the finnish diabetic nephropathy ( finndiane ) study is an ongoing , nationwide , prospective multicenter study seeking clinical , genetic , biochemical , and environmental risk factors for diabetes complications , with an emphasis on diabetic nephropathy . participating study centers comprise diabetes and renal outpatient clinics at all five university central hospitals , all 16 central hospitals , the majority ( n = 27 ) of regional hospitals , and 31 major primary health care centers in finland . patients with t1d ( international classification of diseases , 10th revision , code e10 ) were recruited at routine outpatient visits . on the basis of medical records , the study protocol is in accordance with the declaration of helsinki as revised in 2000 and approved by the local ethics committee in each study center . written informed consent was obtained from each patient . at baseline , patients underwent a thorough clinical investigation that took place in conjunction with a regular visit to the attending physician . follow - up data on the occurrence of cvd and verified renal status were collected by reexamination of the patients or review of the medical files . the median ( range ) follow - up time for the study population was 5.3 ( 0.014.0 ) years . after the patient had rested for at least 10 min , blood pressure was measured twice in a sitting position by a trained nurse . pp was calculated as ( sbp  dbp in mmhg ) , and mean arterial pressure was calculated as ( 1/3 sbp + 2/3 dbp in mmhg ) . cvd was defined as any of the following events : myocardial infarction , coronary artery procedure ( bypass surgery or angioplasty ) , stroke ( ischemic or hemorrhagic ) , limb amputation because of ischemia , or a peripheral artery procedure . renal status was based on the urinary albumin excretion rate ( aer ) in two of three consecutive overnight or 24-h urine collections . normal aer was defined as < 20 g / min or < 30 mg/24 h , microalbuminuria was defined as 20 g / min  aer < 200 g / min or 30 mg/24 h  aer < 300 mg/24 h , and macroalbuminuria was defined as aer 200 g / min or aer 300 mg/24 h. end - stage renal disease ( esrd ) was defined as patients undergoing dialysis or having received a kidney transplant . progression was defined as a change from one level to a higher level of aer or the development of esrd . data on cvd events and progression of albuminuria were available in 3,110 patients ( 69% of all patients with data on pp ) versus 3,424 patients ( 76% ) , respectively . in a subpopulation of 408 patients , both arterial stiffness measured by pulse - wave analysis ( pwa ) and the median ( range ) follow - up time was 6.1 ( 0.011.0 ) years . applanation tonometry ( sphygmocor , atcor medical , sydney , australia ) is a widely used noninvasive method to estimate arterial stiffness by analyzing arterial pressure waveforms ( 12 ) . the pulse wave was recorded from the radial artery of the right arm with a high - fidelity micromanometer ( spt-301 , millar instruments , houston , tx ) . a model of the central pressure waveform was synthesized by the sphygmocor software using a validated generalized mathematic transformation to calculate the augmentation index ( aix ) and aortic pp as indicators of arterial stiffness ( 13 ) . hba1c was determined locally by standardized assays , and serum lipid and lipoprotein concentrations were determined centrally by automated enzymatic methods ( hoffman - laroche , basel , switzerland ) . estimated glomerular filtration rate was calculated using the modification of diet in renal disease four - variable equation ( 14,15 ) . baseline characteristics are presented as means  sd for normally distributed values and as median with interquartile range for non - normally distributed values and percentages . differences between groups for normally distributed variables were tested using anova , and for nonparametric data the mann  whitney or kruskal  wallis test was used . when p values were adjusted for age , ancova was used for continuous variables and logistic regression for categoric variables . for categoric variables , risk factors for the progression of diabetes complications were assessed using cox proportional hazard survival regression showing results as hazard ratios with 95% cis . age , sex , hba1c , total cholesterol , estimated glomerular filtration rate , history of smoking , use of antihypertensive medication , and pp were used as covariates . to account for a potential multicolinearity , we chose to use age but not duration of diabetes in the models , because the associations were stronger between age at baseline and incident events at follow - up . similarly sbp was not included in the analysis because of the strong association with pp ( r = 0.83 ; p < 0.001 . ) cvd was defined as any of the following events : myocardial infarction , coronary artery procedure ( bypass surgery or angioplasty ) , stroke ( ischemic or hemorrhagic ) , limb amputation because of ischemia , or a peripheral artery procedure . renal status was based on the urinary albumin excretion rate ( aer ) in two of three consecutive overnight or 24-h urine collections . normal aer was defined as < 20 g / min or < 30 mg/24 h , microalbuminuria was defined as 20 g / min  aer < 200 g / min or 30 mg/24 h  aer < 300 mg/24 h , and macroalbuminuria was defined as aer 200 g / min or aer 300 mg/24 h. end - stage renal disease ( esrd ) was defined as patients undergoing dialysis or having received a kidney transplant . progression was defined as a change from one level to a higher level of aer or the development of esrd . data on cvd events and progression of albuminuria were available in 3,110 patients ( 69% of all patients with data on pp ) versus 3,424 patients ( 76% ) , respectively . in a subpopulation of 408 patients , both arterial stiffness measured by pulse - wave analysis ( pwa ) and follow - up data were available . the median ( range ) follow - up time was 6.1 ( 0.011.0 ) years . applanation tonometry ( sphygmocor , atcor medical , sydney , australia ) is a widely used noninvasive method to estimate arterial stiffness by analyzing arterial pressure waveforms ( 12 ) . the pulse wave was recorded from the radial artery of the right arm with a high - fidelity micromanometer ( spt-301 , millar instruments , houston , tx ) . a model of the central pressure waveform was synthesized by the sphygmocor software using a validated generalized mathematic transformation to calculate the augmentation index ( aix ) and aortic pp as indicators of arterial stiffness ( 13 ) . hba1c was determined locally by standardized assays , and serum lipid and lipoprotein concentrations were determined centrally by automated enzymatic methods ( hoffman - laroche , basel , switzerland ) . estimated glomerular filtration rate was calculated using the modification of diet in renal disease four - variable equation ( 14,15 ) . baseline characteristics are presented as means  sd for normally distributed values and as median with interquartile range for non - normally distributed values and percentages . differences between groups for normally distributed variables were tested using anova , and for nonparametric data the mann  whitney or kruskal  wallis test was used . when p values were adjusted for age , ancova was used for continuous variables and logistic regression for categoric variables . for categoric variables , risk factors for the progression of diabetes complications were assessed using cox proportional hazard survival regression showing results as hazard ratios with 95% cis . age , sex , hba1c , total cholesterol , estimated glomerular filtration rate , history of smoking , use of antihypertensive medication , and pp were used as covariates . to account for a potential multicolinearity , we chose to use age but not duration of diabetes in the models , because the associations were stronger between age at baseline and incident events at follow - up . similarly sbp was not included in the analysis because of the strong association with pp ( r = 0.83 ; p < 0.001 . ) at baseline their mean age was 39  12 years , sbp was 134  19 mmhg , dbp was 80  10 mmhg , pp was 55  16 mmhg , and hba1c was 8.5  1.5% . a total of 2,763 patients had normal aer , 561 patients had microalbuminuria , 611 patients had macroalbuminuria , 292 patients had esrd , and 282 patients could not be classified with respect to their renal status because of insufficient number of urine collections or disease duration < 15 years . at baseline , patient characteristics according to baseline quartiles of pulse pressure values are expressed as means  sd , percent , or median ( interquartile range ) . a total of 269 patients ( 8.6% ) had an incident cvd event during follow - up . of those , altogether , 370 patients ( 10.8% ) progressed to a higher level of albuminuria or to esrd during follow - up ( 148 to microalbuminuria , 75 to macroalbuminuria , and 147 to esrd ) . baseline characteristics according to occurrence of an incident cvd event ( coronary event , stroke , peripheral vascular event ) and progression in renal status ( defined as any increase in albuminuria level or progression to esrd ) during follow - up values are expressed as number , means  sd , or percentage . egfr , estimated glomerular filtration rate ; na , not applicable . * p < 0.05 vs. no event . age - adjusted survival curves demonstrate a positive association between pp and the occurrence of an incident hard cvd event during follow - up ( fig . thus , patients in the highest pp quartiles ( third and fourth ) more often had a cvd event than those in the first and second quartiles . 1b ) . a : age - adjusted survival curves for an incident cvd event ( coronary event , stroke , peripheral vascular event ) by quartiles of pp . b : age - adjusted survival curves for any progression in renal status ( defined as any increase in albuminuria level or progression to esrd ) by quartiles of pp . because of the high proportion of patients with a previous cvd event at baseline , only patients who had their first ever cvd event ( n = 178 ) during follow - up ( table 3 ) were included in the cox regression analysis . cox regression analysis for an incident cvd event ( coronary event , stroke , peripheral vascular event ) and progression in renal status ( defined as any increase in albuminuria level or progression to esrd ) variables are from baseline . furthermore , no associations were observed between pp and progression to microalbuminuria , macroalbuminuria , or esrd when analyzed separately . after dividing the patients by albuminuria at baseline , a similar cox regression analysis the number of first ever cvd events at follow - up was 51 in patients with normal aer , 27 in patients with microalbuminuria , and 77 in patients with macroalbuminuria . pp and age independently predicted a first ever cvd event at follow - up in all groups . cox regression analysis for an incident cvd event ( coronary event , stroke , peripheral vascular event ) in patients by albuminuria status at baseline variables are from baseline . egfr , estimated glomerular filtration rate ; hr , hazard ratio . of the 408 patients with pwa data available , 35 had an incident cvd event during follow - up . both aortic pp ( 61  21 vs. 46  18 mmhg , p < 0.001 ) and aix ( 24.3  9.0 vs. 19.5  12.1% , p < 0.05 ) were increased in the patients with an incident cvd event . similarly , age ( 61  21 vs. 46  18 years , p < 0.001 ) , brachial sbp ( 151  23 vs. 137  22 mmhg , p < 0.001 ) , and brachial pp ( 75  21 vs. 63  17 mmhg , p < 0.001 ) were higher in the patients with a cvd event . a larger proportion of the patients with an incident cvd event had diabetic nephropathy ( 57 vs. 37% , p < 0.001 ) and previous cvd events ( 80 vs. 7% , p aortic pp was independently associated with incident cvd events during follow - up ( 1.29 [ 1.021.62 ] per 10 mmhg , p = 0.03 ) after adjusting for age , sex , total cholesterol , hba1c , diabetic nephropathy , and history of smoking in the cox model . however , after inclusion of previous cvd in the model , aortic pp was no longer a predictor . finally , aix was not independently associated with an incident cvd event in a similar model . age - adjusted survival curves demonstrate a positive association between pp and the occurrence of an incident hard cvd event during follow - up ( fig . thus , patients in the highest pp quartiles ( third and fourth ) more often had a cvd event than those in the first and second quartiles . 1b ) . a : age - adjusted survival curves for an incident cvd event ( coronary event , stroke , peripheral vascular event ) by quartiles of pp . b : age - adjusted survival curves for any progression in renal status ( defined as any increase in albuminuria level or progression to esrd ) by quartiles of pp . because of the high proportion of patients with a previous cvd event at baseline , only patients who had their first ever cvd event ( n = 178 ) during follow - up ( table 3 ) were included in the cox regression analysis . cox regression analysis for an incident cvd event ( coronary event , stroke , peripheral vascular event ) and progression in renal status ( defined as any increase in albuminuria level or progression to esrd ) variables are from baseline . , no associations were observed between pp and progression to microalbuminuria , macroalbuminuria , or esrd when analyzed separately . after dividing the patients by albuminuria at baseline , a similar cox regression analysis the number of first ever cvd events at follow - up was 51 in patients with normal aer , 27 in patients with microalbuminuria , and 77 in patients with macroalbuminuria . pp and age independently predicted a first ever cvd event at follow - up in all groups . cox regression analysis for an incident cvd event ( coronary event , stroke , peripheral vascular event ) in patients by albuminuria status at baseline variables are from baseline . of the 408 patients with pwa data available , 35 had an incident cvd event during follow - up . both aortic pp ( 61  21 vs. 46  18 mmhg , p < 0.001 ) and aix ( 24.3  9.0 vs. 19.5  12.1% , p < 0.05 ) were increased in the patients with an incident cvd event . similarly , age ( 61  21 vs. 46  18 years , p < 0.001 ) , brachial sbp ( 151  23 vs. 137  22 mmhg , p < 0.001 ) , and brachial pp ( 75  21 vs. 63  17 mmhg , p < 0.001 ) were higher in the patients with a cvd event . a larger proportion of the patients with an incident cvd event had diabetic nephropathy ( 57 vs. 37% , p < 0.001 ) and previous cvd events ( 80 vs. 7% , p < 0.001 ) at baseline . aortic pp was independently associated with incident cvd events during follow - up ( 1.29 [ 1.021.62 ] per 10 mmhg , p = 0.03 ) after adjusting for age , sex , total cholesterol , hba1c , diabetic nephropathy , and history of smoking in the cox model . however , after inclusion of previous cvd in the model , aortic pp was no longer a predictor . finally , aix was not independently associated with an incident cvd event in a similar model . the main finding of this study was that pp predicted a first ever cvd event even after adjustments for renal disease in patients with t1d . another novel finding was that pp also predicted incident cvd in diabetic patients irrespectively of the degree of diabetic nephropathy . we previously showed a premature increase in pp in patients with t1d compared with nondiabetic control subjects ( 3 ) . however , because of the cross - sectional design of that study , we could not answer the question whether an early increase in pp also increased the risk for cvd in these patients . the current study , on the other hand , shows that pp indeed increases the risk for a first ever cvd event in these patients . this risk increased by 1841% ( per 10 mmhg pp ) depending on renal status . our results are in line with earlier data showing pp to be a predictor of cvd in patients with diabetes . in the hoorn study , pp correlated positively with cardiovascular mortality ( 16 ) . however , despite the large study sample ( n = 2,484 ) , it included no more than 208 patients with type 2 diabetes . ( 17 ) reported pp to predict coronary heart disease in a large - scale study of patients with type 2 diabetes . in t1d , results from the eurodiab cohort showed pp to associate with incident cvd after correcting for age and sex in a multivariate model ( 6 ) . this is important because the presence and severity of diabetic nephropathy are shown to be strongly linked to the excess mortality associated with t1d ( 7 ) . moreover , we included only patients with hard cvd events ( coronary event , stroke , peripheral vascular event ) in the analysis , whereas patients with electrocardiogram abnormalities and angina pectoris were included in the eurodiab study . we did not observe an association between pp and progression in renal status . to our knowledge , there are no other prospective studies on pp and diabetic nephropathy in t1d in the literature , but blood pressure per se has been demonstrated to play a role in the development of microvascular complications ( 18 ) . mean arterial pressure predicted the development of microalbuminuria and macroalbuminuria in patients with t1d from the steno diabetes center ( 10 ) . notably , there are also data available demonstrating no difference in blood pressure in patients who progress in renal status and those who do not ( 9,11,20 ) . the data in the small subset of patients in whom pwa was measured support the findings . we recently showed that central pp is more strongly associated with cvd than aix in patients with t1d in the finndiane cohort ( 21 ) . therefore , it was not surprising that central pp was associated with incident cvd in this prospective analysis . ( 22 ) , who reported central pp to be a strong predictor of incident cvd in a large - scale study . this study can not provide the mechanisms behind the relationship between arterial stiffness and cvd events . however , as the arteries stiffen , less energy is absorbed during the systolic cardiac phase and released during the diastolic phase ( 23 ) . the phenomenon results in increased aortic stiffness , increased left ventricular afterload , increased lv mass and oxygen demand , and decreased stroke volume , and consequently potentiates the development of arterial disease ( 24 ) . the increase in brachial pp can be considered a robust measure of arterial stiffness , especially in older subjects ( 5,25 ) . because the increase in pp occurs 15 to 20 years earlier in patients with t1d and is indicative of accelerated vascular aging , pp may be used as a predictor of future cvd events in these patients ( 3 ) . the strengths of this study are the large number of well - characterized patients and the prospective study design . the finndiane represents a homogenous , nationwide cohort of adults with t1d studied between 1997 and 2010 . however , if anything , this only would dilute our findings . in view of the combined results , pp , a marker of arterial stiffness , is a risk factor for cardiovascular complications but not for diabetic nephropathy in patients with t1d .
objectivepulse pressure ( pp ) , an estimate of arterial stiffness , has been shown to be associated with incident cardiovascular disease ( cvd ) in patients with type 1 diabetes ( t1d ) . 
 however , diabetic kidney disease , a strong predictor of cvd , was not previously taken into account . 
 furthermore , the role of pp as a predictor of diabetic nephropathy is not known . 
 therefore , we prospectively investigated the associations between pp and these diabetes complications in patients with t1d.research design and methodsa total of 4,509 patients from the finndiane study participated . 
 follow - up data on incident cvd events and renal status ( median 5.3 years ) were available in 69 and 76% of the patients , respectively . altogether , 269 patients ( 8.6% ) had an incident cvd event and 370 patients ( 10.8% ) progressed to a higher level of albuminuria or to end - stage renal disease.resultspp was higher at baseline in patients who experienced a cvd event ( 66  18 vs. 52  14 mmhg ; p < 0.001 ) or progressed in their renal status ( 58  18 vs. 54  15 mmhg ; p < 0.01 ) during follow - up . in a cox regression model , 
 pp was independently associated with a first ever cvd event ( hazard ratio per 10 mmhg 1.22 [ 95% ci 1.101.34 ] ) but not progression of renal disease ( 1.00 [ 0.891.12 ] ) after adjustments for traditional risk factors.conclusionspp , a marker of arterial stiffness , is a risk factor for cardiovascular complications but not for diabetic nephropathy in patients with t1d .