Diastolic Blood Pressure and Mortality in the Elderly With Cardiovascular Disease

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1 Diastolic Blood Pressure and Mortality in the Elderly With Cardiovascular Disease Athanase D. Protogerou, Michel E. Safar, Pierre Iaria, Hélène Safar, Katia Le Dudal, Jan Filipovsky, Olivier Henry, Pierre Ducimetière, Jacques Blacher Abstract Isolated systolic hypertension is predominantly observed in the elderly because of increased arterial stiffness. Aggressive treatment leads to excessive lowering of diastolic blood pressure and favors the presence of a J-shaped curve association with mortality. We investigated whether, in the elderly, this pattern of association is a simple epiphenomenon of increased arterial stiffness and impaired cardiac function. In a cohort of 331 hospitalized subjects 70 years old (mean age SD: 85 7 years), aortic pulse wave velocity and pressure wave reflections, by pulse wave analysis, and cardiac function, by ultrasound, were assessed. During a 2-year follow-up period, 110 subjects died. No association of prognosis with systolic pressure, pulse pressure, or pulse wave velocity was observed. A J-shaped association between diastolic pressure and overall and cardiovascular mortality was observed. Unadjusted Cox regression analysis showed that patients in the first tertile of diastolic pressure ( 60 mm Hg) had higher mortality. In Cox regression analysis, diastolic pressure 60 mm Hg was a predictor of mortality independently from cardiac vascular properties, cardiovascular risk factors, and drug treatment. Multivariate regression analysis showed that increased age and low total peripheral resistance, but not left ventricular function, were the cardinal determinants of low diastolic pressure. An optimal diastolic pressure of 70 mm Hg in subjects with isolated systolic hypertension was found. We showed that, in the frail elderly, a value of diastolic blood pressure 60 mm Hg is associated with reduced survival, independent from large artery stiffness and left ventricular function, suggesting that more rational antihypertensive therapy, not only based on systolic pressure level, is needed. (Hypertension. 2007;50: ) Key Words: diastolic blood pressure mortality elderly arterial stiffness pressure wave reflections total peripheral resistance The goal of antihypertensive treatment is to prevent cardiovascular (CV) complications through the reduction of systolic (SBP) and diastolic blood pressure (DBP). However, since the primary work of Cruickshank et al, 1 several reports, but not all, have shown that, in hypertensive subjects treated with drugs, low DBP is frequently associated with increased mortality (reviewed in Reference 2 ). This finding was constantly difficult to evaluate. First, it is difficult in epidemiological studies to assess a J- or U-shaped association with mortality, and it is often easier, using a semilogarithmic scale, to show a linear relation between DBP and mortality. Second, in humans, the decrease of DBP is the consequence of both the aging process 3 and the result of drug treatment, making the net drug effect quite difficult to define. Finally it should be noted that isolated systolic hypertension is difficult to treat and, therefore, aggressive treatment may lead to excessive lowering of diastolic blood pressure and that, in the oldest old, treating high SBP is not always related to reduced overall mortality. 3 6 In the recent years, in subjects 50 years of age with advanced renal failure, Blacher et al 7 showed that increased aortic stiffness and low DBP were independent predictors of CV risk. The distinction between these 2 pathophysiological mechanisms is challenging, because DBP is a component of pulse pressure (PP), increased PP is the principal hemodynamic consequence of increased aortic stiffness, and no data are available until now. In 1998, in a population of subjects followed for 13 years, Tuomilehto et al 8 indicated that low DBP alone was a significant predictor of CV and non-cv mortality among persons aged 50 years (most 70 years). However, the evaluation of the underlying pathophysiological mechanisms was limited, particularly regarding hemodynamic parameters. In this study, a cohort of very old frail subjects was investigated prospectively (mean age SD: 85 7 years). We tried to delineate for the first time the pathophysiological role of DBP on total and CV mortality in relation to large artery Received February 20, 2007; first decision March 12, 2007; revision accepted April 25, From the Paris-Descartes University (A.D.P., M.E.S., P.I., H.S., K.L.D., O.H., J.B.), Faculty of Medicine, AP-HP, Hôtel-Dieu Hospital, Diagnosis and Therapeutic Center, Paris, France; the Department of Internal Medicine II (J.F.), Charles University, Pilsen, Czech Republic; and INSERM U 258 (P.D., J.B.), Villejuif, France. Correspondence to Jacques Blacher, Centre de Diagnostic et de Thérapeutique, Hôtel-Dieu, 1, Place du Parvis Notre-Dame, Paris Cedex 04, France. jacques.blacher@htd.aphp.fr 2007 American Heart Association, Inc. Hypertension is available at DOI: /HYPERTENSIONAHA

2 Protogerou et al Diastolic Pressure and Mortality in the Oldest Old 173 stiffness and pressure wave reflections, as well as to total peripheral resistance and cardiac function. Methods Study Cohort From May 2000 to November 2001, 331 consecutive patients entering the geriatric departments of Charles Foix and Emile Roux Hospitals, Ile de France, were included in the PRonostic cardiovasculaire Optimisation Therapeutique En GERiatric Study with respect to the following inclusion criteria: age 70 years old; past story of CV disease involving coronary heart disease, cerebrovascular disease, hypertension, or any other CV events of the upper or lower limbs, thoracic or abdominal aorta, or renal arteries; Mini Mental Status Examination 15 of 30; absence of fatal disease with life expectancy 1 month; and willingness to give a written informed consent to participate in this study. Patients with cachexia (body mass index: 17 kg/m 2 ) and/or evolutive cancer and/or advanced renal failure (plasma creatinine: 250 mol/l) were not included in the study. The study cohort was then composed of 331 subjects (86 men and 245 women) with mean age SD of 85 7 years. The PRonostic cardiovasculaire Optimisation Therapeutique En GERiatric Study was approved by the Committee for the Protection of Human Subjects in Biomedical Research of Saint Germain Hospital (Ile de France). Written informed consent was obtained from all participants after relevant information was provided to them and to their relatives. Only the parameters that are relevant to the present analysis are presented here. Social, Anthropometric, and Clinical Parameters Information compiled from the questionnaire filled out at inclusion included gender, age, weight, height, personal history of CV event, the presence of diabetes mellitus, dyslipidemia, hypertension, smoking habits, and previous diseases. The reason for hospitalization and the level of education (1 indicates primary school; 2, college degree; 3, bachelor degree; and 4, university degree) were also registered. In all of the subjects, such information agreed with that given by relatives and/or recorded from the most recent previous hospitalization. Medications Antihypertensive drugs included diuretics (38.0%), calcium channel antagonists (27.9%), angiotensin-converting enzyme inhibitors (26.1%), -blockers (12.3%), -blockers (4.0%), and central-acting agents (3.1%), either alone or in combination. Three percent of patients were medically treated for dyslipidemia (drugs including statins or fibrates). Fourteen percent of patients were medically treated for diabetes mellitus (drugs including sulfonamides and/or biguanids or insulin). Assessment of BP, Arterial Stiffness, and Pressure Wave Reflections The measurements were performed in the morning, after an overnight fast, with each patient in the supine position. Brachial BP was measured after 15 minutes of rest using the semiautomatic oscillometric device Dynamap (Kontron). Five measurements 2 minutes apart were averaged. Data on the validity of the oscillometric devices in the elderly and especially in the presence of increased levels of arterial stiffness are lacking; therefore, our results should be viewed under this limitation. The relative enhancement of carotid SBP because of reflected pressure waves (augmentation index [AI]%) was assessed by means of applanation tonometry and application of pulse wave analysis at the level of the carotid artery; the carotid pressure waveform was calculated as described previously. 9 It was available in 296 subjects. Aortic hemodynamics were also estimated by the use of generalized transfer function from radial pressure wave (Sphygmocor AtCor). The time of the arrival of the reflected wave (reflected wave time transit) and the timing at the level of the central arteries (reflected wave time transit/left ventricular ejection time) were measured. The ratio of diastolic pressure time index versus tension time index (ie, the integral of pressure and time during diastole and systole, respectively), has been shown to correlate well with the ratio of subepicardial to subendocardial blood flow, and, therefore, it represents an index of subendocardial viability, defined as subendocardial viability ratio (Buckberg index). 10,11 It was automatically obtained from the aortic pressure waveform by the Sphygmocor apparatus. Because the validity of the generalized transfer function in such an elderly population is not known, the data that are presented on central AI in this study are derived from direct carotid artery tonometry, which is a very good surrogate of invasively acquired aortic AI. 9 Aortic pulse wave velocity (PWV) was determined using the foot-to-foot method as described previously 12 (Complior, Colson); it was available in 283 subjects. The superficial distance covered by the pulse wave was measured directly from the carotid to the femoral artery. This method for distance assessment may overestimate PWV by 2 m/s on average. 13 Measurement of Carotid and Cardiac Ultrasound Parameters The common carotid artery intima media thickness and wall motion were measured by a high-resolution B-mode (7.5 MHz transducer, Kontron 440; n 291). Measurements were done on the right and left common carotid artery, 2 cm proximal to the bifurcation, always performed in plaque-free arterial segments. It was automatically determined from changes of density on the section perpendicular to the vessel wall using specific software. Echocardiograms were recorded with an ultrasound system (Kontron 440) using a 2.5-MHz phase-array transducer (n 297). Cardiac measurements were performed according to the American Society of Echocardiography by M-mode measurements. It was possible to evaluate left ventricular volumes (v) only with left ventricular diameters (D) assuming that the geometric shape of the ventricle was a prolate ellipse. 14 Then the volume of this ellipse was expressed as follows: V (4 /3) (2D/2) (D/2) (D/2) D 3 /3 D 3. Cardiac output (Q) was calculated with the formula: SV heart rate, where SV is stroke volume. Total peripheral vascular resistance (TPR), as: TPR MBP/Q, where MBP indicates mean blood pressure. Echocardiograms were also used to evaluate the diastolic index: E wave deceleration slope time (DT). Measurement of Biological Parameters Venous blood samples were obtained in subjects after an overnight fast and after determination of routine biochemistry and lipid profile by standard methods was performed. Follow-Up Procedures Follow-up started from the baseline examination and lasted until April Of all 331 participants in the present study, 3 (1%) were lost to follow-up. Information was obtained from the patient himself, from relatives, or from general practitioners. Interim telephone and clinic contacts were used to assess all of the hospitalizations, outpatient CV diagnoses, and overall mortality. In the case of hospitalization, discharge reports from medical specialists were obtained. Fatal and nonfatal CV events and all-cause mortality were reported. Follow-up time was defined by the time from the baseline visit until the first event date (for those who had an event) or was censored at the last contact date (for those who did not have any event or for the 3 patients who were lost to follow-up). Statistical Analysis In this exploratory analysis, the proportions of subjects were pooled by 10-mm Hg strata of DBP, SBP, and PP, and the distribution of events (%) was evaluated to determine whether statistical relations were linear. Survival analysis based on Kaplan Meier curves and log-rank tests was used to assess the unadjusted association between tertiles of DBP (first tertile [n 114]: 60 mm Hg; second tertile [n 110]: 61

3 174 Hypertension July 2007 Figure 1. Percentage of (a) all-cause death and (b) CV death by DBP strata of 10 mm Hg. to 70 mm Hg; third tertile [n 102]: 70 mm Hg). To test the effect of other peripheral and central hemodynamics (focusing mainly on the cardiac and vascular properties), we performed a similar analysis according to tertiles for SBP, PP, MBP, TPR, heart rate, large artery stiffness (PWV), pressure wave reflections (AI), and left ventricular systolic and diastolic function (ejection factor [EF] and DT, respectively). Multivariate linear regression analysis was applied to find the determinants of DBP. All of the CV risk factors, as well as functional and structural vascular and cardiac parameters, were evaluated by means of bivariate correlation with DBP. Then multivariate linear regression analysis was applied to find the independent predictors of DBP. The final model was verified by the enter, backward, and stepwise methods (final results represent stepwise analysis). In addition, the validity of the association between DBP and all-cause mortality, as well as CV mortality, was tested using extended adjustments by various Cox regression models. In these models, all of the potential confounding factors (hospital of inclusion, socioeconomic parameters, classical CV risk factors, drugs, cardiac parameters, biochemical indices, and especially vascular parameters) were entered step by step. In the Cox models, DBP was used either as a dichotomized variable (first tertile [ 60 mm Hg] versus second and third tertiles [ 60 mm Hg]), because no significant difference regarding survival was observed between the second and third tertiles of DBP. Finally, subgroup analysis of those subjects with uncontrolled systolic hypertension (SBP 140 mm Hg) was performed regarding the effect of DBP and SBP on overall mortality. T test for continuous variables and 2 test for qualitative parameters were applied to investigate for differences between subjects with DBP 60 mm Hg and DBP 60 mm Hg. Statistical analysis was performed on an SPSS P 0.05 was considered statistically significant. Results Percentage of All-Cause Death and CV Death by 10 mm Hg of BP Strata The percentage of all-cause death and CV death (Figure 1a and 1b) was related to DBP in a J-shaped pattern. On the contrary, a flat relation among SBP, PP, and overall mortality was found (Figures 2a and 3a), as well as an inverse linear relation between SBP and CV mortality and a J-shaped relation between PP and CV mortality. Unadjusted Kaplan Meier Curves: BP and Arterial Stiffness In Figure 4, a clear association of the DBP tertile (brachial or carotid) with (Figure 4a) the total mortality-free survival (P 0.004; Figure 4b) and CV mortality-free survival (P 0.008) is described. Corresponding P values for other brachial BP, PWV, AI, TPR, left ventricular systolic and diastolic function (EF and DT, respectively), and heart rate Figure 2. Percentage of (a) all-cause death and (b) CV death by SBP strata of 10 mm Hg.

4 Protogerou et al Diastolic Pressure and Mortality in the Oldest Old 175 Figure 3. Percentage of (a) all-cause death and (b) CV death by PP strata of 10 mm Hg. are shown in Table 1. Note that none of these factors were related to overall and/or CV mortality except for EF. Unadjusted Kaplan Meier curves also showed that the presence of diabetes mellitus, the lower tertile of hematocrit and plasma albumin, and the higher tertile of plasma creatinine were significantly associated with reduced survival (data not shown). Figure 4. Univariate Kaplan Meier curves for tertiles of SBP (DBPtert; a) on total mortality-free survival and (b) on CV disease mortality-free survival. Determinants of DBP In Table 2, the independent predictors of DBP are described. Age, TPR, AI, PWV, heart rate, and the educational status were independent predictors of DBP. Cox Regression Models In Table 3, the predicting effect of DBP as a dichotomous variable (first DBP tertile versus the [second and third added] DBP tertile) on total mortality-free survival and on CV mortality-free survival was adjusted by various Cox regression models. DBP 60 mm Hg was an independent predictor of mortality even after adjustment for age, gender, and hospital of inclusion (model 1), as well as for additional adjustment for mental status (model 2); classical CV risk factors and previous coronary heart disease and stroke (model 3); medication (model 4); cardiac function and structure (model 5); PWV (model 6a); TPR (model 6b); and AI (model 6c). Only after adjustment for the combined effect of vascular TABLE 1. Univariate Kaplan Meier Curves for Tertiles of Blood Pressure, Vascular, and Cardiac Parameters on Total Mortality-Free Survival and on CV Mortality-Free Survival Tertiles of Total Mortality, Log Rank P CV Mortality, Log Rank P MBP, mm Hg DBP, mm Hg SBP brachial, mm Hg PP brachial, mm Hg PWV, m/s AI, % Heart rate, bpm DT, ms EF, %* TPR, PRU PRU indicates peripheral resistance unit (mm Hg/mL per minute). *The first tertile of EF was related to higher mortality. Including only subjects with EF 45% and no hypokinesias of the left ventricle (77 vs 145), similar results were found on the totality of the population (data not shown).

5 176 Hypertension July 2007 TABLE 2. Independent Predictors of DBP by Multivariate Linear Regression Analysis Independent Predictors Standardized -Coefficients R 2,% P Age, y TPR AI carotid, % PWV, m/s Heart rate, bpm Educational level, 1 to Educational level is defined in the text. properties (PWV, AI, and TPR) did DBP 60 mm Hg lose its predicting value. Similar results were found concerning DBP and CV mortality-free survival (Table 2). The independent effect of DBP was lost after adjustment for the effect of vascular properties. Similarly, after adjustment for biochemical factors (hematocrit, plasma albumin, and plasma creatinine) or weight, low DBP was an independent predictor of overall and CV mortality (data not shown). Comparison of First DBP Tertile (<60 mm Hg) versus Combined Second and Third DBP Tertile (>60 mm Hg) Subjects with DBP 60 mm Hg were older and had smaller weight, hematocrit, plasma albumin, total cholesterol, lowdensity lipoprotein cholesterol, and triglycerides (Table 4). No differences were found regarding other classical CV risk factors, biochemical and social parameters (education level and living habits), study design parameters (center effect; data not shown), and the reason of hospitalization (data not shown). Subjects with DBP 60 mm Hg tended to be treated with more drugs (P 0.079) and a higher percentage of diuretics (P 0.071). Subjects with DBP 60 mm Hg (Table 5) had lower SBP, PP, and MBP. Carotid femoral PWV and carotid intima media thickness did not differ significantly between the 2 groups. AI was lower in subjects with DBP 60 mm Hg, but this difference was abolished after adjustment for MBP. On the contrary, the Buckberg index was lower in subjects with low DBP after adjustment for MBP. Ejection fraction, LV mass, and DT were similar between the 2 groups. Finally, subjects with low DBP had lower TPR (Table 5). Subgroup Analysis In subjects with uncontrolled SBP ( 140 mm Hg), subgroup analysis verified the lack of association between tertiles of SBP and total mortality (first: 13 events/39 subjects 33.3%; second: 11 events/36 subjects 30.5%; third: 10 events/36 subjects 27.7%; log rank by Kaplan Meier P 0.863). On the contrary, subjects in both the lowest (n 37, mean DBP SD: mm Hg) and the highest (n 40, mean DBP SD: mm Hg) tertiles of DBP had higher mortality events (14 events/37 subjects 37.4% and 14 events/40 subjects 35%, respectively) than the middle tertile (n 34, mean DBP SD: TABLE 3. Influence of DBP as a Dichotomized Variable (First Tertile: DBP <60 mm Hg vs Second and Third Tertiles: DBP >60 mm Hg) on Total and CV Mortality After Various Adjustments (Models) by Cox Regression Analysis Total Mortality CV Mortality Models of Adjustment Exp (B) (95% CI) P Exp (B) (95% CI) P Model 1 (usual confounders): age,* sex,* center effect (1.216 to 2.598) 0.003* (0.201 to 0.768) 0.006* Model 2 (mental status): age,* sex,* center effect, (1.241 to 2.699) 0.002* (1.342 to 0.593) 0.005* MMS,* education level* Model 3 (major cardiovascular diseases: risk factors): (1.232 to 2.679) 0.003* (1450 to 5.489) 0.003* age,* sex, center effect, stroke,* CHD,* DM,* smoking Model 4a (medication): age,* sex,* center effect, (1.185 to 2.592) 0.005* (1.258 to 5.124) 0.009* non anti-htn drugs Model 4b (medication): age,* sex,* center effect, (1.227 to 2.652) 0.003* (1.306 to 5.313) 0.007* anti-htn drugs Model 5 (cardiac structure and function): age,* sex,* (1.232 to 2.764) 0.003* (1.146 to 4.900) 0.020* center effect, heart rate,* EF, LV mass Model 6a (vascular parameters: arterial stiffness: (1.098 to 2.540) 0.016* (1.367 to 5.798) 0.005* PWV): age,* sex,* center effect, PWV Model 6b (vascular parameters: microcirculation: (1.172 to 2.589) 0.006* (1.217 to 5.063) 0.012* TPR): age,* sex,* center effect, TPR Model 6c (vascular parameters: pressure wave (1.051 to 2.394) 0.028* (0.860 to 3.854) reflections: AI): age,* sex,* center effect, AI Model 6d (vascular parameters to PWV, AI, TPR): (0.819 to 2.124) (0.701 to 3.929) age,* sex,* center effect, PWV, AI, TPR Exp indicates exponential; LV, left ventricular; MMS, mini mental scale; DM, diabetes mellitus; HTN, hypertensive. *Only parameters that remained in the models (with DBP) as independent predictors of mortality.

6 Protogerou et al Diastolic Pressure and Mortality in the Oldest Old 177 TABLE 4. Cardiovascular Risk Factors, Drug Treatment, and Biochemical and Social Parameters in the 2 Subgroups of Subjects With DBP <60 mm Hg (First Tertile) and >60 mm Hg (Second and Third Tertiles) Variable First DBP Tertile Second and Third Tertiles P Cardiovascular risk factors Age (SE), y 86.3 (0.6) 84.4 (0.4) Weight (SE), kg 57.1 (1.2) 63.6 (1.1) Height (SE), m (0.01) (0.6) MMS (SE), % 72.4 (1.6) 74.9 (1.1) Educational level: primary school, % Educational level: college degree, % Educational level: bachelor degree, % Educational level: university degree, % Diabetes mellitus, % Dyslipidemia, % Current smokers, % Ex-smokers, % Hypertension, % Previous stroke, % Coronary heart disease, % Drug treatment Total anti-htn drugs (SE), n 1.35 (0.09) 1.15 (0.06) Subjects with No. of anti-htn drugs: 1, % Subjects with No. of anti-htn drugs: 2, % Subjects with No. of anti-htn drugs: 3, % Subjects with No. of anti-htn drugs: 4, % Diuretics, % Blockers, % Blockers, % Central acting agents, % Calcium channel antagonists, % Angiotensin-converting enzyme inhibitors, % Biochemical parameters Hematocrit (SE), % 35.3 (0.4) 36.5 (0.5) Albumin (SE), g/dl 3.36 (0.04) 3.49 (0.03) Creatinine (SE), mg/dl 0.96 (0.03) 0,97 (0.02) Total cholesterol (SE), mg/dl (11.1) (8.1) LDL cholesterol (SE), mg/dl (9.4) (7.2) HDL cholesterol (SE), mg/dl 43.5 (0.3) 47.8 (0.2) Triglycerides (SE), mg/dl (5.2) (7.0) MMS indicates mini mental status, LDL, low-density lipoprotein; HDL, high-density lipoprotein. Education level: 1 to 4, please see text (Methods section) for details mm Hg, 6 events/34 subjects 17.6%). Kaplan Meier analysis of the second versus the combined first and third tertiles of DBP showed a marginally significant difference (P 0.056). Discussion This study was the first prospective investigation in an elderly population in which pressure wave reflections, arterial stiffness, cardiac function, and TPR were measured to investigate the potential pathophysiological association of low DBP and mortality. We showed that, in this very aged population, a J-curved association between DBP and mortality (all-cause or CV) was present. DBP was modulated by age, TPR, pressure wave reflections (AI), large artery stiffness (PWV), heart rate, and educational level. The lower survival in subjects with DBP 60 mm Hg was independent from the hospital of inclusion, mini mental status examination, classical CV risk factors, previous health state, coronary heart disease and stroke, and bio-

7 178 Hypertension July 2007 TABLE 5. Hemodynamic, Vascular, and Cardiac Parameters in the 2 Subgroups of Subjects With DBP <60 mm Hg (First Tertile) and >60 mm Hg (Second and Third Tertiles) Hemodynamic, Vascular, and Cardiac Parameters First Tertile Second and Third Tertiles P Heart rate (SE), bpm 68.3 (1.1) 69.3 (0.9) SBP (SE), mm Hg (1.5) (1.2) DBP (SE), mm Hg 53.4 (0.7) 71.7 (0.5) PP (SE), mm Hg 62.0 (1.4) 68.7 (1.1) MBP (SE), mm Hg 78.8 (1.1) 97.9 (0.8) Carotid IMT (SE), mm (0.015) (0.011) AI carotid (SE), %* (2.2) (1.6) AI carotid (SE), % (2.6) (1.7) PWV (SE), m/s* 14.5 (0.4) 14.3 (0.3) RWTT (SE), ms (1.5) (1.1) RWTT/LVED (SE) (0.03) (0.004) Buckberg index (SE), %* (2.8) (2.3) Buckberg index (SE), % (3.1) (2.1) EF (SE), % 60.3 (1.4) 60.9 (1.4) EF 45%, n (%) 14 (13) 18 (9.5) Stroke volume (SE), ml 83.0 (2.5) 87.9 (1.8) LV mass, g (6.3) (4.6) DT (SE), ms (6.8) (4.6) Total peripheral resistance (PRU) (SE) (0.001) (0.001) All data are age and gender adjusted. RWTT indicates reflected wave time travel; LVED, left ventricular end-diastolic diameter; IMT, intima media thickness (average of right and left common carotid); PRU, peripheral resistance unit (millimeters of mercury per milliliter per minute). Additional adjustment for *heart rate and heart rate and MBP. Data include only subjects with EF 45% and no hypokinesias of the left ventricle (77 vs 145), but similar results were found on the totality of the population (data not shown). chemical parameters, as well as drug treatment. Moreover, no cardiac or vascular parameter could solely explain this association. Considerations on the Population The population of the present study carries many particularities because of the high prevalence of atherosclerotic disease (coronary, cerebral, and peripheral vascular disease reaching 62%), which must be carefully considered and may potentially limit the extrapolation of our results to other elderly populations. Only 80 subjects were 80 years of age, and 131 were 90 years old (mean age: 85.1 years; range: 70 to 103 years). This major trait of the population may be responsible for a number of CV particularities. First, carotid femoral PWV was consistently augmented, passing the 20 m/s in 10% of the population (mean PWV: 14.4 m/s; range: 7.2 to 28.9 m/s). Nevertheless, large arterial wall properties (assessed by PWV) were identical between DBP groups. We have shown in the past that, at 70 years of age, PWV no longer correlated with age. 15 Second, and in relation to the first, only 10% of the subjects had seriously impaired left ventricular function (EF: 45%). Third, one third of the population had an extreme decrease of DBP, that is, 60 mm Hg, and only 8 subjects had uncontrolled DBP 90 mm Hg; 111 subjects (one third of the population) had uncontrolled SBP 140 mm Hg. Taken together, these findings suggest that the overall population was composed mainly of survivors. 16 Our negative results concerning prediction of mortality by hemodynamic parameters are important to consider. SBP and PP were not associated with prognosis, all-cause mortality, or CV mortality. Previous study in the oldest old reported this absence of relation between SBP and overall mortality. 17 One could considerer that the patients with the more severe hypertension had probably died before having the age opportunity of entering this study. The remaining poorly controlled subjects with hypertension in this survey could benefit from a survival effect. Similar explanation could be given for PP and PWV. Considerations on the Pathophysiology of the J Curve Four potential pathophysiological mechanisms have been proposed to explain the existence of a J curve. First, the J curve may be an epiphenomenon of more severe underlying chronic illness, which thereby increases mortality. 4 Second, low DBP could also be a marker of cardiac function. Indeed, in the population of North Karelia, 8 especially in patients 70 years of age, the DBP mortality relation was considered as a direct main result of cardiac failure, and there was an age dependence regarding the effect of low DBP on mortality. Third, the J curve may represent an epiphenomenon of increased arterial stiffness, a well-known independent marker of advance vascular disease and of increased mortality, leading to high PP and low DBP Finally, low DBP may

8 Protogerou et al Diastolic Pressure and Mortality in the Oldest Old 179 compromise coronary perfusion during the diastolic phase of the cardiac cycle, especially in subjects with coronary heart disease. 1,2,21 In the current study we found some differences concerning indices of chronic illness between DBP groups (weight, plasma albumin, lipids, and hematocrit), but none of them was sufficient, from a statistical point of view, to explain the association of low DBP with mortality (adjusted data not shown). Moreover, we excluded from the study all of the patients with cachexia, evolutive cancer, and/or advanced renal failure. Concerning the presence of pre-existing CV disease and/or risk factors, no significant differences were found between the 2 groups. Finally, no significant differences regarding the reason for admission in the hospital, before inclusion in the study, were found. In the hospitalized population presented in this study, a low prevalence of heart failure was observed, suggesting other pathophysiological mechanisms underneath the J-shaped curve. Moreover, adjustment for both structural and functional cardiac status did not modify the results. Finally, intima media thickness of the carotid artery, as well as PWV, that is, 2 classical markers of the CV health state, were also similar between the 2 groups. We also showed that, although low DBP is classically related to higher PWV, in this study the effect of DBP on mortality was independent from arterial stiffness and/or pressure wave reflections and was not associated with an increase in PP. Age and low TPR (consequently lower pressure wave reflections), but not EF, account for 13% of DBP variation and may be responsible for the low level of DBP in the first tertile. Because the peripheral resistance and the pressure wave reflections are closely interrelated and both affect DBP, it is difficult to define their individual effects on mortality. Yet, our results imply, for the first time, that low AI may have a deleterious effect, independent from TPR, exclusively on CV mortality. Although this study did not provide direct proof for the deleterious effect of extreme low DBP on coronary perfusion during diastole, epidemiological data 1,2,21 support this pathophysiological approach. Even in the absence of evident contractile dysfunction in older subjects, subendocardial myocardial dysfunction may exist. 22 Indirect evidence from this study support this hypothesis, suggesting that, for the same level of MBP, the subendocardial viability index (Buckberg index) is reduced in subjects with DBP 60 mm Hg. Recent epidemiological data have shown that for the same cutoff value ( 60 mm Hg), DBP had a deleterious effect on the survival of patients with coronary artery disease. 2 We suggest that, in the frail elderly with a high burden of CV disease, even in the absence of evident severe coronary heart disease, in a nonhypertrophied fibrotic heart, oxygen delivery may be impaired in the case of DBP 60 mm Hg and, further, could impair subendocardial contractility. Finally, it should be noted that, although every possible effort to identify the cause of death was done, CV mortality was probably underestimated. Perspectives Our subgroup analysis in subjects with uncontrolled systolic hypertension showed that low DBP at 60 mm Hg was as harmful as a value of 80 mm Hg and that the optimal DBP level was 70 mm Hg. Therefore, aggressive treatment of isolated systolic hypertension, in a fragile population with low systemic TPR, as the one included in this study, may counterbalance the potential favorable effect from SBP decrease. Taking into consideration that in these subjects their limited life expectancy may restrict the actual impact of treatment, this seems to be a real-life scenario. In conclusion, we showed that in the frail oldest old with a high burden of CV disease, DBP is not linearly, but in a J-shaped curve, associated with mortality, with a cutoff level at 60 mm Hg. We also showed that this association was not a simple epiphenomenon because of concomitant chronic illness, cardiac failure, or increased arterial stiffness but was associated with reduced peripheral resistance/pressure wave reflections and potentially aggressive blood pressure reduction, possibly jeopardizing coronary perfusion. More data are needed on the necessity to hold back antihypertensive medications in elderly with low TPR and DBP 70 mm Hg. Acknowledgments We are deeply indebted to the PROTEGER patients and their relatives, who made this study possible. Sources of Funding This work was supported by the Société Française d Hypertension Artérielle and the Fondation de France. None. Disclosures References 1. Cruickshank JM, Thorp JM, Zacharias FJ. Benefits and potential harm from lowering high blood pressure. Lancet. 1987;1: Messerli FH, Mancia G, Conti R, Hewkin AC, Kupfer A, Champion A, Kolloch R, Benetos A, Pepine CJ. Dogma disputed: can aggressively lowered blood pressure in hypertensive patients with coronary artery disease be dangerous Ann Intern Med. 2006;144: Franklin SS, Larson MG, Khan SA, Wong ND, Leip EP, Kannel WB, Levy D. Does the relation of blood pressure to coronary heart disease risk change with aging? The Framingham Heart Study. Circulation. 2001; 103: Boshuizen HC, Izaks G, van Buuren S, Ligthart GJ. Blood pressure and mortality in elderly people aged 85 and older: community based study. BMJ. 1998;316: Dahlof B, Lindholm LH, Hansson L, Schersten B, Ekbom T, Wester PO. Morbidity and mortality in the Swedish trial in the old patients with hypertension (STOP-Hypertension). Lancet. 1991;338: Amery A, Birkenhager W, Brixko R, Bulpitt C, Clement D, Deruyttere M, De Schaepdryver A, Dollery C, Fagard R, Forette F. Efficacy of antihypertensive drug treatment according to age, sex, blood pressure and previous cardiovascular disease in patients over the age of 60. Lancet. 1986;2: Blacher J, Guerin A, Pannier B, Marchais S, Safar M, London G. Impact of aortic stiffness on survival in end-stage renal disease. Circulation. 1999;99: Tuomilehto J, Ryynanen OP, Koistinen A, Rastenyte D, Nissinen A, Puska P. Low diastolic blood pressure and mortality in a population-based cohort of hypertensive patients in North Karelia, Finland. J Hypertens. 1998;16: Protogerou AD, Papaioannou TG, Blacher J, Papamichael Ch, Lekakis J, Safar M. Central blood pressure: do we need them in the management of cardiovascular disease Is it a feasible therapeutic target J Hypertens. 2007;25: Sarnoff SJ, Braunwald E, Welch GH Jr, Case RB, Stainsby WN, Macruz R. Hemodynamic determinants of oxygen consumption of the heart with

9 180 Hypertension July 2007 special reference to tension-time index. Am J Physiol. 1958;192: Buckberg GD, Fixler DE, Archie JP, Hoffman JIE. Experimental subendocardial ischemia after cardiopulmonary bypass. J Thorac Cardiovasc Surg. 1972;64: Asmar R, Benetos A, Topouchian J, Laurent P, Pannier B, Brisac AM, Target R, Levy BI. Assessment of arterial distensibility by automatic pulse wave velocity measurement: validation and clinical application studies. Hypertension. 1995;26: Van Bortel. Is arterial stiffness ready for daily clinical practice? J Hypertens. 2006;24: Popp RL, Harrison DC. Ultrasonic cardiac echocardiography for determining stroke volume and valvular regurgitation. Circulation. 1970;16: Meaume S, Rudnichi A, Lynch A, Bussy C, Sebban C, Benetos A, Safar ME. Aortic pulse wave velocity, an independent marker of cardiovascular disease. J Hypertens. 2001;19: Langer RD, Ganiats TG, Barret-Connor F. Factors associated with paradoxical survival at higher blood pressures in the very old. Am J Epidemiol. 1991;134: Meaume S, Benetos A, Henry OF, Rudnichi A, Safar ME. Aortic pulse wave velocity predicts cardiovascular mortality in subjects 70 years of age. Arterioscler Thromb Vasc Biol. 2001;21: Benetos A, Rudnichi A, Safar M, Guize L. Pulse pressure and cardiovascular mortality in normotensive and hypertensive subjects. Hypertension. 1998;32: Blacher J, Protogerou AD, Safar ME. Cardiovascular risk and the macrocirculation. In: Safar ME, ed. Macro- and Microcirculation in Hypertension. London, UK: Lippincott Williams & Wilkins; 2005: Kannel WB, Wilson PWF, Nam BH, D Agostino RB, Li J. A likely explanation for the J-curve of blood pressure cardiovascular risk. Am J Cardiol. 2004;94: Cruickshank JM. Coronary blood flow reserve and the J curve relation between diastolic blood pressure and myocardial infarction. BMJ. 1988; 297: Lumens J, Delhaas T, Arts T, Cowan BR, Young AA. Impaired subendocardial contractile myofiber function in asymptomatic aged humans, as detected using MRI. Am J Physiol. 2006;291:H1573 H1579.