Emerging biomarkers in cardiometabolic disease

Abstract
The epidemiological association between diabetes and heart failure is well-established and the two entities are
emerging as global threats, both individually and synergistically, to an aging population. The exploration of multiple
proteins can shed light on pathophysiological pathways in both diabetes and cardiovascular disease. This can
possibly provide novel diagnostic, prognostic and hopefully therapeutic implications.
The overall aim of this dissertation was to explore novel biomarkers in cardiometabolic disease especially in heart
failure.
This thesis was based on epidemiological data from the Malmö Preventive Project Re-Examination (MPP-RES)
study and the Heart and brain failure investigation trial (HARVEST-Malmö). In Paper 1 we used a multiplex
proteomic panel consisting of 92 proteins with known or alleged associations with cardiovascular disease,
metabolism and inflammation to explore novel biomarkers for incident diabetes in the population-based cohort
MPP-RES (n=1026). We were able to identify seven proteins associated with incident diabetes, of which four not
previously described. Two of these (Galectin-4 and Paraoxonase-3) were associated with diabetes independently
of fasting plasma glucose implying an glucose-independent association with diabetes.
In Paper 2, we built upon the results from Paper 1, since one of our ultimate aims with this thesis was to explore
common pathophysiological pathways between diabetes and cardiovascular disease. Using the seven proteins
identified in Paper 1 we investigated whether these were associated with pertinent cardiovascular outcomes such
as all-cause and cardiovascular mortality, incident coronary events and incident heart failure. We found that two
proteins (Galectin-4 and Cathepsin D) were associated with all investigated outcomes in multivariable Cox
regression analyses and represented novel findings. Galectin-4 may possibly exert its effect on cardiometabolic
disease through the incretin system and Cathepsin-D has previously been described to reduce the antioxidative
effects of high-density lipoprotein.
In Paper 3, we switched from the population-based MPP-RES cohort to the HARVEST-Malmö study which
consists of heart failure patients admitted to the cardiology and internal medicine wards at Skånes University
Hospital in Malmö, Sweden. We assessed the predictive ability in terms of mortality and re-hospitalization, of five
different proteins (midregional pro-adrenomedullin, copeptin, NT-proBNP, CT-pro-endothelin-1 and cystatin C).
The investigated proteins represent different pathophysiological mechanisms involved in heart failure such as the
neuroendocrine response, cardiovascular stress and renal function. Higher plasma levels of all proteins but CTpro-
endothelin-1 were associated with increased risk of post-discharge mortality but only NT-proBNP, which in
many ways is the gold standard for biomarkers in heart failure, was associated with increased risk of rehospitalization.
Finally, in Paper 4, which was a collaboration with an Italian heart failure study (GREAT Rome Network) we
investigated the effects of two emerging biomarkers in heart failure; bioactive adrenomedullin (bio-ADM) which is
considered a marker for congestion, and proenkephalin A (penKid), which is a marker for renal dysfunction. While
NT-proBNP has many uses, it has not been shown to adequately assess residual congestion in heart failure
patients. We were able to show that increased levels of bio-ADM were associated with increased congestion
measured through a clinical congestion score where peripheral edema was the strongest and driving association.
Furthermore, we showed that bio-ADM was predictive of 1-year mortality, increased risk of re-hospitalization and
length of hospital stay. PenKid levels responded approximately 48 hours prior to creatinine in the setting of acute
kidney injury and we showed that penKid was associated with worsening renal function as well as with in-hospital
and 1-year mortality.