【JACC CardioOncol】Danish epidemiological study: MGUS patients have a widespread increase in cardiovascular risk

Monoclonal gammopathy of unspecified significance (MGUS) refers to the presence of monoclonal immunoglobulins
in the absence of lymphoproliferative disorders.
Although MGUS has traditionally been considered a benign precursor to malignancy, recent evidence suggests that patients with MGUS are at increased risk of developing a variety of conditions, including bone disease, recurrent infections, autoimmune diseases, peripheral neuropathy, and kidney disease, even
in the absence of lymphoproliferative disease.
However, cardiovascular risk in patients with MGUS is not fully understood
.

In a recent article published in JACC:CardioOncology, Danish scholars analyzed the incidence of cardiovascular diseases between MGUS patients in the Danish National Patient Registry and age- and sex-matched control patients, including atherosclerotic disease (acute myocardial infarction, peripheral arterial disease, ischemic stroke), structural heart disease (heart failure, conduction disease), pulmonary hypertension (cor pulmonale), valvular disease (aortic stenosis, aortic regurgitation, mitral stenosis, Mitral regurgitation), aortic disease (aortic dissection, aneurysm), pericarditis, and arrhythmias (atrial fibrillation), and MGUS patients are at significantly increased
risk of heart failure, acute myocardial infarction, ischaemic stroke, atrial fibrillation, aortic aneurysm, aortic stenosis, aortic regurgitation, heart block, peripheral arterial disease, cor pulmonale, and venous thromboembolism.

Research methods

The Danish National Patient Registry is a comprehensive national database that collects all inpatient and outpatient visits in Denmark since 1978
.
The authors collected all diagnoses of MGUS using the Danish National Patient Registry, excluded multiple myeloma, lymphoma, and amyloid disease at baseline, and calculated incidence for broad cardiovascular outcomes, as well as the risk
of all-cause and cardiovascular mortality.
Patients were matched to a control population (1:10) from the Danish Central Population Registry based on MGUS' year of birth and sex, and the risk ratio (HR)
was calculated using the Cox proportional hazards regression model.

Research results

Baseline characteristics

Between January 1, 1995 and December 31, 2018, 8189 patients with MGUS (51.
2% male; The mean age was 69.
8±11.
7 years), and the matching control group was 81890 cases (51.
2% male, age 69.
8±11.
7 years).

Patients with MGUS had higher rates of comorbidities than controls, including hypertension (48.
0 versus 38.
5 percent), type 2 diabetes (13.
0 versus 9.
3 percent), cancer (13.
0 versus 11.
0 percent), chronic kidney disease (6.
4 versus 2.
0 percent), and dialysis use (1.
2 versus 0.
4 percent).

In addition, 13% of MGUS patients and 11% of control patients had prior cancer, with an equal distribution of major cancer subtypes (e.
g.
, 18% of breast cancer, 14% to 16% of prostate cancer, and 15% to 16% of gastrointestinal cancer).

Patients with MGUS have slightly higher drug use at baseline (including β blockers, ACE inhibitors, angiotensin-II receptor blockers, aspirin, clopidogrel, statins, direct oral anticoagulants, and warfarin).

All baseline comorbidities and drug use are shown in Table 1
.

morbidity

In age- and sex-adjusted logistic regression analysis, patients with MGUS had significantly higher odds for most cardiovascular diseases, including heart failure, atrial fibrillation, acute myocardial infarction, ischaemic stroke, aortic aneurysm, aortic dissection, aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation, conduction disease, pericarditis, peripheral artery disease, aortic aneurysm, venous thromboembolism, and cardiac device implantation compared with control patients (Table 2).

The prevalence of aortic dissection was similar in patients with and without MGUS (OR=0.
86).

finale

The mean follow-up of MGUS patients and control patients was 4.
3 and 4.
8 years, respectively, and the median follow-up was 3.
2 and 3.
6 years
, respectively.
The cumulative incidence of each cardiovascular disease during follow-up was higher in patients with MGUS compared with control patients (Figure 1).

Similarly, in an age- and sex-adjusted model, patients with MGUS had an elevated HR for all cardiovascular outcomes compared with control patients (Table 2).

After multivariate adjustment, estimates were partially weakened but there were statistically significant increases for most endpoints, including heart failure (HR=1.
55), atrial fibrillation (HR=1.
32), acute myocardial infarction (HR=1.
22), and aortic stenosis (HR=1.
60).

Conduction disease (HR=1.
32), peripheral arterial disease (HR=1.
69), pulmonary heart disease (HR=2.
06), and venous thromboembolic disease (HR=1.
43) (Table 2).

In addition, the overall mortality rate of MGUS patients was higher than that of control patients: 5.
86 per 100 person-years in the MGUS group (total 2432 people) and 3.
59 per 100 person-years (total 16619 in total) in the control group (multivariate adjusted HR = 1.
55).

Sensitivity analysis

In sensitivity analysis, the authors further analyzed the cohort of MGUS patients without type 2 diabetes, hypertension, previous myocardial infarction, and chronic kidney disease (n=3540 in MGUS cases versus n=45534 in control patients).

The risk of harm for all primary endpoints of patients with MGUS compared with control patients was substantially similar to the overall analysis (Table 3), including heart failure (HR=1.
67), peripheral arterial disease (HR=2.
17), heart block (HR=1.
54), venous thromboembolism (HR=1.
54), and mortality (HR=1.
86).

In addition, the authors excluded the first 6 months of follow-up after the diagnosis of MGUS in sensitivity analyses, with similar
results.

The authors also performed sensitivity analyses to censor patients who developed multiple myeloma, lymphoma, or amyloidosis during follow-up, with results similar
to those of the primary model.
Finally, the authors limited the analysis to cardiovascular mortality (7528 events) with similar results to the primary analysis (multivariate adjusted HR = 1.
55; P< 0.
0001).

discuss

This study used a large sample of MGUS patients to measure a wide range of cardiovascular outcomes associated with MGUS, and found that the risk of most cardiovascular diseases, including ischaemic stroke, acute myocardial infarction, and deep vein thrombosis
, remained increased after adjusting for common comorbidities and medications.
However, the risk of previous outcomes associated with invasive and structural heart disease, such as heart failure, cor pulmonale, and certain types of valvular disease (centre diagram),
is slightly higher.

This Danish national epidemiological study suggests that MGUS is associated with an increased risk of broad cardiovascular outcomes, not just the more widely known venous thromboembolic disease, and that for most cardiovascular diseases, risk estimates are elevated even after adjustment for common comorbidities and drug use, suggesting a possible causal effect
of MGUS on the panvascular system.
Although the relative risk of disease is elevated in arterial and venous thrombotic disease, the degree of risk generally appears to be higher
in outcomes associated with invasive and inflammatory diseases.

Although the pathophysiology driving increased cardiovascular risk in patients with MGUS is not fully understood, further research is needed to test several of the proposed hypotheses
.
MGUS can contribute to a variety of mechanisms that increase the risk of arterial and venous thrombosis, with higher levels of factor VIII and von pseudo-haemophilia factor demonstrated in MGUS patients, and clonal hematopoiesis associated with atherosclerotic disease
.
Even in the absence of myeloma, MGUS is associated with several changes in the microenvironment, including increased inflammation, bone resorption, and altered angiogenesis, in addition to paraprotein deposition involved in the pathogenesis of
MGUS.

In addition, population-based systematic screening studies of MGUS (regardless of symptoms) are necessary to confirm the results of this registry-based study
.
Future research should also assess the utility of increased screening and more aggressive management of cardiovascular risk factors in MGUS patients
.

References

Schwartz B,Schou M,Ruberg FL,et al.
Cardiovascular Morbidity in Monoclonal Gammopathy of Undetermined Significance: A Danish Nationwide Study.
JACC CardioOncol .
2022 Jul 19; 4(3):313-322.
doi: 10.
1016/j.
jaccao.
2022.
05.
009.

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