma, lymphoma, or amyloidosis or other related disorders – was matched with 10 controls based on birth year and sex. At baseline, the patients with MGUS tended to have more comorbidities than the controls, including hypertension, diabetes, and chronic kidney disease. The median follow-up time was 3.2 years for the patients with MGUS versus 3.6 years for the controls.
The risk of incident cardiovascular disease was higher for the MGUS group after adjusting for an array of comorbidities including hypertension, diabetes, kidney disease, acute myocardial infarction, atrial fibrillation, stroke, peripheral artery disease, prior venous thromboembolism (VTE), and medications including beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, aspirin, and statins.
Patients with MGUS were 52% more likely to have heart disease in the study period, 32% more likely to have atrial fibrillation, 19% more likely to have acute myocardial infarction, 15% more likely to have ischemic stroke, 51% more likely to have aortic aneurysm, 43% more likely to have VTE, 67% more likely to have peripheral artery disease, 99% more likely to have cor pulmonale, and 2.58 times more likely to have aortic stenosis.
There are several factors that could play into these increased risks, researchers said. Biomarkers related to bone metabolism, such as OPG (osteoprotegerin) and RANKL (receptor activator of nuclear factor-kappa ligand), have been shown to be increased in patients with MGUS, they noted.
“These biomarkers, also reflective of vascular calcification processes, have been strongly associated with atherosclerotic disease formation and valvular disease in general populations, as well as with the burden of aortic calcification in patients with peripheral artery disease,” they said. “Moreover, MGUS is often associated with a low-grade chronic inflammatory state with elevated cytokines, such as interleukin 6.”
Researchers noted the risk was somewhat greater for cardiovascular outcomes associated with infiltrative and structural disease, such as heart failure, cor pulmonale, and some valvular diseases.
“Further studies are needed to understand why,” said Charlotte Andersson, MD, PhD, a cardiology fellow at Boston University and senior study author. She noted that the bone metabolism and inflammatory factors could contribute, potentially along with tissue deposition of the paraproteins involved with MGUS.
“This study should be regarded as hypothesis-generating, being registry-based, but should hopefully stimulate further studies downstream to better understand the associations with … heart failure, valvular disease, and aortopathy, which were strong enough to me to suggest that residual confounding cannot fully explain the associations,” Dr. Andersson said. “If our results are confirmed in other studies, the implications would be large, ranging from trying to understand exactly which mechanisms cause the risk to how preventive strategies could mitigate these risks.”
Brian Schwartz, MD, the primary study author who was then with Boston Medical Center, said the findings support the argument for better screening.
“If these findings are replicated, it has the potential to change the way we monitor patients with MGUS in terms of follow-up and screening for cardiovascular disease over its clinical course.”
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Schwartz B, Schou M, Ruberg F, et al. Cardiovascular morbidity in monoclonal gammopathy of undetermined significance: a Danish nationwide study [published online ahead of print, 2022 July 19]. JACC Card Onc. doi: 10.1016/j.jaccao.2022.05.009.