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Atherosclerosis 233 (2014) 300e306

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Atherosclerosis

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Diastolic blood pressure, aortic atheroma, and prognosis inhypertension: New insights into a complex association

Pierre-Yves Courand a,b,c,*, Hugues Milon a, Giampiero Bricca b,c, Fouad Khettab a,Pierre Lantelme a,b,c

aCardiology Department, European Society of Hypertension Excellence center, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, F-69004 Lyon, FrancebGénomique Fonctionnelle de l’Hypertension artérielle, EA 4173, Université Claude Bernard Lyon1, F-69100 Villeurbanne, FrancecHôpital Nord-Ouest, F-69400 Villefranche sur Saône, France

a r t i c l e i n f o

Article history:Received 5 September 2013Received in revised form27 December 2013Accepted 6 January 2014Available online 21 January 2014

Keywords:Diastolic blood pressureSystolic blood pressureAortic atherosclerosisCardiovascular death

Abbreviations: ANOVA, analysis of variance; ATS,two-modality atherosclerosis score; ATS4, four-modablood pressure; CI, confidence interval; CVD, cardiovablood pressure; ECG, electrocardiogram; PP, pulse prlocity; SBP, systolic blood pressure.* Corresponding author. Cardiology Department, H

Grande Rue de la Croix-Rousse, F-69004 Lyon, Frafax: þ33 472 071 674.

E-mail address: pycourand@hotmail.com (P.-Y. Cou

0021-9150/$ e see front matter � 2014 Elsevier Irelahttp://dx.doi.org/10.1016/j.atherosclerosis.2014.01.004

a b s t r a c t

Objectives: Our study aimed at determining the interaction between the prognostic value of diastolicblood pressure (DBP) and aortic atherosclerosis (ATS).Background: With aging, equal systolic blood pressures (SBPs) become associated with low DBPs; i.e.,high pulse pressures (PPs) become associated with a high risk of cardiovascular death. This association isusually ascribed to aortic stiffening with age but the precise impact of low DBP per se is yet uncertain.Methods: 938 hypertensive patients recruited in the seventies had an aortic ATS score at pretreatmentaortography. All-cause and cardiovascular deaths were assessed 20 years later. The prognostic values ofDBP and SBP were assessed by a multivariate Cox regression model and their interactions with ATSexamined.Results: In the presence of ATS, an increase of 10 mmHg in DBP was associated with a protective effect:hazard ratios 0.84 [0.72e0.99] for cardiovascular death and 0.88 [0.78e1.00] for all-cause death. How-ever, in the absence of ATS, DBP had no prognostic value: hazard ratios 1.05 [0.89e1.23] for cardiovas-cular death and 0.99 [0.88e1.11] for all-cause death (p for interaction: 0.061 and 0.087, respectively). Nointeraction was found between SBP and ATS (p for interaction > 0.40).Conclusions: The prognostic values of DBP and aortic atheroma are not superimposable; yet, they aretightly connected: a low DBP is disadvantageous only in the presence of a pathologic aorta. Aorticatherosclerosis may explain, at least partly, in some high risk populations, the J-shape of the alreadyreported DBP-outcome relationship.

� 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

Many epidemiological studies have shown a continuous rela-tionship between blood pressure (BP), either diastolic (DBP) orsystolic (SBP), and cardiovascular outcomes [1e3]. Nevertheless, ata given SBP level, low DBPs are usually reported as unfavorable [4e6]. This negative effect may be due either to the consequences of

aortic atherosclerosis; ATS2,lity atherosclerosis score; BP,scular disease; DBP, diastolicessure; PWV, pulse wave ve-

ôpital de la Croix-Rousse, 103nce. Tel.: þ33 472 071 667;

rand).

nd Ltd. All rights reserved.

lowDBP per see via a reduced coronary perfusion, for examplee orto the fact that a low DBP is an indication of a remodeled aorta,which is a major risk factor for cardiovascular disease [7e9].

Distinguishing between these two hypotheses is extremelychallenging because DBP and aortic properties are tightly inter-connected. Protogerou et al. have made an attempt in very elderlysubjects; they showed that whatever the pulse wave velocity(PWV), a low DBP was a negative prognostic maker [10]. Yet,because of their advanced age (85 years on average), it is likely thatmost of these subjects had a pathologic aorta precluding a realassessment of the respective effects of low DBP and aortic prop-erties on the outcomes.

Whether a low DBP is disadvantageous by itself, particularly inthe presence of ischemic heart disease [11], or its prognostic valuetotally concealed by aortic damages is an important issue. Indeed,the answer may help determining the level to which BDP can belowered safely and in whom. It may also allow for a better

P.-Y. Courand et al. / Atherosclerosis 233 (2014) 300e306 301

understanding of the J-shaped relationship between DBP and car-diovascular outcomes.

The aim of the present study was to determine the respectivecontributions of aortic atherosclerosis (ATS) and DBP on all-causeand cardiovascular mortality in a large cohort of hypertensive pa-tients with a very long follow-up duration and, above all, withavailable scores of ATS based on aortography.

2. Methods

2.1. Patients

The study cohort has been previously described [12]. Briefly, thecohort included all consecutive patients who visited the CardiologyDepartment at Louis Pradel Hospital (Hugues Milon and AlainFroment, Lyon, France) between January 1969 and December 1976for a work-up of their hypertension (N¼ 1963). At study closure, 24patients were lost of follow-up. Among the 1939 patients with fullfollow-up, 938 have had an aortography at admission and wereretained for the present analysis. Their outcomes were checkedafter a twenty-year follow-up period.

2.2. Protocol

A special form was filled out for every patient. It includedvarious morphometric characteristics, risk factors for cardiovascu-lar events (smoking status, alcohol intake, salt consumption, etc.),history of cardiovascular disease, and current medication andsymptoms.

The smoking status was defined as current tobacco consump-tion or consumption stopped less than 5 years ago. BP wasmeasured with a manual sphygmomanometer after 10 min of restin the supine position. The considered SBP, DBP, and PP were eachof the average of six measurements. Twelve-lead ECG was per-formed in the supine position.

An overnight fasting blood sample was drawn for hemogramand plasma chemistry (electrolytes, creatinine, glucose, and totalcholesterol). Diabetes was retrospectively defined as a fastingglucose �1.26 g/L (�7.9 mmol/L) on two separate occasions orcurrent use of antidiabetic medication. The renal function wasassessed by the Modification in Diet in Renal Disease (MDRD)formula.

Previous cardiovascular diseases (CVDs) included history ofheart failure (clinical or chest radiographic findings such as dys-pnea, edema, cardiomegaly, or pulmonary congestion), coronaryartery disease (clinical findings such as angina pectoris, myocardialinfarction, or Q wave on electrocardiogram), peripheral arterialdisease (walking impairment or pain at rest), and stroke (clinicalfindings).

Aortography was performed by puncture of the femoral artery.Seldinger technique was used to diagnose renal artery stenosisbecause Doppler imaging, computed tomography, and magneticresonance imaging were not available before 1976. It was per-formed unless i) the patient refused; ii) this aortography wasalready done in another centre; or iii) the procedure was notjustified within the clinical context. The descending thoracic andabdominal aorta was explored. Signs of aortic atherosclerosisincluded calcifications, atherosclerotic plaque, stenosis, or aneu-rysms. These were categorized according to a four-modalityatherosclerosis score (ATS4): 0 when absent, 1 for mild athero-sclerosis (few calcifications or atherosclerotic plaques), 2 for mod-erate atherosclerosis (numerous calcifications or atheroscleroticplaques), 3 for severe atherosclerosis (stenosis or aneurysm). Asimplified two-modality score (ATS2) was also used: 0 for ATS4 ¼ 0and 1 for ATS4 ¼ 1, 2, or 3.

2.3. Assessment of outcomes

Patients were not individually followed by our team. Deathswere obtained from the Institut National de la Statistique et desEtudes Economiques (INSEE). All other subjects were considered tobe alive at the end of the follow-up period. The end points used inthis study were all-cause deaths (cardiovascular and non-cardiovascular deaths) and cardiovascular deaths (from cerebro-vascular disease, myocardial infarction, or heart failure).

2.4. Statistical analyses

Continuous variables with close-to-normal distributions weresummarized as means � standard deviations. Continuous variableswith skewed distributions were summarized as medians (inter-quartile ranges). Categorical variables were expressed as percent-ages. Thus, a non-parametric ANOVA was used to comparecontinuous variables between ATS subgroups and c2 testing wasused for between-group comparisons of dichotomous variables.

The prognostic values of ATS and BP were first examined in thewhole cohort as categorical variables: precisely, ATS4 scores, DBPquartiles (<97, 97e109, 110e121, and >121 mmHg), and SBPquartiles (<163,163e182,183e207, and>207mmHg). The times toall-cause or cardiovascular death were analyzed by KaplaneMeiersurvival curves and these curves compared using the log-rank test.

In a second step, adjusted hazard ratios for DBP and SBP werecalculated in the same multivariable Cox regression model (c2

statistic adjusted for age, sex, DBP, SBP, ATS2, diabetes, totalcholesterol, smoking status, previous cardiovascular disease, bodymass index, antihypertensive treatment and estimated glomerularfiltration rate). The proportional hazards hypothesis was tested byintroducing a variable-by-time interaction into the Cox regressionmodel. These interactions were not statistically significant for all-cause or cardiovascular death. The hazard ratios for DBP and SBPwere then recalculated as a function of ATS2 and age (�45 vs. >45years, �50 vs. >50 years, �55 vs. >55 years) as potential effectmodifiers using the same multivariable model as above butexcluding ATS2: i.e., including age (as a continuous variable), sex,DBP, SBP, diabetes, total cholesterol, smoking status, previous car-diovascular disease, body mass index, antihypertensive treatmentand estimated glomerular filtration rate. Smoothing splines wereused to determine the functional form of the association betweenthe risk for all-cause death or cardiovascular death and DBP or SBPas a function of aortic atherosclerosis (ATS2 0 and ATS2 1) in thesame multivariable Cox regression model.

For the graphical representation of the relationship between BPand cardiovascular mortality, the hazard ratios and their 95% CIswere plotted with 180 mmHg SBP and 110 mmHg DBP as refer-ences. These reference levels approximate the mean SBP(186 mmHg) and DBP (110 mmHg) of the study population. Theplotted hazard ratios were based on the covariate-adjusted Coxproportional hazards model with a restricted cubic spline trans-formation of BP that used five knots at 80, 100, 110, 122, and145 mmHg for DBP and 142, 165, 180, 203, and 242 mmHg for SBP.

Sensitivity analyses were performed to address the possibility ofreverse causality. Reverse causality refers here to the possibilitythat low BP may be a consequence rather than a cause of poorhealth condition (e.g., congestive heart failure or malignancy),which is frequently mentioned as an explanation for low BP-associated morbidity and mortality [13e15]. A sensitivity analysiswas performed after exclusion of patients with secondary hyper-tension to rule out a selection bias between the whole cohort andthe subgroup with aortography. Because reverse causality, if pre-sent, would affect short-term rather than long-term outcomes, tworegression analyses were repeated excluding 25 patients who died

P.-Y. Courand et al. / Atherosclerosis 233 (2014) 300e306302

during the first year of follow-up and also after exclusion of 68patients who died during the first three years of follow-up with thesame Cox regression multivariable model. We also investigatedseparately the first half and the second half of deaths in a multi-variable Cox regression adjusted for less variables to increase sta-tistical power: age, sex, SBP, DBP, ATS2, previous cardiovasculardisease, estimated glomerular filtration rate and the interactionbetween DBP and ATS2.

Moreover, to rule out the bias of different causes of death be-tween groups, the causes of death were compared between sub-jects with median baseline SBP lower vs. higher than 180 mmHgand between subjects with median baseline DBP lower vs. higherthan 110 mmHg using a Pearson c2 test. The causes of death werecategorized as vascular death, progressive heart failure, malig-nancy, or other.

The analyses used SPSS software, release 20.0.0 (SPSS, Chicago,USA) and STATA 12 (Stata Corporation, College Station, TX). A pvalue <0.05 was considered for statistical significance, except forthe test of interaction according various potential effect modifiers;in this case a p value <0.10 was retained for statistical significance.

3. Results

On average, the patients had a markedly elevated BP (182/110 mmHg) and 18% of them had a previous cardiovascular disease(Table 1). Nearly half of them were receiving at least one antihy-pertensive drug at baseline: thiazide diuretics (48%), centrallyacting drugs (22%), antialdosterones (13%), or beta-blockers (1%).Precisely, 720 patients (76.8%) had essential hypertension; theother etiologies were: renal artery stenosis (6.0%), renal paren-chymal disease (5.5%), primary aldosteronism (3.1%), aortic coarc-tation (1.3%), and miscellaneous (7.3%). Baseline characteristics ofpatients with or without an aortography (N ¼ 938 and N ¼ 1001respectively) were quite similar with the exception of age and ae-tiologies (Supplementary data, Table S1).

Table 1 shows the gradual association between the ATS4 gradeand the overall severity pattern, particularly regarding the presenceof previous cardiovascular disease. An increase of SBP but not of

Table 1Baseline characteristics according to the four grades of aortic atherosclerosis.

Characteristics Aortic atherosclerosis grade

All grades ATS4 0 A

Number of subjects 938 656 1Demographic characteristicsAge (years) 43.5 � 10.8 40.6 � 10.6 4Women/Men (%) 38.3/61.7 40.2/59.8 4Smokers (%) 52.3 47.5 5BMI (kg/m2) 25.0 (22.4e28.1) 25.2 (22.2e28.1) 2

Cardiac parametersHeart rate (bpm) 79 � 13 80 � 13 8SBP (mmHg) 182 (163e207) 178 (162e200) 1DBP (mmHg) 110 � 19 110 � 19 1PP (mmHg) 73 (60e90) 70 (60e85) 7

Medical historyDiabetes (%) 15.0 12.8 2History of HF (%) 9.8 7.2 1CAD (%) 5.9 3.8 1PAD (%) 3.3 0.6 3Stroke (%) 11.3 8.2 1Treatment of HT (%) 48.6 43.9 5

Biochemical variableseGFR (mL/min/1.73 m2) 81 (65e98) 84 (69e103) 7Total cholesterol (g/L) 2.2 (2.0e2.5) 2.2 (1.9e2.4) 2

Unless otherwise stated, the data are means � SDs or medians (interquartile ranges). BMpulse pressure; HF: heart failure; eGFR: estimated glomerular filtration rate; bpm: beahypertension; ATS4 0: absence of aortic atherosclerosis; ATS4 1: mild aortic atherosclero

DBP was observed across ATS4 subgroups. As a result, the PPincreased along with ATS severity. During the 20-year follow-upperiod, 362 deaths occurred: 184 from a cardiovascular cause, 54from cancer, 15 violent deaths, and 109 from other causes.

3.1. Prognostic value of ATS, DBP, and SBP for cardiovascular andall-cause death

As shown by KaplaneMeier curves (Fig. 1), the survival ratesdecreased with increasing DBP and SBP levels and also withincreasing severity of aortic atherosclerosis (ATS4). This was true forall-cause and cardiovascular deaths (log-rank p < 0.05). In the Coxregression univariate analysis, DBP, SBP, and ATS2 were statisticallyassociated with cardiovascular and all-cause death (Table 2).Testing Pearson’s correlation between log-transformed SBP andDBP values demonstrated a statistically significant correlation(r¼ 0.584, p< 0.001). Yet, the multicollinearity of the two variableswas not strong enough to prevent from building a model adjustedfor both SBP and DBP. In a multivariable analysis, an increased SBPand ATS2 score remained associated with an increased risk for all-cause or cardiovascular death whereas an increased DBP showedonly a non-statistically significant trend toward a protective effect.

3.2. Interaction between ATS, age, and BP levels

Fig. 2A shows the prognostic value of a 10 mmHg increase inDBP according to various conditions. An interaction was foundbetween the prognostic value of DBP and ATS2 for cardiovasculardeath and all-cause death (p for interaction: 0.061 and 0.087,respectively). Indeed, a 10 mmHg increase in DBP was associatedwith a protective effect in the presence of ATS2 (the hazard ratioswere 0.84 [0.72e0.99] for cardiovascular death and 0.88 [0.78e1.00] for all-cause death) but DBP had no prognostic value in theabsence of detectable ATS2 (the hazard ratios were then 1.05 [0.89e1.23] for cardiovascular death and 0.99 [0.88e1.11] for all-causedeath.

There was an interaction between DBP and age for cardiovas-cular death and all-cause death, but only with a cut-off set at 55

p value

TS4 1 ATS4 2 ATS4 3

76 58 48

8.7 � 7.4 51.8 � 8.2 53.2 � 9.7 <0.0012.0/58.0 20.7/79.3 18.8/81.2 0.0013.4 78.9 89.6 <0.0015.0 (23.1e28.1) 24.9 (22.7e27.5) 24.1 (22.1e26.0) 0.186

0 � 13 79 � 12 77 � 13 0.63691 (170e220) 187 (165e215) 208 (182e226) <0.00114 � 19 109 � 16 113 � 18 0.0117 (63e96) 84 (65e98) 90 (65e115) <0.001

2.2 20.7 12.5 0.0102.5 20.7 22.9 <0.0010.2 13.8 8.3 <0.001.0 10.3 33.3 <0.0017.6 19.0 20.8 <0.0016.8 58.6 70.8 <0.001

5 (61e91) 73 (56e90) 69 (45e89) <0.001.3 (2.0e2.6) 2.4 (2.2e2.6) 2.3 (2.1e2.6) <0.001

I: body-mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; PP:ts per minute; CAD: coronary artery disease; PAD: peripheral artery disease; HT:sis; ATS4 2: moderate aortic atherosclerosis; ATS4 3: severe aortic atherosclerosis.

Fig. 1. KaplaneMeier survival curves according to the quartiles of systolic blood pressure, the quartiles of diastolic blood pressure, and the grades of aortic atherosclerosis.

P.-Y. Courand et al. / Atherosclerosis 233 (2014) 300e306 303

Table 2Univariate and multivariate Cox regression analysis for aortic atherosclerosis, sys-tolic blood pressure and diastolic blood pressure. Adjusted hazard ratios [95% CIs].

Variables All-cause death Cardiovascular death

HR [95% CI] p HR [95% CI] p

Univariate analysisATS2 1 vs. ATS2 0 2.51 [2.04e3.08] <0.001 3.00 [2.25e4.01] <0.001SBP (þ10 mmHg) 1.14 [1.11e1.18] <0.001 1.17 [1.13e1.23] <0.001DBP (þ10 mmHg) 1.12 [1.06e1.18] <0.001 1.15 [1.07e1.24] <0.001

Multivariate analysisATS2 1 vs. ATS2 0 1.28 [1.01e1.62] 0.044 1.52 [1.09e2.12] 0.014SBP (þ10 mmHg) 1.10 [1.06e1.15] <0.001 1.14 [1.07e1.21] <0.001DBP (þ10 mmHg) 0.95 [0.88e1.02] 0.174 0.93 [0.84e1.04] 0.199

Multivariate model including age, sex, systolic blood pressure (continuous variable),diastolic blood pressure (continuous variable), diabetes, total cholesterol, smokingstatus, previous cardiovascular disease, estimated glomerular filtration rate(Modification in Diet in Renal Disease formula, continuous variable), antihyper-tensive treatment and body mass index (continuous variable). ATS2 1: atheroscle-rosis present; ATS2 0: atherosclerosis absent.

P.-Y. Courand et al. / Atherosclerosis 233 (2014) 300e306304

years (p for interaction 0.110 and 0.021 respectively). Indeed, a10 mmHg increase in DBP was associated with a protective effect inpatients older than 55 years (the hazard ratios were 0.76 [0.61e0.96] for cardiovascular death and 0.79 [0.66e0.94] for all-causedeath) but DBP had no prognostic value in patients younger than55 years (the hazard ratios were 1.02 [0.89e1.16] for cardiovasculardeath and 1.00 [0.91e1.10] for all-cause death). The prevalence ofaortic atherosclerosis (ATS2) was much higher in patient older than55 years than in patients younger than 55 years (65% vs. 20%,p < 0.001).

The picturewas rather different concerning the prognostic valueof SBP according to the same conditions (Fig. 2B). An increase of SBPwas associated with a higher risk of all-cause or cardiovasculardeath whatever the condition. In particular, there was no interac-tion with ATS2 (p for interaction 0.414 for cardiovascular death and0.363 for all-cause death).

The results of the multivariate survival analyses for cardiovas-cular death that used cubic splines are presented in Fig. 3. Thehazard ratio of DBP in patients without aortic atherosclerosis(ATS2 ¼ 0) was relatively stable after adjustment for SBP; there wasjust a trend for a J-curve (70 vs. 110 mmHg of DBP, hazard ratio 1.92[0.88e5.13]). In the presence of aortic atherosclerosis (ATS2 ¼ 1),patients with DBP lower than 80 mmHg had at least a four-foldhigher risk of cardiovascular death after adjustment for SBP (70vs. 110 mmHg of DBP, hazard ratio 4.26 [1.12e18.19]). Aorticatherosclerosis did not impact the increased risk of cardiovasculardeath associated with 10 mmHg increments of SBP after adjust-ment for DBP.

3.3. Sensitivity analyses

After exclusion of the patients deceased during the first year offollow-up, the univariable and multivariable hazard ratios for ATS4,DBP, and SBP were comparable to those found for the whole cohort(Supplementary data, Table S2). After this exclusion, the prognosticvalues of a 10 mmHg increase in DBP or SBP according to variousconditions were also relatively close to the values found for thewhole cohort (Supplementary data, Figs. S1 and S2).

The shape of the relationship between BP level and cardiovas-cular death did not change after exclusion of the patients deceasedduring the first year of follow-up (Supplementary data, Fig. S3).Similar distributions of the causes of death (categorized as car-diovascular death, cancer, violent death, and other) were found insubjects with ATS2 ¼ 0 vs. ATS2 ¼ 1 (p ¼ 0.597), subjects withSBP� 182 vs.<182mmHg (p¼ 0.225), and subjects with DBP< 110

vs. � 110 mmHg (p ¼ 0.445, Supplementary data, Fig. S4). Afterexclusion of patients deceased in the first three years of follow-up(N ¼ 68), the interaction between DBP and aortic atheroma was ofborderline significance for cardiovascular (p ¼ 0.107) and all-causemortality (p ¼ 0.140). Finally, when the analysis focuses on patientswith essential hypertension (N ¼ 720), we observed a significantinteraction between DBP and aortic atheroma for cardiovascularmortality (p¼ 0.094) and a trend for all-cause mortality (p¼ 0.185).

When we performed our multivariable Cox regression analysisduring the first follow-up period (i.e., 0e9.6 years, first half ofdeath), we observed a p interaction for DBP and aortic atheroma of0.081 for cardiovascular mortality and of 0.169 for all-cause mor-tality. During the second follow-up period (i.e., 9.6e20 years, sec-ond half of death), the results were quite similar with a pinteraction for DBP and aortic atheroma of 0.122 for cardiovascularmortality and of 0.174 for all-cause mortality.

4. Discussion

The present study provides new insights into the prognosticvalue of DBP. It shows that the prognostic values of DBP and aorticatheroma are not superimposable; yet, they are tightly connected, alowDBP being associated with an unfavorable prognosis only in thepresence of a pathologic aorta. Aortic atherosclerosis may explain,at least partly, the J-shape of the DBP-outcome relationship.

The strong link between high BP and cardiovascular outcomes isnow well-documented [1e3]. With aging, the positive relationshipbetween SBP and the cardiovascular risk persists whereas a nega-tive relationship between DBP and this risk is often reported[13,16,17]. The latter relationship may be even more complex andtake the shape of a J-curve. Interpreting these relationships isdifficult because of the confounding effect of the changes in aorticproperties with age. Indeed, it is well known that the age-inducedaortic stiffening leads to major changes in BP level at both the pe-ripheral and the central levels. While SBP keeps on increasing withage, DBP starts to decrease by 55 or 60 years of age, which leads to amarked increase in PP [18]. Thus, at a given SBP level, a low DBP isusually an indicator of a stiffened aorta.

Aortic stiffness is an unfavorable factor by itself; this has beenshown using PWV, a direct marker of aortic stiffness [7e9], or PP, anindirect marker [4,5,19]. The present results confirm this prognosticvalue because worse outcomes were observed with increasing se-verities of aortic atherosclerosis. Though ATS4 does not strictlycorrespond to a measurement of aortic stiffness, we believe it isprobably a good proxy. Indeed, it has been shown in healthy vol-unteers that aortic calcification, as assessed by computed tomog-raphy, was positively associated with high PWV [20]. Furthermore,as internal validation, our ATS4 variable was tightly related to PP.

In this context, the unresolved issue is the precise role of DBP. Isa low DBP harmful by itself or is its prognostic value totally con-cealed by that of aortic remodeling? This is an important questionbecause it raises other ones: to which level can DBP be loweredsafely and in whom? If aortic damage overcomes DBP in terms ofprognostic significance, then lowering DBP will not be a problem. Ifnot, lowering DBP will be harmful.

Most epidemiological studies are confounded by the fact that PPis used both as a marker of low DBP and as a surrogate of aorticremodeling, namely stiffening. In elderly subjects, Protogerou et al.tried to cope with this bias by using PWV, a direct index of aorticstiffness [10]. They showed that the prognostic value of DBP wasindependent of PWV, suggesting a pathological role for lowDBP perse. However, it is likely that most of these elderly subjects had anabnormal aorta, which limits the scope of the findings. In thisrespect, the present study presents the advantage of dissociatingaortic properties from DBP.

Fig. 2. Predictive value of diastolic blood pressure (panel A) or systolic blood pressure (panel B) as a continuous variable (þ10 mmHg) according to various potential effect modifiers(20 years follow-up). Cox regression model with diastolic blood pressure (panel A) or systolic blood pressure (panel B) as continuous variable (þ10 mmHg) adjusted for the majorrisk factors: age, sex, systolic blood pressure (panel A) or diastolic blood pressure (panel B), diabetes, total cholesterol, smoking status, estimated glomerular filtration rate, bodymass index, previous cardiovascular diseases, and anti-hypertensive treatment. Four additional effect modifiers were considered: atherosclerosis, ATS2 (0, 1) and three different agecut-offs (45, 50, and 55 years). HR: hazard ratio; CI: confidence interval; ATS2 1: atherosclerosis present; ATS2 0: atherosclerosis absent.

P.-Y. Courand et al. / Atherosclerosis 233 (2014) 300e306 305

Analyzing the entire cohort after adjustment for the majorconfounders, including SBP and ATS, the study found a non-significant trend for a deleterious effect of low DBP. More impor-tantly, when examined as a function of aortic damage, the harmfuleffect of low DBP was observed only in the presence of a pathologicaorta, suggesting a major prognostic interaction between aorticproperties and DBP. This interaction was further supported by themodulating effect of age on the predictive value of DBP. In contrast,there was no modulating effect of aortic properties or age on theprognostic value of SBP. This emphasizes the differences in thepathological consequences of changes in the two types of BP.

The effect of the interaction between DBP and ATS on the out-comes may have several explanations. It can be due to the centralpressure. Indeed, ATS, via its plausible association with PWV in-crease, may favor an early return of the reflected wave over theincident wave whose consequence is a further increase in centralSBP but a decrease central DBP [21]. This is able to promoteischemic events. Another explanation is that aortic ATS is a markerof poor general vascular status, especially at the coronary level [22e24]. This is supported here by the fact that the prevalence of cor-onary disease tended to increase with the severity of aorticatherosclerosis and, in fact, the pathological role of low DBP in the

Fig. 3. Hazard ratio for cardiovascular mortality with SBP or DBP as a function of aortic atheras continuous variable (þ10 mmHg, cubic spline transformation) according to aortic atherosblood pressure and 110 mmHg for diastolic blood pressure. Model adjusted for the major riskfor cubic spline transformation), diabetes, total cholesterol, smoking status, estimated glohypertensive treatment. HR: hazard ratio; CI: confidence interval; ATS2 1: atherosclerosis p

presence of coronary disease has been already shown [11]. Finally,the prognostic impact of a low DBP may be due to a reverse cau-sality, which would be in accordance with some observationsshowing that the association between lowDBP and outcome is seenonly over the short term [25]. However, this hypothesis was notsupported here by the sensitivity analysis carried out after removalof the first-year deaths.

Finally, our results are in perfect agreement with the currentknowledge on the J-curve and may have practical implications. Thepresence of aortic damage may explain, at least partly, the fact thatthe J-shaped relationship between DBP and cardiovascular events ismainly reported in studies on patients with previous cardiovasculardisease or diabetes [13,17,26e28] but not in populations with lowerrisks [1]. This calls for caution in lowering the DBP in the formerpopulation whereas DBP lowering is less risky in the latter.

The main limitation of this study is the lack of a direct estima-tion of aortic stiffness (PWV) and the fact that ATS evaluation wasperformed via an angiographic score not available routinely inhypertensive patients. In this respect, our results may not bedirectly applicable to clinical practice and should be regarded as “aproof of concept”. Even if our ATS variable has several advantagesbeing a pressure-independent index undoubtedly highly related to

osclerosis. Cox regression model with systolic blood pressure or diastolic blood pressureclerosis condition. The reference values for the hazard ratio are 180 mmHg for systolicfactors: age, sex, diastolic or systolic blood pressure (depending on the one consideredmerular filtration rate, body mass index, previous cardiovascular diseases and anti-resent; ATS2 0: atherosclerosis absent.

P.-Y. Courand et al. / Atherosclerosis 233 (2014) 300e306306

aortic stiffness, our results deserve confirmation with a directestimation of stiffness by PWV. Still, the major strengths of thisstudy are the large size of the cohort, the detailed baseline char-acteristics, the very long duration of the follow-up, and the highnumber and robustness of the events considered.

In conclusion, we showed that a low DBP is associated with apoor outcome only in the context of a pathologic aorta. No suchassociation was found in case of “normal aorta”.

Acknowledgments

The authors thank Jean Iwaz (Hospices Civils de Lyon) for athorough editing of the manuscript.

Appendix A. Supplementary data

Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.atherosclerosis.2014.01.004.

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