Diabetes Care 1 Arterial Stiffness Predicts Anniina Tynjal¨ a,¨ 1,2,3 Carol Forsblom,1,2,3 Valma Harjutsalo,1,2,3,4 Mortality in Individuals With Per-Henrik Groop,1,2,3,5 and Daniel Gordin,1,2,3,6 on behalf of the Type 1 Diabetes FinnDiane Study Group https://doi.org/10.2337/dc20-0078 OBJECTIVE Type 1 diabetes is accompanied by a significant burden of cardiovascular disease (CVD), which is poorly explained by traditional risk factors. We therefore aimed to explore whether arterial stiffness estimated by the augmentation index (AIx) predicts mortality in individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS After baseline examination comprising pulse wave analysis by applanation to- nometry alongside assessment of traditional cardiovascular risk factors, 906 indi- viduals with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study were followed up for a median of 8.2 (5.7–9.7) years. Associations be- tween baseline hemodynamics, including AIx, and all-cause mortality as well as a composite of cardiovascular and/or diabetes-related mortality were investigated using multivariable Cox regression models. RESULTS The 67 individuals who died during follow-up had higher baseline AIx (28% [21–33] vs. 19% [9–27]; P < 0.001) compared with those alive. This association was CARDIOVASCULAR AND METABOLIC RISK independent of conventional risk factors (age, sex, BMI, HbA1c, estimated glo- merular filtration rate [eGFR], and previous CVD event) in Cox regression analysis 1Folkhalsan¨ Institute of Genetics, Folkhalsan¨ Re- (standardized hazard ratio 1.71 [1.10–2.65]; P 5 0.017) and sustained in a search Center, Helsinki, Finland 2 subanalysis of individuals with chronic kidney disease. Similarly, higher AIx was Abdominal Center Nephrology, Helsinki Univer- sity Hospital, University of Helsinki, Helsinki, associated with the composite secondary end point of cardiovascular and diabetes- Finland related death (N 5 53) after adjustments for sex, BMI, eGFR, previous CVD event, 3Research Program for Clinical and Molecular and height (standardized hazard ratio 2.30 [1.38–3.83]; P 5 0.001). Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland 4 CONCLUSIONS National Institute for Health and Welfare, Hel- sinki, Finland AIx predicts all-cause mortality as well as a composite cardiovascular and/or 5Department of Diabetes, Central Clinical School, diabetes-related cause of death in individuals with type 1 diabetes, independent of Monash University, Melbourne, Victoria, Australia 6 established cardiovascular risk factors. Joslin Diabetes Center, Harvard Medical School, Boston, MA Corresponding author: Per-Henrik Groop, per- henrik.groop@helsinki.fi Cardiovascular disease (CVD) is the leading cause of the excess morbidity and Received 11 January 2020 and accepted 15 June mortality observed in individuals with type 1 diabetes, and the standardized mortality 2020 ratio is known to increase by each stage of diabetic nephropathy (1,2). This © 2020 by the American Diabetes Association. predisposition is only partly attributable to traditional risk factors, and, in fact, Readers may use this article as long as the work is properly cited, the use is educational and not for cardiovascular risk scores developed for the general population and type 2 diabetes profit, and the work is not altered. More infor- are poorly applicable in type 1 diabetes (3). Thus, a unique risk factor profile is likely to mation is available at https://www.diabetesjournals prevail in these individuals and merits further characterization. .org/content/license. Diabetes Care Publish Ahead of Print, published online July 9, 2020 2 Arterial Stiffness and Mortality in Diabetes Diabetes Care Arterial stiffness is a well-known pre- Study Population which no autopsy has been performed. dictor of mortality in the general pop- In this substudy, individuals with avail- Therefore, we combined cardiovascular ulation and in selected groups, including able baseline data on arterial stiffness by and/or diabetes-related causes of death those with type 2 diabetes, yet no lon- the year 2015 were included. Further into one secondary end point in the gitudinal studies have been carried out in inclusion criteria were age .18 years, survival analysis, alongside all-cause and individuals with type 1 diabetes (4,5). type 1 diabetes diagnosed by 40 years of cardiovascular mortality. Interestingly, arterial stiffening seems to age, and insulin treatment initiated occur early in individuals with type 1 within 1 year of the diagnosis. The base- Statistical Methods diabetes, as their pulse pressure (PP), a line population comprised 906 individu- Univariable analyses of established car- crude estimate of arterial stiffness, in- als (416 men) with a mean age of 43.2 diovascular risk factors and hemodynamic creases up to 15–20 years earlier than in years (SD 12.2), including 134 individuals variables from pulse wave analysis were healthy control subjects (6). This phe- with chronic kidney disease (CKD), de- run to detect differences between those nomenon of early arterial aging made fined as an estimated glomerular filtra- who died during follow-up and those who us hypothesize that arterial stiffness tion rate (eGFR) ,60 mL/min/1.73 m2, survived. The x2 tests were used for di- might be an important mediating factor ongoing hemodialysis, or having received a chotomous variables and t tests or Mann– leading to premature death in type 1 renal transplant, as well as 98 individuals Whitney U tests for continuous variables. diabetes. Because microangiopathy is a with a previous CVD event, defined as Data are presented as mean 6 SD (nor- major manifestation of complicated type 1 myocardial infarction, coronary revascu- mally distributed) or median with inter- diabetes, we further hypothesized that larization, stroke, lower extremity revas- quartile range (nonnormally distributed) early signs of arterial stiffening could cularization, or nontraumatic amputation. for continuous variables and as percen- be detected by the augmentation index tages for dichotomous variables. (AIx), which, as a measure of arterial Pulse Wave Analysis Longitudinal analysis was performed pulse wave reflections, is particularly Applanation tonometry (SphygmoCor; At- using Kaplan-Meier survival curves with affected by stiffness in the small resis- Cor Medical, Sydney, New South Wales, log-rank tests. For multivariable analyses, tance arteries (7). We previously showed Australia) is a noninvasive reproducible continuous covariates were standardized that AIx correlates with microvascular method to estimate central (aortic) blood by dividing the difference of each value and macrovascular complications in type pressure variables and arterial stiffness and the covariate mean by the SD of that 1 diabetes in a cross-sectional setting (8). through pulse wave analysis (10,11). A covariate. The best-fit regression model The aim of this study was therefore to high-fidelity micromanometer (SPC-301; for each end point was selected using the explore whether AIx predicts all-cause as Millar Instruments, Houston, TX) is used Akaike information criterion and further well as cardiovascular and/or diabetes- to record peripheral pressure waveforms adjusted for sex and the variable of in- related mortality in type 1 diabetes. from the radial artery of the right arm, and terest from pulse wave analysis. Indepen- three readings with a pattern of at least dent associations with mortality were 20 valid waveforms are selected for the determined by Cox regression analysis RESEARCH DESIGN AND METHODS analysis. The software generates a cen- and are presented as standardized hazard The Finnish Diabetic Nephropathy tral pressure waveform using a validated ratios (sHRs) with 95% CI. P values ,0.05 Cohort transfer function. This enables determi- were considered statistically significant. This prospective observational follow-up nation of central systolic blood pressure study is part of the ongoing nationwide (CSBP) and diastolic blood pressure (CDBP); RESULTS 5 2 Finnish Diabetic Nephropathy (Finn- central PP (CPP) CSBP CDBP; central Baseline Characteristics Diane) Study, in which .5,400 individ- mean arterial pressure (CMAP) 5 1/3 3 After a median follow-up of 8.2 (5.7–9.7) uals with type 1 diabetes have been CSBP 1 2/3 3 CDBP; central end-systolic years, 67 (7.4%) individuals had died characterized since 1997. The study pro- pressure (CESP); ejection duration; as well (Table 1). These individuals were older, tocol has been approved by the local as subendocardial viability ratio (SEVR), had a longer diabetes duration, higher which indirectly estimates myocardial ethics committees, and written informed office SBP, PP, HbA1c, and triglycerides, as consent was obtained from each partic- perfusion. To assess stiffness in the small well as lower BMI and eGFR at baseline, ipant. The FinnDiane protocol has been resistance arteries, AIx is calculated as a compared with those who survived. Sim- previously described in detail (9). Briefly, quotient of two measures: the difference ilarly, those who died had more often baseline data on cardiovascular risk of the second and the first systolic peak been prescribed antihypertensive and factors and diabetic complications are of the pressure waveform (corrected for lipid-lowering medication and had more collected from standardized question- heart rate) and CPP. often a previous CVD event at baseline. In naires and medical files, as well as through the pulse wave analysis, AIx (28% [21–33] clinical examination and biochemical