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European Heart Journal Advance Access originally published online on September 25, 2007
European Heart Journal 2007 28(21):2644-2652; doi:10.1093/eurheartj/ehm399
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

Plasma renin and risk of cardiovascular disease and mortality: the Framingham Heart Study

Nisha I. Parikh1,4, Philimon Gona1,3, Martin G. Larson1,3,4, Thomas J. Wang1,2, Christopher Newton-Cheh1,2, Daniel Levy1,5, Emelia J. Benjamin1,6, William B. Kannel1 and Ramachandran S. Vasan1,6,*

1 Framingham Heart Study, Boston University School of Medicine, 73 Mount Wayte Avenue, Suite 2, Framingham, MA 01702-5803, USA
2 Division of Cardiology, Massachusetts General Hospital, USA
3 Department of Mathematics and Statistics, Boston University, Boston, MA, USA
4 Boston University, Boston, MA, USA
5 The National Heart, Lung and Blood Institute, Bethesda, MD, USA
6 Preventive Medicine and Cardiology Sections, Boston University School of Medicine, Boston, MA, USA

Received 19 March 2007; revised 13 August 2007; accepted 24 August 2007; online publish-ahead-of-print 25 September 2007.

* Corresponding author. Tel: + 1 508 935 3450; fax: + 1 508 626 1262. E-mail address: vasan{at}bu.edu

See page 2557 for the editorial comment on this article (doi:10.1093/eurheartj/ehm371)


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusions
 Funding
 Appendix
 References
 
Aims: Previous studies relating plasma renin to cardiovascular disease (CVD) and mortality yielded conflicting results. We related plasma renin to incidence of CVD and mortality in 3408 individuals (mean age 59; 53% women) and in a hypertensive subset (n = 1413).

Methods and results: On follow-up (mean 7.1 years), 176 participants (122 hypertensives) developed CVD and 215 individuals (127 hypertensives) died. Overall, log-renin was associated with mortality [multivariable-adjusted hazards ratio (HR) per SD increment: in whole sample, 1.14, 95% confidence interval (CI) 1.00–1.30, P = 0.046; hypertensives, 1.16, 95% CI 1.00–1.35, P = 0.046], but relations varied over time (P < 0.02). Log-renin was associated with mortality at 2.5 years of follow-up (HR per SD increment: whole sample at 2.5 years, 1.23, 95% CI 1.04–1.45; hypertensives at 2 years, 1.28, 95% CI 1.06–1.54), but not during longer follow-up (HR per SD increment at 5 years: whole sample, 1.02, 95% CI 0.80–1.29; hypertensives, 0.98, 95% CI 0.74–1.30). The time-dependent relation of renin and mortality risk was maintained upon excluding participants with prevalent CVD. Renin was not associated with CVD incidence (HR per SD increment log-renin: whole sample, 0.99, 95% CI 0.85–1.14; hypertensives, 0.96, 95% CI 0.82–1.12).

Conclusion: Higher plasma renin was associated with greater short-term mortality but not with CVD incidence in the community.

Key Words: Renin • Cardiovascular disease • Hypertension • All-cause mortality • Epidemiology


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusions
 Funding
 Appendix
 References
 
The prognostic significance of plasma renin levels in hypertensive patients has been a subject of debate for many decades. Although individuals with hypertension should have lower plasma renin levels (relative to persons without hypertension) because of a physiological feedback response to higher blood pressure (BP),1 between 12 and 20% of hypertensive patients have plasma renin levels at the upper end of the distribution.2,3 Experimental research suggests that higher plasma renin levels may increase vascular risk via several mechanisms. Higher plasma renin is associated with increased activity of the renin-angiotensin-aldosterone system (RAAS), which may directly contribute to vascular injury.4,5 Additional mechanisms include myocardial remodelling initiated by downstream RAAS components, especially in post-myocardial infarction patients.6 Indeed, blockade of downstream RAAS components by angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and aldosterone antagonists are among the critical pharmacological advances for preventing mortality and cardiovascular (CVD) morbidity in patients with coronary artery disease, hypertension, or congestive heart failure.7–14

The experimental and clinical studies noted above have fuelled the expectation that knowledge of plasma renin may aid vascular risk stratification. However, clinical investigations examining this premise have yielded inconsistent results. In a large prospective community-based study, plasma renin activity (PRA) was not associated with the risk of myocardial infarction among non-hypertensive people or in hypertensive individuals.15 Two separate studies that focused on hypertensive patients reported a significantly increased risk of myocardial infarction, CVD, and all-cause mortality among those with higher PRA.2,16 Based on the results of the latter two reports, some experts have advocated renin profiling of hypertensive patients in order to identify high-risk individuals who may derive maximal benefit from pharmacological blockade of RAAS system.17 A post hoc, nested case-control study of a clinical trial of ACE-inhibitors in stroke patients also suggested that those with higher baseline renin values were at greater risk of incident myocardial infarction.18 Recently, Framingham investigators reported a positive association between plasma renin and all-cause mortality in a study evaluating a multimarker strategy of risk prediction; that report did not examine the association of plasma renin with CVD and mortality in the subset of persons with hypertension.19 Accordingly, we investigated the relations of plasma renin levels to all-cause mortality and CVD risk in hypertensive individuals, and among all participants in our large community-based sample.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusions
 Funding
 Appendix
 References
 
Study sample
The design and selection criteria of the Framingham Offspring study (including quadrennial examinations) have been described previously.20 Participants attending the sixth Offspring examination from 1995 to 1998 (n = 3532) were eligible for our investigation. We excluded participants with missing plasma renin (n = 103) or serum creatinine values >2 mg/dL (n = 21). After exclusions, 3408 participants (91% of attendees, 53% women) remained eligible for analysis of all-cause mortality risk, including 1413 individuals with hypertension (defined as a systolic BP≥140, or diastolic BP≥90 mm Hg or use of antihypertensive medications).21 For the analysis of CVD outcomes, we excluded persons with prevalent CVD (n = 190). Thus, 3218 participants remained eligible for the analysis of incident first CVD events, 1276 with hypertension. All participants provided written informed consent and the study protocol was approved by the Boston University Medical Center Institutional Review Board.

Risk factor assessment
At the sixth examination cycle, participants underwent routine physical examination, anthropometry, and laboratory assessment of vascular risk factors. Participants rested in a chair for 5 min before BP was measured and the average of two physician-obtained readings was considered as the examination BP.

Laboratory assessment of plasma renin
Venous blood was collected by phlebotomy from fasting participants who rested supine for about 10 min, typically between 7:30 AM and 9:00 AM. Plasma was separated immediately and stored at –80°C without freeze-thaw cycles until assay. Plasma renin was measured (blinded to all clinical data) with a highly sensitive and specific immunochemiluminometric assay (Nichols Advantage® Direct Renin assay). The intra-assay coefficient of variation ranged from 3.7 (at high levels) to 7.2% (at low levels), with corresponding inter-assay coefficients of variation ranging from 4.9 to 10%. The direct renin assay has been demonstrated to yield measurements that have a high correlation with plasma renin activity (PRA).22,23

Serum aldosterone (modelled as a covariate in secondary analyses as detailed below) was also measured at the same examination from extracted and fractionated serum with the use of a radioimmunoassay (Quest Diagnostics) with a sensitivity of less than 1 ng/dL (28 pmol/L).24 The intra-assay coefficient of variation ranged from 3.8 (at high levels) to 6.0% (at low levels), with corresponding inter-assay coefficients of variation ranging from 4.0 to 9.8%.

Assessment of primary and secondary outcomes
Primary outcomes for our investigation were incidence of all-cause mortality and a first ‘hard’ CVD event. Framingham Heart Study participants are under continuous surveillance for death and CVD events. CVD adjudication criteria have been described previously.25 Incident ‘hard’ CVD was defined as fatal or non-fatal myocardial infarction, unstable angina pectoris, stroke, or congestive heart failure.

We studied the following secondary outcomes: first CVD (‘hard’ CVD, as defined above, plus stable angina, transient ischaemic attack, and intermittent claudication), ‘hard’ coronary heart disease (CHD) event (myocardial infarction, unstable angina, and CHD-death), and CVD-related mortality. The follow-up period was from the baseline examination up to December 2004.

Statistical analysis
We used Cox proportional hazards regression26 to relate plasma renin to the primary outcomes of all-cause mortality and incident hard CVD, and the secondary outcomes of hard CHD, any CVD, and CVD-related mortality. Analyses were performed in the entire sample, and for the subset of participants with hypertension. Separate analyses were performed for all-cause mortality and hard CVD incidence; individuals with prevalent CVD were excluded for the analyses of CVD incidence, as noted above. We tested the assumption of proportionality of hazards for the outcomes of CVD and mortality, by adding to the Cox model interaction terms of follow-up time with renin. If the assumption of proportionality of hazards was violated, we evaluated the relations of renin to the outcome of interest at half-yearly intervals up to 5 years of follow-up (events after 5 years were censored).

Plasma renin was treated both as a continuous variable (with natural-logarithmic transformation to normalize the positively skewed distribution) and as a categorical variable (modelled as sex-specific quartiles defined for the entire sample). We modelled natural log-transformed renin standardized within each sex because of the different distributions in men vs. women. In quartile-based analyses, we compared the risk in second, third, and fourth quartiles of plasma renin with the first quartile that served as referent, and tested for a linear trend for increasing risk across quartiles.

Multivariable models were adjusted for age, sex, systolic BP, diastolic BP, hypertension treatment, smoking status, ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol, diabetes, and serum creatinine. Multivariable models for the outcome of all-cause mortality were additionally adjusted for prevalent CVD. Criteria for these covariates have been defined elsewhere.27 We tested for effect modification by age, sex, and serum aldosterone (for analyses of both primary outcomes in the entire sample and in hypertensives).

Secondary analyses
Because plasma renin levels may be influenced by antihypertensive medications, we repeated all analyses excluding participants who were on antihypertensive medications at baseline examinations. Since individuals with prevalent CVD have a greater all-cause mortality risk, we repeated analyses for all-cause mortality excluding these individuals. Additionally, we performed secondary analyses adjusting for non-steroidal anti-inflammatory medications and aspirin use. We related serum aldosterone and the aldosterone-to-renin ratio to the risk of CVD and all-cause mortality in the entire sample, and in the subset of hypertensive individuals. Multivariable models considering serum aldosterone were additionally adjusted for log-renin.

A two-sided P-value of less than 0.05 was considered to indicate statistical significance. All statistical analyses were performed with the use of the SAS statistical software (version 9.0).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusions
 Funding
 Appendix
 References
 
Baseline characteristics
The baseline characteristics of study participants are shown in Table 1 according to plasma renin quartile. Participants in the highest renin quartile were more likely to be younger and on treatment for hypertension.


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  		Table 1 Baseline characteristics among all participants and hypertensive participants, according to sex-specific quartiles calculated from the entire study sample

 
There was no evidence of effect modification by sex for either of the two outcomes (interaction terms of log-renin and sex were not statistically significant); therefore, all analyses were performed for pooled sexes.

Plasma renin and all-cause mortality
The assumption of proportionality of hazards was violated for the primary outcome of all-cause mortality and the secondary outcome of CVD-mortality in the whole sample, and in hypertensive individuals (P < 0.02 for log-renin x time interaction for both outcomes, Appendix, Figure A).


Figure 1A
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  		Figure A A plot of log-cumulative hazard ratio (Y-axis) for mortality against log-survival time (X-axis) for individual renin quarters. Non-parallel lines of renin quarter hazard rates indicate violation of the proportional hazards assumption.

 
On follow-up (mean 7.1 years), 215 participants (75 women) died (127 in hypertensive subgroup, including 43 women). Table 2 shows the age- and sex-adjusted event rates for all-cause mortality according to plasma renin quartile in the whole sample, and in hypertensive participants.


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  		Table 2 Crude event numbers and age- and sex-adjusted incidence of mortality and hard cardiovascular disease events per 1000-person years of follow-up

 
In Cox models that ignored the violation of the assumption of proportionality of hazards, log-renin was associated with increased all-cause mortality risk among all participants (multivariable-adjusted HR per SD increment 1.14, 95% CI 1.00–1.30, P = 0.046) (Table 3). Quartile-based analyses suggested a statistically non-significant increased risk of all-cause mortality in the highest relative to lowest quartile (multivariable-adjusted HR 1.27, 95% CI 0.87–1.84 P = 0.21). In analyses restricted to hypertensive individuals, results were similar (multivariable-adjusted HR per SD increment log-renin 1.16, 95% CI 1.00–1.35, P = 0.046) (Table 3). Analyses of quartiles suggested a statistically non-significant higher risk of all-cause mortality among hypertensive participants in the fourth quartile relative to the first (multivariable-adjusted HR 1.39, 95% CI, 0.87–2.21, P = 0.16).


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  		Table 3 Plasma renin and mortality

 
We did not observe any effect modification by age or serum aldosterone (P-values for interactions exceeded 0.05). In analyses excluding participants with prevalent CVD, renin was not associated with all-cause mortality either in the whole group or in hypertensive individuals (Table 3). In secondary analyses, exclusion of participants on antihypertensive medications from analyses did not change our results (data not shown). Adjustment for non-steroidal anti-inflammatory medications and aspirin did not change our results (data not shown).

Log-aldosterone was not associated with all-cause mortality (multivariable-adjusted HR per SD increment: in all participants 1.06, 95% CI 0.83–1.34, P = 0.64; in hypertensive individuals, 1.13, 95% CI 0.84–1.52, P = 0.43). Similarly, the aldosterone-to-renin ratio was not associated with all-cause mortality risk (multivariable-adjusted HR per SD increment log aldosterone-to-renin ratio: in all participants 0.91, 95% CI 0.81–1.04, P = 0.17; in hypertensive individuals, 0.91, 95% CI 0.79–1.05, P = 0.19).

Time-dependent analyses: all-cause and cardiovascular mortality
Because the proportionality of hazards assumption was violated for the outcome of all-cause mortality, additional models focused on variation over time in the risks of all-cause mortality and CVD-mortality associated with baseline plasma renin. Among all participants, renin was associated with increased risk of all-cause mortality at 0.5 years of follow-up (multivariable-adjusted HR per SD increment log-renin 1.89, 95% CI 1.31–2.74, P < 0.001) that declined at 2.5 years of follow-up (multivariable-adjusted HR per SD increment log-renin 1.23, 95% CI 1.04–1.45, P = 0.02) and became statistically non-significant at 3 years (Figure 1A). Similarly, among hypertensive individuals, all-cause mortality risk increased with higher renin levels at 0.5 years of follow-up (multivariable-adjusted HR per SD increment log-renin 1.89, 95% CI 1.25–2.86, P = .002), which declined at 2 years of follow-up (multivariable-adjusted HR per SD increment log renin 1.28, 95% CI 1.06–1.54) and was statistically non-significant at 2.5 years of follow-up and beyond (Figure 1B).


Figure 1
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  		Figure 1 Plasma renin and mortality: time-dependent variation in hazards. The figure shows estimates of the time-varying hazard ratio for mortality, represented for 1 SD increment of log renin. Whereas the survival model contained all events up to 5 years after baseline exam (events after 5 years were censored), the hazard ratio estimates are shown only at 0.5 year time points. (A, all participants): The number of deaths for each 0.5 year time-period increment on follow-up are: 0.5 years = 11, 1 year = 12, 1.5 years = 10, 2 years = 12, 2.5 years = 7, 3 years = 8, 3.5 years = 8, 4 years = 13, 4.5 years = 12, 5 years = 17. (B, hypertensive participants): The number of deaths for each 0.5 year time-period increment on follow-up are: 0.5 years = 8, 1 year = 7, 1.5 years = 7, 2 years = 5, 2.5 years = 4, 3 years = 8, 3.5 years = 7, 4 years = 8, 4.5 years = 6, 5 years = 14.

 
Upon excluding participants with prevalent CVD from the sample, the assumption of proportionality of hazards was still violated for the outcome of all-cause mortality (P-values for interaction terms of log-renin and time were<0.01 for all participants and for hypertensive participants). Time-dependent models in the subset of participants without prevalent CVD yielded results that were similar to those for the entire sample: log-renin was associated with all-cause mortality during short-term (up to 2 years) follow-up but not thereafter (Appendix, Table A).

Log-renin was significantly associated with CVD-mortality in all participants, and in hypertensive participants at 1 year of follow-up (multivariable-adjusted HR per SD increment: 2.42, 95% CI 1.20–4.89 in all participants; 2.97, 95% CI 1.02–8.65 in hypertensive individuals), but this association diminished in strength over subsequent time periods (at 5 years, multivariable-adjusted HR per SD increment: 2.08, 95% CI 1.27–3.41 in all participants; 1.84, 95% CI 1.00–3.40 in hypertensive individuals).

Among untreated hypertensive participants, the assumption of proportionality of hazards was satisfied (P = 0.32). Time-dependent analysis in this subset suggested a similar trend to that observed for the entire sample: log-renin was associated with a higher hazard of all-cause mortality during early compared to later time period of follow-up (Appendix, Table B). However, there were too few events in each time period, which likely limited our statistical power to detect time-varying relations of plasma renin in the subset of participants with untreated hypertension.

Plasma renin and the risk of cardiovascular disease
On follow-up (mean 7 years), 176 participants (73 women) experienced a first hard CVD event (122 in hypertensive subgroup, 45 women). Among 122 participants with hypertension experiencing hard CVD events, 93 were on antihypertensive medications and 29 were not. Age- and sex-adjusted hard CVD event rates did not differ according to plasma renin quartiles among all participants or among hypertensive participants (Table 2).

The assumption of proportionality of hazards was met for incidence of hard CVD. Plasma renin was not associated with incidence of hard CVD events in the entire sample or in the subgroup with hypertension in multivariable analyses (Table 4).


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  		Table 4 Plasma renin and risk of hard cardiovascular disease events

 
We did not observe effect modification by age or serum aldosterone (P-values for all interactions exceeded 0.12). Log-aldosterone was not associated with hard CVD incidence (multivariable-adjusted HR per SD increment: in all participants 0.98, 95% CI 0.75–1.28, P = 0.87; in hypertensive individuals, 1.18, 95% CI 0.86–1.61, P = 0.30). The aldosterone-to-renin ratio was not associated with incidence of hard CVD events (multivariable-adjusted HR per SD increment log-ratio: all participants 1.01, 95% CI 0.88–1.16, P = 0.88; hypertensive individuals, 1.08, 95% CI 0.93–1.25, P = 0.33).

In secondary analyses, use of a broad CVD definition (that included angina, transient ischaemic attacks, and intermittent claudication) did not change our results (data not shown). Also, the exclusion of participants on antihypertensive medications did not change our results (data not shown). Plasma renin was not associated with hard CHD in the whole sample or among hypertensive individuals (data not shown). Additional adjustment for non-steroidal anti-inflammatory medications and aspirin did not change our results.

Statistical power to examine associations
Given the lack of significant association of renin with CVD risk, we estimated our statistical power to detect modest effects. At an alpha of 0.05, we had at least 80% power for each outcome (hard CVD and all-cause mortality), in the full sample and in the hypertensive sub-sample, if the true HR is 1.25 per SD of log-renin. For the outcome of all-cause mortality, at an alpha of 0.05, we had at least 80% power for detecting an association in the full sample if the true HR is 1.23 per SD of log-renin. Among the subset of untreated hypertensive participants, power was more limited: at an alpha of 0.05, we had at least 80% power to detect HR of 1.95 per SD of log-renin for all-cause mortality, and a HR of 2.10 per SD of log-renin for CVD.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusions
 Funding
 Appendix
 References
 
Principal findings
The present investigation has two major findings. First, plasma renin was associated with increased all-cause mortality risk in both the whole sample and in hypertensive individuals. However, relations to mortality varied with time being evident only during short-term follow-up. Exclusion of persons with prevalent CVD did not change the time-dependent association between renin and all-cause mortality. Second, plasma renin was not associated with the incidence of hard CVD events either in the whole sample or in hypertensive participants. Similar results were obtained for hard CHD events.

Context with published literature
Plasma renin and mortality
Overall, plasma renin was associated with all-cause mortality. The strength of the hazard ratios between plasma renin and all-cause mortality was similar in the entire sample and in the sample of non-hypertensive individuals. We performed standard Cox's proportional hazards regression despite the violation of the assumption of proportionality of hazards in order to facilitate comparison of our results with those of previous studies. A recent report from the Framingham Study demonstrated that plasma renin was positively related to all-cause mortality when a panel of biomarkers from distinct biologic pathways was evaluated.19 The hazard ratio in that study (1.19 per SD increment of log-renin) was quite similar to that observed in the current investigation (1.14 per SD increment); the slight difference in point estimates of the hazard ratios is likely attributable to differences in statistical models and the covariates chosen. The objective of the previous report was to determine which biomarkers (of a panel of 10 that included renin) predicted mortality.19 The current investigation focused on plasma renin alone and sought to assess the potential utility of measuring renin levels for the purpose of CVD risk prediction. Therefore, the current study extends prior reports by specifically examining the association of renin and mortality among hypertensive persons, and by elucidating the time-dependent relations of plasma renin to all-cause mortality hazard. We observed that the association of renin with mortality was present only during short-term follow-up (until ~3 years after baseline). These data are consistent with those reported by Alderman et al.2 who noted a positive association of PRA with all-cause mortality risk over a follow-up period of 3.6 years. Additional studies of renin and all-cause mortality with a longer duration of follow-up are warranted to confirm or to refute our observation that the association of plasma renin with all-cause mortality risk may diminish over time.

Plasma renin and cardiovascular disease
Our results are consistent with the findings of Meade et al.15 who reported no association of PRA with overall risk of CHD among male industrial workers with a range of BP values (including people with and without hypertension), over a follow-up period of 19 years. Meade et al.15 analysed a subset of individuals with hypertension and noted a statistically non-significant greater risk of CHD risk in the highest vs. the lowest tertile of PRA (RR = 1.26, 95% CI 0.63–2.56). In our study, which had greater statistical power to detect associations, we did not observe any association of plasma renin with the risk of hard CVD events among hypertensive participants.

Alderman et al.2 reported an independent association between PRA and the risk of myocardial infarction among hypertensive individuals (rate ratio for PRA per 2 ng/mL/ h increment of 1.3, 95% CI 1.2–2.1) sampled from a worksite-based systemic hypertension control program. This investigation used a higher BP cut point for defining hypertension, i.e. systolic BP ≥160 mmHg and diastolic BP ≥95 mmHg.2 Therefore, the lack of a referral bias and the study of individuals with less severe hypertension may explain why our results differ from those reported by Alderman et al. Additionally, our hypertensive sample included participants on beta-blockers, angiotensin-converting enzyme inhibitors and diuretics, whereas Alderman et al. studied a sample of patients who did not use anti-hypertensive medications for at least 1 month prior to baseline renin measurements. However, exclusion of individuals on antihypertensive agents from our sample did not alter our results.

A recent study of patients with prevalent stroke reported an elevated risk of myocardial infarction among those with high plasma renin (odds ratio for the highest vs. lowest renin quartile of 1.7; 95%, 1.1–2.8).18 We excluded individuals with prevalent CVD in our analyses of incident CVD and did not evaluate the risk of recurrent CVD events.

Strengths and limitations
There are several strengths of our investigation. We measured plasma renin in a large, community-based sample not selected on the basis of hypertension or prior CVD, thereby minimizing referral bias. Our analysis had statistical power to detect modest effects. Several limitations must be acknowledged, however. Our study sample is primarily of European ancestry; therefore, associations between plasma renin and the risk of CVD or mortality may not be generalizable to other ethnic groups. Previous studies suggest that the distribution of plasma renin varies among black men vs. women, as well as compared to their white counterparts.2,28 Because of the practical constraints inherent in a large epidemiological study, our study participants were recumbent for only 10 min before undergoing phlebotomy and were ambulatory before that time, which could have altered plasma renin levels. An important limitation of our study was that nearly two-thirds of hypertensive individuals in our sample were on antihypertensive therapy; such therapy can variably influence plasma renin levels, being raised by diuretics and ACE-inhibitors but lowered by beta-blockers.29 We did control for antihypertensive medication use in our analyses and performed secondary analyses excluding individuals on antihypertensive therapy.

Implications
The present investigation does not corroborate prior reports suggesting that plasma renin predicts CVD among hypertensive individuals. Therefore, our findings do not support renin profiling of individuals with hypertension in the community for the purpose of risk stratification. It is important to note that other downstream components of the RAAS (such as angiotensin II and angiotensin-converting enzyme and aldosterone) have been directly implicated in vascular and myocardial damage;30–35 therefore, it is conceivable that these other RAAS biomarkers (rather than renin) may be related to CVD risk. Furthermore, there is evidence that tissue renin may play a more important role in mediating myocardial and vascular damage, and such tissue activity may not be reflected by plasma renin levels.36–39 Finally, it is possible that higher plasma renin levels are a marker of subclinical CVD, rather than a cause of overt CVD.


   Conclusions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
Funding
 Appendix
 References
 
In our large community-based sample of middle-aged men and women, plasma renin was positively related to all-cause mortality but was not related to the risk of hard CVD events. The association between plasma renin and all-cause mortality was more pronounced during short-term follow-up and remained present upon excluding those with prevalent CVD. Additional investigations are warranted to confirm our findings.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Funding
Appendix
 References
 
Supported by a National Institute of Health/National Heart, Lung, and Blood Institute, contract N01-HC-25195 to Boston University, research grants R01HL67288, 2K24HL04334 to RSV, and K23HL074077 to TJW.

Conflict of interest: none declared.


   Appendix
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Funding
 Appendix
References
 

Table A Plasma renin and mortality: time-dependent variation in hazards among participants without prevalent cardiovascular disease

Hazards ratio* (95% CI) per SD increment log renin on follow-up
0.5 year 1 year 1.5 year 2 year 2.5 year 3 year 3.5 year 4 year 4.5 year 5 year
All participants (n = 3218)
N = 3 N = 9 N = 8 N = 10 N = 10 N = 7 N = 18 N = 15 N = 13 N = 18
1.91 (1.27–2.86) 1.54 (1.18–2.01) 1.36 (1.10–1.68) 1.24 (1.03–1.50) 1.16 (0.96–1.40) 1.10 (0.90–1.34) 1.05 (0.85–1.30) 1.01 (0.80–1.26) 0.97 (0.76–1.24) 0.94 (0.72–1.22)
Hypertensive participants (n = 1276)
N = 2 N = 5 N = 5 N = 7 N = 6 N = 5 N = 12 N = 5 N = 6 N = 11
1.94 (1.23–3.06) 1.56 (1.16–2.11) 1.38 (1.09–1.74) 1.26 (1.02–1.55) 1.17 (0.95–1.45) 1.11 (0.89–1.39) 1.06 (0.83–1.35) 1.01 (0.78–1.32) 0.98 (0.74–1.30) 0.95 (0.70–1.28)

N indicates the number of deaths during follow-up for each 0.5 year increment. Note that the hazards ratios are for log-renin at different points in time during follow-up (up to 5 years; deaths after 5 years were censored for this analysis).

*Adjusted for age, sex, systolic blood pressure, hypertension treatment, smoking, diabetes, total/HDL cholesterol, creatinine.


Table B Plasma renin and mortality: time-dependent variation in hazards among untreated hypertensive participants (n = 456)

Hazards ratio* (95% CI) per SD increment log renin on follow-up
0.5 year 1 year 1.5 year 2 year 2.5 year 3 year 3.5 year 4 year 4.5 year 5 year
N = 4 N = 2 N = 2 N = 4 N = 2 N = 1 N = 2 N = 1 N = 6 N = 9
1.70 (0.47–6.19) 1.47 (0.63–3.41) 1.35 (0.71–2.56) 1.27 (0.72–2.24) 1.21 (0.69–2.13) 1.17 (0.64–2.13) 1.23 (0.59–2.17) 1.10 (0.54–2.24) 1.10 (0.49–2.32) 1.05 (0.46–2.4)

N indicates the number of deaths during follow-up for each 0.5 year increment. Note that the hazards ratios are for log-renin at different points in time during follow-up (up to 5 years; deaths after 5 years were censored for this analysis).

*Adjusted for age, sex, systolic blood pressure, smoking, diabetes, total/HDL cholesterol, creatinine.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Funding
 Appendix
 References
 

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