Elevated Plasma Levels of Nt-proBNP in Patients With Type 2 Diabetes Without Overt Cardiovascular Disease MARTIN MAGNUSSON, MD 1 OLLE MELANDER, MD, PHD 2 BO ISRAELSSON, MD, PHD 1 ANDERS GRUBB, MD, PHD 3 LEIF GROOP, MD, PHD 2 STEFAN JOVINGE, MD, PHD 1,4,5 OBJECTIVE — The NH 2 -terminal portion of the precursor of brain natriuretic peptide (Nt- proBNP) has been reported to be elevated in left ventricular dysfunction. This peptide is a split product from the proBNP molecule, and its level in the circulation is not, as the mature BNP peptide, dependent on the peripheral number of BNP receptors. We aimed to test the hypothesis that asymptomatic left ventricular dysfunction (ALVD), as estimated by Nt-proBNP, would be more prevalent in patients with type 2 diabetes without overt cardiovascular disease in compar- ison with matched control subjects. RESEARCH DESIGN AND METHODS — The study population consisted of 253 pa- tients with type 2 diabetes and 230 matched control subjects aged 40 –70 years without any overt heart disease from primary care centers in Western Finland and Southern Sweden. Nt-proBNP was measured in plasma by competitive enzyme immunosorbent assay. RESULTS — Patients with type 2 diabetes were shown to have higher Nt-proBNP values (360.9 pmol/l [262.6 – 467.9]) than control subjects (302.7 pmol/l [215.4 – 419.2]) (P  0.001). Nt-proBNP levels were independently related to diabetes after adjustment for age, sex, systolic and diastolic blood pressure, BMI, heart rate, drug treatment, serum creatinine, and cystatin C. CONCLUSIONS — Our data suggest that the secretion of Nt-proBNP is increased in type 2 diabetic patients with no overt heart disease, suggesting that type 2 diabetes is associated with a higher prevalence of ALVD than hitherto thought. Nt-proBNP may thus serve as a screening instrument to select patients with type 2 diabetes who could benefit from an echocardiographical examination. Diabetes Care 27:1929 –1935, 2004 T he incidence and prevalence of type 2 diabetes increases worldwide. In the adult population all over the world, the average prevalence for diabetes is estimated to be at least 4.0% (1). This figure is predicted to double until the year 2015 (2). Although microangiopathy rep- resents a severe threat to the population with diabetes, macroangiopathy and sub- sequent cardiovascular disease are the major causes of morbidity and mortality in these patients. Screening for kidney and retinal complications is already an es- tablished part of routine diabetes care to- day, but there is no comparable reoccurring screening for cardiac compli- cations of diabetes. This may simply be due to the lack of cost-effective methods; an echocardiographical examination is both expensive and time consuming and, therefore, not suited for screening pur- poses. The most evident cardiac compli- cation is coronary atherosclerosis. Not only is the extent of coronary atheroscle- rosis increased, the disease becomes clin- ical earlier and is more generalized in the coronary tree compared with the subjects without diabetes (3). Diabetes is also more prevalent among patients with heart failure. In the Framingham study, male patients with diabetes had twice the risk and female patients five times the risk of a control population to develop heart fail- ure (4). At least partially, this could be explained by the increase in severity and incidence of ischemic heart disease among patients with diabetes. However, data from autopsy studies have suggested that hearts from patients with diabetes also have an increased collagen content (5). Moreover, patients with diabetes have a disproportional increase in left ventricular mass independent of blood pressure (6 – 8). All of these factors may contribute to increased myocardial stiff- ness. This is especially important because left ventricular hypertrophy in a meta- analysis has been associated with a 1.5- to 3.5-fold increased risk of future cardio- vascular morbidity and a 1.5- to 6.8-fold increase of all-cause mortality (9). Thus, taken together, there are several mecha- nisms beside the more aggressive athero- sclerosis that could explain why patients with diabetes have a higher cardiac mor- bidity and mortality. Brain natriuretic peptide (BNP) is a 32–amino acid peptide (10). It is synthe- sized predominantly in the left ventricle of the heart as the 108 –amino acid pro- hormone preproBNP (-BNP) (11–13). The hormone is a potent vasodilator and a natriuretic factor regulating salt and water homeostasis. BNP is stored in the human cardiac tissue mainly as BNP-32 with a lesser amount of the precursor pre- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● From the 1 Department of Cardiology, University Hospital MAS, Lund University, Sweden; the 2 Department of Endocrinology, University Hospital MAS, Lund University, Lund, Sweden; the 3 Department of Clinical Chemistry, University Hospital in Lund, Lund University, Lund, Sweden; the 4 Cardiovascular Research Group, Wallenberg Laboratory University Hospital MAS, Lund University, Lund, Sweden; and the 5 Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund, Sweden. Address correspondence to Dr. Stefan Jovinge, Department of Cardiology, Ing 35 Univ Hosp MAS, S-205 02 Malmo ¨ , Sweden. E-mail: stefan.jovinge@stemcell.lu.se. Received for publication 1 December 2003 and accepted in revised form 25 March 2004. Abbreviations: ALVD, asymptomatic left ventricular dysfunction; BNP, brain natriuretic peptide; LVD, left ventricular dysfunction; Nt-proBNP, NH 2 -terminal portion of the precursor of BNP; SBP, systolic blood pressure. A table elsewhere in this issue shows conventional and Syste `me International (SI) units and conversion factors for many substances. © 2004 by the American Diabetes Association. Emerging Treatments and Technologies O R I G I N A L A R T I C L E DIABETES CARE, VOLUME 27, NUMBER 8, AUGUST 2004 1929