the mdc ( malm diet and cancer ) study is a population - based , prospective cohort of 28,449 individuals examined between 1991 and 1996 ( 20 ) . from this cohort , a random sample , examined between november 1991 and february 1994 (
n  = 6,103 ) , was included in the mdc cardiovascular cohort , with the primary aim of studying the epidemiology of carotid artery disease ( 21 ) .
after exclusion of individuals lacking values from fasting plasma samples and thus missing data on prevalence of diabetes mellitus or fasting values of hdl - c , ldl - c , or gh , the cohort consisted of 4,452 persons . of these , 129 individuals had a history of cad , stroke , or chf and were excluded from further analysis .
thus , 4,323 persons , age 46 to 68 years , remained to comprise the primary study cohort .
all participants provided written consent , and the ethical committee at lund university , lund , sweden approved the study . at baseline ( 1991 to 1996 ) , participants underwent a medical history , physical examination , and laboratory assessment .
diabetes mellitus was defined as either self - report of a physician diagnosis , use of diabetes medication , or fasting venous whole blood glucose > 6.0 mmol / l ( 109 mg / dl ) .
levels of hdl - c , total cholesterol , creatinine , glycated hemoglobin ( hba1c ) , and insulin were measured according to standard procedures at the department of clinical chemistry , university hospital of malm .
levels of n - terminal pro - brain natriuretic peptide ( nt - probnp ) were determined using the dimension rxl automated nt - probnp method ( siemens diagnostics , nrnberg , germany ) ( 22 ) .
all samples of plasma and whole blood were obtained after overnight fasting , and samples were drawn between 7:30 am and 9:00 am .
gh levels were measured in stored fasting plasma samples , which were frozen immediately to  80c at the malm diet and cancer study  cardiovascular cohort baseline examination .
the measurement was made with a high - sensitivity chemiluminescence sandwich immunoassay similar to 1 previously described ( sphingotec gmbh , borgsdorf , germany ) ( 19 ) .
the analytical assay sensitivity ( mean relative light units of 20 determinations of gh free sample  + 2  sd ) was 2 pg / ml gh . the functional assay sensitivity ( < 20% interassay coefficient of variation ) was 10  pg / ml .
individuals with a gh value equal to 0 ( n  =  13 ) were censored in all analyses and are not included in the count of 4,323 persons discussed earlier .
we examined 5 primary outcomes : cad , stroke , chf , cardiovascular mortality , and total mortality .
the endpoints were retrieved through record linkage of the personal identification number of each swedish individual and the swedish hospital discharge register , the swedish cause of death register , the stroke in malm register , and the swedish coronary angiography and angioplasty registry .
cad was defined as fatal or nonfatal myocardial infarction , death due to ischemic heart disease , percutaneous coronary intervention , or coronary artery bypass grafting , whichever came first .
cardiovascular mortality was defined as a cardiovascular disease as the cause of death . codes , which are the basis for the events , are specified in the online appendix .
fasting values of hs - gh , insulin , and nt - probnp exhibited a right - skewed distribution and were transformed into natural logarithms before analysis . to determine if gh displayed any correlation with traditional cardiovascular risk factors ( 27 ) , cross - sectional analyses were performed at baseline using linear regression models with standardized logarithmic hs - gh as the dependent variable and age , sex , current smoking , antihypertensive medication , diabetes mellitus , and the standardized values for : systolic blood pressure , bmi , hdl - c , and ldl - c as independent variables entered either separately ( crude ) or simultaneously ( multivariate adjusted ) .
multivariable cox proportional hazard models were performed to examine the association between gh and incidence of cardiovascular events and mortality .
all models were adjusted for age , sex , systolic blood pressure , use of antihypertensive medication , current smoking , diabetes mellitus , bmi , and levels of ldl - c and hdl - c .
hazard ratios ( hrs ) for gh were expressed per 1-sd increment of the natural logarithm of hs - gh .
values of hs - gh were standardized separately in each sex before being used in sex - combined models , due to the large difference of hs - gh between the sexes . to establish if there were any significant sex differences , a sex interaction test was performed .
a limited number of other cardiovascular risk factors or factors assumed to be associated with gh ( nt - probnp , creatinine , waist circumference , body fat percentage , insulin , and hba1c ) were then added to the models to evaluate the stability of the results . to evaluate if gh had any predictive potential we calculated the category - free net reclassification improvement ( nri ) ( > 0 ) according to previously described methods ( 28 ) .
we used multivariable risk scores with the parameters mentioned in the preceding text to estimate the risk of developing a cardiovascular event and then examined whether the addition of hs - gh improved the model and reclassified subjects , thus obtaining the nri ( > 0 ) .
up - classification in the risk of individuals who developed an event or down - classification of individuals who did not develop an event improves the risk model , whereas the opposite deteriorates the model .
calculation of c statistics ( harrell s ) ( 29 ) was used to assess model discrimination .
a post - hoc analysis was made examining the case fatality of myocardial infarctions versus hs - gh .
odds ratios were calculated by means of logistic regression analyses and adjusted for the risk factors included in our original model , with the addition of year of event and age at event replacing age at baseline .
odds ratios for gh were expressed per 1-sd increment of the natural logarithm of hs - gh .
all analyses were made with stata software version 11 ( statacorp , college station , texas ) .
women had significantly higher fasting values of hs - gh than men ( table  1 ) .
individuals excluded from the study due to missing plasma samples or prevalent cardiovascular disease differed slightly in their baseline characteristics ( online table  1 ) . with the exception of age in women and systolic blood pressure and antihypertensive medication in men ( online table  2 ) ,
most variables were significant determinants of hs - gh in the crude regression models . in the adjusted models , age , current smoking , and hdl - c had a significant positive correlation with hs - gh , whereas ldl - c and bmi exhibited significant negative correlation in both sexes ( table  2 , online tables 3 and 4 ) .
prevalence of diabetes mellitus had a positive correlation with hs - gh in males and a negative correlation in females .
the multiple regression models had an r value of 9.5% for males and 11.8% for females .
median follow - up time ranged from 16.1 years ( interquartile range : 15.4 to 16.7 years ) in cad to 16.2 years ( interquartile range : 15.6 to 16.7 years ) in the mortality analyses .
all of the cox proportional hazards models were significant when analyzing the whole cohort , with increasing hs - gh levels associated with elevated cardiovascular morbidity and mortality , independent of other cardiovascular risk factors ( table  3 ) .
hrs for each sd increase of baseline hs - gh ranged from 1.11 in cad to 1.43 in cardiovascular mortality .
a total of 4 of 5 male analyses were significant , with hrs ranging from 1.17 in cad to 1.44 in cardiovascular mortality , and the 5th analysis , which was chf , was nonsignificant . in females ,
a significant sex interaction was found in the analysis of total mortality ( p  = 0.02 ) . when comparing the quartile with the highest values of hs - gh with the bottom quartile , hrs ranged from 1.33 ( 95% confidence interval [ ci ] : 0.99 to 1.79 ; p  = 0.05 ) in cad to 2.83 ( 95% ci : 1.74 to 4.61 ; p  <  0.001 ) in cardiovascular mortality ( table  3 ) .
male hrs were significant in cad ( hr : 1.45 ; 95% ci : 1.01 to 2.08 ; p  =  0.05 ) , total mortality ( hr : 2.05 ; 95% ci : 1.44 to 2.92 ; p  <
0.001 ) , and cardiovascular mortality ( hr : 3.32 ; 95% ci : 1.65 to 6.70 ; p  <
female quartile analyses were significant in cardiovascular mortality ( hr : 2.36 ; 95% ci : 1.16 to 4.80 ; p  = 0.02 ) when comparing the highest quartile of hs - gh to the lowest .
we investigated whether our findings were independent of known gh - associated variables and other cardiovascular risk factors by adding insulin , hba1c ,  creatinine , nt - probnp , waist circumference , and body fat percentage to the different cox models mentioned previously . generally , these variables had only minor effects on hrs or cis , with nt - probnp and hba1c having the largest effects , resulting in a slight attenuation of some results ( online tables  5 and 6 ) .
if the analyses were performed crude , the results were similar , but not identical ( online table  7 , online figures 1 to 9 ) . in the reclassification analyses ,
the nri ( > 0 ) was significant for the whole cohort in stroke ( 0.179 ; 95%  ci : 0.003 to 0.293 ) , total mortality ( 0.207 ; 95% ci : 0.020 to 0.383 ) , and cardiovascular mortality ( 0.542 ; 95% ci : 0.205 to 0.840 ) ( table  4 , online table  8) .
the 2 mortality analyses were significant for males , whereas the female analyses were significant in cardiovascular mortality .
improvement mostly stemmed from down - classification of nonevents in the  total mortality analysis and up - classification of events in cardiovascular mortality . to evaluate the reclassification model , we tried adding creatinine and  nt - probnp to the basic model before calculating the nri ( > 0 ) for hs - gh .
this attenuated the nri ( > 0 )  in  stroke and total mortality , whereas the association in cardiovascular mortality remained the same ( table  4 ) .
overall , the effects on the c - statistics when adding gh to the basic model were modest . in analysis of cardiovascular mortality
the c - statistics increased from 0.783 ( 95% ci : 0.752 to 0.814 ) to 0.794 ( 95% ci : 0.763 to 0.825 ) in the whole cohort , 0.751 ( 95% ci : 0.705 to 0.797 ) to 0.764 ( 95% ci : 0.719 to 0.809 ) in males , and 0.797 ( 95% ci : 0.751 to 0.844 ) to 0.807 ( 95% ci : 0.760 to 0.854 ) in females ( table  5 ) .
a post - hoc analysis of the 24-h case fatality of myocardial infarctions versus hs - gh was performed to investigate the strong relationship between hs - gh and cardiovascular mortality . in a multivariate - adjusted logistic regression ,
the odds ratio per 1-sd increment of fasting hs - gh at baseline was 1.54 ( 310  events , 69 fatal ; 95% ci : 1.13 to 2.09 ; p  = 0.006 ) in the total cohort , 1.50 ( 187 events , 37 fatal ; 95%  ci :  1.00 to  2.23 ; p  = 0.05 ) among males , and 1.67 ( 123 events , 32  fatal ; 95% ci : 0.98 to 2.85 ; p  = 0.06 ) among females .
we examined whether fasting values of hs - gh predict cardiovascular morbidity and mortality in a large population - based cohort free from cad , chf , and stroke at baseline with a longitudinal follow - up time exceeding 66,000 person - years .
increasing fasting hs - gh levels were associated with higher incidence of cad , stroke , chf , all - cause mortality , and cardiovascular mortality , independent of traditional cardiovascular risk factors .
adult ghd patients have an adverse cardiovascular risk factor profile ( 6,7 ) and were reported to have an increased risk of all - cause and cardiovascular mortality ( 24 ) .
although gh substitution ameliorates some aspects of the cardiovascular risk factor profile ( 6,810 ) , there are no randomized placebo - controlled trials evaluating this therapy in relation to hard endpoints such as cardiovascular morbidity and mortality .
interestingly , at the population level , we found that patients with low hs - gh levels resembled ghd patients in having an unfavorable body composition and lipoprotein profile ( online table  9 ) .
however , the relationship between hs - gh and cardiovascular morbidity and mortality was the opposite of that expected from the observations in ghd patients : subjects with low hs - gh had low risk , whereas subjects with high hs - gh had high risk . although our study was performed in healthy subjects and does not prove a causal relationship between increasing gh and cardiovascular morbidity and mortality , it does cast doubts on whether gh replacement therapy in adult ghd patients is beneficial for cardiovascular health .
most commonly , ghd patients are deficient for a reason , and previous cranial irradiation , surgery , and other causes may affect mortality rates independently from ghd .
rather , our results , together with the only previous study of fasting gh in relation to all - cause and cardiovascular mortality in healthy subjects ( 15 ) , suggest that elevated fasting gh is an independent risk factor for cardiovascular morbidity and mortality , and thus call for randomized placebo - controlled trials of gh replacement therapy to determine its effect on cardiovascular morbidity and mortality . today , gh use is not limited to individuals with ghd .
for example , gh has been used as an antiaging therapy , and athletes also use it .
a systematic review concluded that gh could not be recommended as antiaging therapy , and our results further highlight the impropriety and possible dangers of this practice ( 30 ) .
the use of gh in sports is classed as doping , and its performance - enhancing capabilities are , in many areas , doubtful ( 31 ) .
physical exercise results in secretion of gh ; however , regular exercise has not been shown to alter the baseline resting levels ( 32 ) , which may indicate that regular physical activity does not affect the fasting value of gh .
as would be expected , studies in rodents showed that mice overexpressing gh genes have a drastically shortened life span ( 33 ) .
what is more surprising is that mice that are either missing the gh receptor ( growth hormone receptor knockout , ghrko ) or ames mice ( deficient in gh , prolactin , and thyroid - stimulating hormone ) live longer than normal mice ( 34,35 ) while being obese compared with their siblings ( 36,37 ) .
although the relevance of these experimental data for humans is unclear , they suggest a link between reduced gh signaling and a phenotype of obesity and longer life span .
this somewhat resembles the situation in humans with low hs - gh who have higher bmis , waist circumference , and body fat , but live longer in comparison with subjects with high hs - gh ( central illustration ) .
the outcome with the strongest independent relationship to baseline fasting hs - gh was cardiovascular mortality . in this outcome , adding hs - gh to traditional cardiovascular risk factors resulted in increments of the nri ( > 0 ) of 0.542 in the total cohort , suggesting that addition of hs - gh improved the basic predictive model .
even with the addition of creatinine and nt - probnp , the association remained significant .
interestingly , the nri ( > 0 ) in cardiovascular mortality was driven to a larger extent by up - classification of subjects with a cardiovascular death than by down - classification of healthy subjects . even though the clinical use of hs - gh for prediction would be associated with many drawbacks ,
these results still  indicate that the predictive possibility is not negligible . in general , we found a stronger relationship between hs - gh in men than in women .
our finding that women have in the order of 10-fold higher values  of fasting gh than men has been previously described ( 38 ) .
the 24-h profiles of gh secretion in women were shown to be more irregular and to have shorter oscillatory periods and higher trough values than in men ( 3941 ) . it should be kept in mind that fasting gh values are not a standard clinical test , and it is not known how these values relate to overall gh production .
when examining 24-h gh profiles from previous publications , morning values in men appear quite low and stable , whereas the variation in women is larger ( 1618 ) .
it can thus be speculated that the more stable gh levels in the morning hours in men than in women makes a single fasting hs - gh a more accurate measure of gh secretion in men , which , in turn , could explain why associations with various outcomes are stronger in males .
part of the sex discrepancy may also be attributable to power differences , as all outcomes occurred at a higher incidence rate in the male population . to date
, it is unclear to what extent a fasting value of hs - gh reflects overall gh secretion .
the pulsatile mode of secretion is a limitation and makes gh difficult to use in a clinical setting .
it is not clear whether our findings represent a linear relationship between gh and the various outcomes , although the quartile analyses were done to evaluate this .
unfortunately , splitting the material caused power difficulties and made a clear - cut answer impossible .
an effort to analyze the 10th and 90th percentile versus the middle ( data not shown ) was also hampered by power , but did not indicate a different association .
in addition , we did not measure circulating or tissue insulin - like growth factor-1 , which mediates several effects of gh . despite these issues
, we did observe relationships between hs - gh and gh - related phenotypes at baseline as well as associations with long - term outcomes , especially the risk of cardiovascular mortality , suggesting that fasting hs - gh does reflect a medically relevant measure .
the association of higher hs - gh values with increased likelihood of a myocardial infarction being fatal may explain why our strongest findings were in the cardiovascular mortality outcome . because this was an observational study
, we do not prove causation between hs - gh and our various endpoints . also , the number of nonaccepters to the initial invitation was quite large , which could have biased selection of a more healthy population .
although gh secretion is known to have a strong positive correlation with estradiol levels , we have not excluded pre - menopausal or perimenopausal women from the study ( 42 ) ; this may be a potential confounder in the female analyses
. however , the consequence of this would be younger women exhibiting higher gh values , which logically would weaken a positive correlation between hs - gh and the various outcomes .
differences in baseline characteristics in people excluded due to missing plasma samples compared with the study cohort were minor and did not raise any suspicions of selection bias .
to date , it is unclear to what extent a fasting value of hs - gh reflects overall gh secretion .
the pulsatile mode of secretion is a limitation and makes gh difficult to use in a clinical setting .
it is not clear whether our findings represent a linear relationship between gh and the various outcomes , although the quartile analyses were done to evaluate this .
unfortunately , splitting the material caused power difficulties and made a clear - cut answer impossible .
an effort to analyze the 10th and 90th percentile versus the middle ( data not shown ) was also hampered by power , but did not indicate a different association .
in addition , we did not measure circulating or tissue insulin - like growth factor-1 , which mediates several effects of gh . despite these issues
, we did observe relationships between hs - gh and gh - related phenotypes at baseline as well as associations with long - term outcomes , especially the risk of cardiovascular mortality , suggesting that fasting hs - gh does reflect a medically relevant measure .
the association of higher hs - gh values with increased likelihood of a myocardial infarction being fatal may explain why our strongest findings were in the cardiovascular mortality outcome . because this was an observational study
, we do not prove causation between hs - gh and our various endpoints . also , the number of nonaccepters to the initial invitation was quite large , which could have biased selection of a more healthy population .
although gh secretion is known to have a strong positive correlation with estradiol levels , we have not excluded pre - menopausal or perimenopausal women from the study ( 42 ) ; this may be a potential confounder in the female analyses .
however , the consequence of this would be younger women exhibiting higher gh values , which logically would weaken a positive correlation between hs - gh and the various outcomes .
differences in baseline characteristics in people excluded due to missing plasma samples compared with the study cohort were minor and did not raise any suspicions of selection bias .
we demonstrate that higher fasting values of hs - gh are associated with cardiovascular morbidity , all - cause mortality , and , in particular , cardiovascular mortality .
further research is needed to elucidate the mechanisms of this association in the general population and its potential implications in the subgroups of patients with a disturbance in gh secretion.perspectivescompetency in medical knowledge : in healthy middle - aged people , higher fasting levels of gh are associated with greater cardiovascular morbidity and mortality independent of traditional cardiovascular risk factors.competency in patient care : in healthy middle - aged individuals , measurement of fasting gh in plasma may be useful  in risk stratification for cardiovascular mortality and aid clinical decision - making for primary prevention of ischemic events.translational outlook : randomized trials  are needed to investigate the effect of gh replacement on cardiovascular outcomes in patients with ghd .
competency in medical knowledge : in healthy middle - aged people , higher fasting levels of gh are associated with greater cardiovascular morbidity and mortality independent of traditional cardiovascular risk factors .
competency in patient care : in healthy middle - aged individuals , measurement of fasting gh in plasma may be useful  in risk stratification for cardiovascular mortality and aid clinical decision - making for primary prevention of ischemic events .
translational outlook : randomized trials  are needed to investigate the effect of gh replacement on cardiovascular outcomes in patients with ghd .
 backgroundboth pathological excess and deficiency of growth hormone ( gh ) are associated with cardiovascular mortality.objectivesthe goal of this study was to test whether fasting levels of growth hormone measured with a high - sensitivity assay ( hs - gh ) predict cardiovascular morbidity and mortality at the population level.methodswe studied 4,323 participants ( age 46 to 68 years ; mean age 58 years ; 59% women ) of the swedish , population - based malm diet and cancer study examined in 1991 to 1994 . using multivariate - adjusted cox proportional hazards models , 
 we related baseline levels of fasting hs - gh to incidence of coronary artery disease , stroke , congestive heart failure , all - cause mortality , and cardiovascular mortality.resultsduring a median follow - up of 16.2 years , hs - gh ( hazard ratio [ hr]/sd increment of natural logarithm of fasting hs - gh ) was independently associated with increased risk of coronary artery disease ( 397 events ; hr : 1.11 ; 95% confidence interval [ ci ] : 1.01 to 1.23 ; p  = 0.04 ) , stroke ( 251 events ; hr : 1.18 ; 95% ci : 1.04 to 1.34 ; p  = 0.01 ) , congestive heart failure ( 107 events ; hr : 1.25 ; 95% ci : 1.03 to 1.52 ; p  = 0.02 ) , all - cause mortality ( 645 events ; hr : 1.17 ; 95% ci : 1.08 to 1.26 ; p  < 0.001 ) and cardiovascular mortality ( 186 events ; hr : 1.43 ; 95% ci : 1.24 to 1.66 ; p  < 0.001 ) . 
 the addition of hs - gh to a model with conventional cardiovascular risk factors significantly reclassified risk , with a category - free net reclassification improvement ( > 0 ) of 0.542 ( 95% ci : 
 0.205 to 0.840 ) in cardiovascular mortality.conclusionshigher values of hs - gh were associated with an increased risk of cardiovascular morbidity and mortality . 
Methods
Results
Discussion
Study limitations
Conclusions
Appendix