Ambulatory Blood Pressure Parameters and Heart Failure With Reduced or Preserved Ejection Fraction in Elderly Treated Hypertensive Patients

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1 Original Article Ambulatory Blood Pressure Parameters and Heart Failure With Reduced or Preserved Ejection Fraction in Elderly Treated Hypertensive Patients Sante D. Pierdomenico, 1,2 Anna M. Pierdomenico, 2,3 Francesca Coccina, 3 Domenico Lapenna, 2,3 and Ettore Porreca 2,3 BACKGROUND The association between ambulatory blood pressure (BP) and future risk of heart failure (HF) is unclear. We investigated the association between ambulatory BP parameters and risk of HF with reduced ejection fraction (HFREF) or preserved ejection fraction (HFPEF) in elderly treated hypertensive patients. METHODS The occurrence of HFREF and HFPEF was evaluated in 1,191 elderly treated hypertensive patients who underwent clinical and instrumental evaluation, including ambulatory BP monitoring to evaluate daytime, nighttime, and 24-hour BP, dipping status, and morning surge (MS) of BP. RESULTS During the follow-up (9.1 ± 4.9 years, range years), 123 patients developed HF, of whom 56 had HFREF and 67 had HFPEF. After adjustment for other covariates, Cox regression analysis showed that 24-hour Heart failure (HF) is a major public health problem with high morbidity, mortality, hospitalization rates, and cost, especially in the elderly. 1 We now recognize 2 subtypes of HF, that is, HF with reduced ejection fraction (HFREF) and HF with preserved ejection fraction (HFPEF), 1,2 which is the most common form in older adults and its prevalence is increasing as the population ages. Some studies have evaluated predicting factors and comorbidities of these 2 subtypes of HF. 3 9 While survival has improved over time for patients with HFREF due to advances in therapies, it did not substantially change in those with HFPEF. 1,2 Indeed, HFPEF remains a challenging problem because our understanding of its pathophysiology is incomplete and there is no robust evidence that any treatment can modify its natural history In such a context, a better knowledge of factors associated with HF, particularly with HFPEF, could be helpful in order to prevent and/or better plan therapeutic strategies for these conditions. Hypertension is a frequent comorbidity in both patients systolic BP, but not clinic BP, was independently associated with risk of both HFREF (hazard ratio (HR): 1.36, 95% confidence interval (CI): , per 10 mm Hg increment) and HFPEF (HR: 1.35, 95% CI: , per 10 mm Hg increment); moreover, high MS of BP (>23 mm Hg) in dippers was independently associated with risk of HFREF (HR: 2.27, 95% CI: ) and nondipping was independently associated with risk of HFPEF (HR: 2.78, 95% CI: ). CONCLUSIONS In elderly treated hypertensive patients, 24-hour systolic BP is independently associated with future risk of both HFREF and HFPEF, whereas high MS is independently associated with risk of HFREF and nondipping is independently associated with risk of HFPEF. Keywords: ambulatory blood pressure; dippers; heart failure; hypertension; morning surge; nondippers. doi: /ajh/hpw015 with HFREF and HFPEF. 3 9 However, clinic blood pressure (BP) does not entirely depict its detrimental effect. Indeed, various studies have repeatedly shown that ambulatory BP and circadian BP changes are superior to clinic BP in predicting cardiovascular outcome To the best of our knowledge, there is a single study 22 in the literature specifically evaluating the influence of ambulatory BP and circadian BP changes on the occurrence of HF, with no distinction between HFREF and HFPEF. The aim of this study was to investigate the relationship between ambulatory BP parameters and incidence of HFREF or HFPEF in an elderly treated hypertensive population. METHODS Subjects Since 1992 we built 2 prospective databases of our initially untreated or initially treated hypertensive patients with the Correspondence: Sante D. Pierdomenico (pierdomenico@unich.it). Initially submitted December 8, 2015; date of first revision December 27, 2015; accepted for publication January 25, 2016; online publication March 18, Dipartimento di Scienze Mediche, Orali e Biotecnologiche, Università Gabriele d Annunzio, Chieti, Italy; 2 Centro di Ricerca Clinica, Fondazione Università Gabriele d Annunzio, Chieti, Italy; 3 Dipartimento di Medicina e Scienze dell Invecchiamento, Università Gabriele d Annunzio, Chieti, Italy. American Journal of Hypertension, Ltd All rights reserved. For Permissions, please journals.permissions@oup.com American Journal of Hypertension 29(8) August

2 Pierdomenico et al. purpose to evaluate the prognostic value of ambulatory BP parameters and other risk markers. The present study is one of those carried out with the database of initially treated subjects. We studied 1,191 sequential treated hypertensive patients aged 60 years (range years) prospectively recruited from December 1992 to December 2012 who were referred to our hospital outpatient clinic for management of uncontrolled hypertension. Sixty-two patients were lost during follow-up. Subjects with secondary hypertension were excluded. All the patients underwent clinical evaluation, electrocardiogram, routine laboratory tests, echocardiographic examination, and noninvasive ambulatory BP monitoring. Study population came from the same geographical area (Chieti and Pescara, Abruzzo, Italy). The study was in accordance with the Second Declaration of Helsinki and was approved by the institutional review committee. Subjects gave informed consent. Office BP measurements Clinic systolic and diastolic BP recordings were performed by a physician by using a mercury sphygmomanometer and appropriate-sized cuffs. Phase V was used to determine diastolic BP. Measurements were performed in triplicate, 2 minutes apart, and the mean value was used as the BP for the visit. Ambulatory BP monitoring Ambulatory BP monitoring was performed with a portable noninvasive recorder (SpaceLabs 90207, Redmond, WA) on a day of typical activity, within 1 week from clinic BP measurement. Each time a reading was taken, subjects were instructed to remain motionless and to record their activity on a diary sheet. Technical aspects have been previously reported. 23 Ambulatory BP readings were obtained at 15-minutes intervals from 6 am to midnight and at 30-minutes intervals from midnight to 6 am. The following ambulatory BP parameters were evaluated: daytime (awake period), nighttime (asleep period), and 24-hour systolic and diastolic BP, the extent of BP reduction from day to night (those with BP reduction <10% were defined as nondippers and those with BP reduction 10% were defined as dippers), and pre-awakening morning surge (MS) of BP defined as the difference between the mean BP during the 2 hours after waking and the mean BP during the 2 hours before waking. As reported, 20,21 in this population, we divided nondippers and dippers according to group-specific tertiles of MS of systolic BP; dippers with MS in the upper tertile (>23 mm Hg) were defined as having high MS. Recordings were automatically edited (that is, excluded) if systolic BP was >260 or <70 mm Hg or if diastolic BP was >150 or <40 mm Hg and pulse pressure was >150 or <20 mm Hg. 23 Subjects had recordings of good technical quality (at least 70% of valid readings). In the present population, from exploratory analysis, systolic BP was a better predictor of cardiovascular events than diastolic BP. Moreover, it has been reported that systolic BP is superior to diastolic BP in predicting prognosis in older subjects. 24 Thus, in the present study, we used systolic BP to define various parameters American Journal of Hypertension 29(8) August 2016 Echocardiography Left atrial (LA) and left ventricular (LV) measurements and calculation of LV mass were made according to standardized methods. 25 LA diameter (cm) was indexed by body surface area (m 2 ) and LA enlargement was defined as LA diameter/body surface area 2.4 cm/m LV mass was indexed by height 2.7 and LV hypertrophy was defined as LV mass/height 2.7 >50 g/m 2.7 in men and >47 g/m 2.7 in women. 26 LV hypertrophy was defined as eccentric or concentric when the relative wall thickness (posterior wall thickness + septal wall thickness/lv internal diameter) was < or 45%, respectively. LV ejection fraction was calculated using the Teichholz formula or the Simpson rule 25 and defined as low when it was <50%. Echocardiography was performed within 30 days from ambulatory BP monitoring. Follow-up Subjects were followed up in our hospital outpatient clinic or by their family doctors. The occurrence of cardiovascular events was recorded during follow-up visits or by telephone interview of the patient followed by a clinical visit. Data were collected by the authors of this study. Those reviewing the endpoints were blinded to other patients data. In the present report, we focused on HFREF or HFPEF requiring hospitalization (only first hospitalization was included). Diagnosis of HFREF or HFPEF was based on symptoms and signs of HF and an ejection fraction < or 50%, respectively, at the time of HF event. Statistical analysis Standard descriptive statistics were used. Groups were compared by using analysis of variance followed by a multiple comparison test, and chi-square test or Fisher s exact test, where appropriate. Event rates are expressed as the number of events per 1,000 patient-years based on the ratio of the observed number of events to the total number of patientyears of exposure up to the terminating event or censor. Cox regression analysis was used to evaluate univariate and multivariable association of factors with HFREF or HFPEF. We fitted separate models for each type of HF in turn, treating the other type of HF as censored data at the time of HF event. First, we evaluated univariate association between outcomes and age, gender, body mass index, smoking, previous events, diabetes, estimated glomerular filtration rate, low-density lipoprotein cholesterol, LV hypertrophy (normal LV mass as reference group and concentric and eccentric LV hypertrophy as comparing groups), asymptomatic LV systolic dysfunction at baseline, LA enlargement, clinic and daytime, nighttime and 24-hour BP, circadian BP changes (dippers with normal MS as reference group and dippers with high MS and nondippers as comparing groups), antihypertensive, antiplatelet and statin therapy at baseline, atrial fibrillation (AF) occurred during follow-up, and nonfatal myocardial infarction (NFMI) occurred during follow-up. Then, multiple regression analysis was performed reporting in the final models variables that were significantly (P < 0.05) associated with outcome in univariate analysis. The forced entry model

3 Ambulatory BP and Heart Failure in the Elderly was used. Statistical significance was defined as P <0.05. Analyses were made with the SPSS 21 software package (SPSS Inc., Chicago, IL). Graphs were made with GraphPad Prism 6 (GraphPad software Inc., San Diego, CA). RESULTS Characteristics and BP values of patients with and without future HFREF or HFPEF are summarized in Table 1. At baseline, subjects with future HFREF or HFPEF had higher daytime, nighttime, and 24-hour systolic and diastolic BP than those without HF. Prevalence of concentric LV hypertrophy, nondipping, and AF (during follow-up) were higher in patients with future HFPEF. Prevalence of eccentric LVH, asymptomatic LV systolic dysfunction, dipping with high MS, and NFMI (during follow-up) were higher in patients with future HFREF. The other variables were not significantly different among the groups. Table 1. Characteristics of patients with and without future HF Baseline antihypertensive therapy is reported in Table 2. Antihypertensive drug class, and single, double, and triple therapy were not significantly different among the groups. Number of medications was higher in patients with future HFPEF than in those with no HF. At baseline, use of aspirin and statin were not significantly different among patients without HF and those with future HFREF and HFPEF (23% vs. 14% vs. 28%, respectively, P = 0.18 and 12% vs. 9% vs. 7%, respectively, P = During the follow-up (9.1 ± 4.9 years, range years), 123 patients developed HF, of whom 56 had HFREF and 67 had HFPEF. The event rate was 11.4, 5.2, and 6.2 per 1,000 patient-years, for HF, HFREF, and HFPEF, respectively. Moreover, permanent and paroxysmal AF occurred in 73 and 22 patients, respectively, and NFMI occurred in 54 patients (in addition 35 patients had fatal myocardial infarction and 31 had coronary revascularization). Univariate analysis showed that diabetes (hazard ratio (HR): 2.64, 95% confidence interval (CI): ), Parameter No HF (n = 1,068) HFREF (n = 56) HFPEF (n = 67) P Age, years 68.7 ± ± ± Men, n (%) 446 (42) 29 (52) 31 (46) 0.27 Body mass index, kg/m ± ± ± Smokers, n (%) 119 (11) 11 (20) 11 (16) 0.08 Previous events, n (%) 98 (9) 2 (4) 4 (6) 0.25 Diabetes, n (%) 130 (12) 9 (16) 9 (13) 0.67 egfr, ml/min/1.73 m ± ± ± LDL cholesterol, mg/dl 128 ± ± ± Concentric LVH, n (%) 176 (16) 11 (20) 27 (40)*, <0.01 Eccentric LVH, n (%) 128 (12) 18 (32)* 9 (13) <0.01 LA enlargement, n (%) 229 (21) 16 (29) 18 (27) 0.28 ALVSD, n (%) 37 (3.5) 16 (29)* 0 (0) <0.01 Clinic SBP, mm Hg 150 ± ± ± Clinic DBP, mm Hg 87 ± ± ± Daytime SBP, mm Hg ± ± 16* ± 14* <0.01 Daytime DBP, mm Hg 78 ± 9 82 ± 11* 81 ± 9* <0.01 Nighttime SBP, mm Hg 122 ± ± 16* 134 ± 15* <0.01 Nighttime DBP, mm Hg 67 ± 9 71 ± 12* 72 ± 9* < hour SBP, mm Hg 131 ± ± 15* 140 ± 14* < hour DBP, mm Hg 75 ± 8 79 ± 11* 78 ± 9* <0.01 Nondippers SBP, n (%) 566 (53) 28 (50) 49 (73)*, <0.01 Dippers (high MS SBP), n (%) 160 (32) 17 (61)* 8 (44) <0.01 Atrial fibrillation, n (%) a 77 (7) 6 (11) 12 (18)* <0.01 Nonfatal AMI, n (%) a 48 (5) 6 (11) 0 (0) 0.02 Abbreviations: ALVSD, asymptomatic left ventricular systolic dysfunction (ejection fraction <50%); AMI, acute myocardial infarction; DBP, diastolic blood pressure; egfr, estimated glomerular filtration rate; HF, heart failure; HFPEF, heart failure with preserved ejection fraction; HFREF, heart failure with reduced ejection fraction; LA, left atrial; LDL, low-density lipoprotein; LVH, left ventricular hypertrophy; MS, morning surge (high MS means SBP > 23 mm Hg); SBP, systolic blood pressure. a Variables occurred during follow-up (see text). Previous events include coronary events, stroke, and peripheral artery disease. *P < 0.05 vs. no HF. P < 0.05 vs. HFREF. American Journal of Hypertension 29(8) August

4 Pierdomenico et al. Table 2. Baseline antihypertensive therapy of patients with and without future HF Parameter No HF (n = 1,068) HFREF (n = 56) HFPEF (n = 67) P Diuretic, n (%) 612 (57) 29 (52) 43 (64) 0.37 Beta-blocker, n (%) 327 (31) 16 (29) 22 (33) 0.88 Calcium antagonist, n (%) 354 (33) 21 (37) 26 (39) 0.52 ACE-I/ARB, n (%) 795 (74) 43 (77) 58 (86) 0.08 Alpha-blocker, n (%) 143 (13) 9 (16) 12 (18) 0.51 Single therapy, n (%) 268 (25) 13 (23) 10 (15) 0.16 Double therapy, n (%) 507 (48) 25 (45) 30 (45) 0.84 Triple therapy, n (%) 293 (27) 18 (32) 27 (40) 0.06 Number of medications 2.02 ± ± ± 0.70* 0.04 Abbreviations: ACE-I/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; HF, heart failure; HFPEF, heart failure with preserved ejection fraction; HFREF, heart failure with reduced ejection fraction. *P < 0.05 vs. no HF. Figure 1. Risk of HFREF and HFPEF by CSBP (per 10 mm Hg increase), 24-h SBP (per 10 mm Hg increase), DHMS, and ND. Data are adjusted for variables that were significantly associated with the specific outcome in univariate analysis (see text). As to HFREF, HR (CI) values are 1.14 ( ) for CSBP, 1.36 ( ) for 24-h SBP, 2.27 ( ) for DHMS, and 1.11 ( ) for ND. Concerning HFPEF, values are 1.06 ( ) for CSBP, 1.35 ( ) for 24-h SBP, 1.46 ( ) for DHMS, and 2.78 ( ) for ND. Abbreviations: 24-h SBP, 24-hours systolic blood pressure; CI, confidence interval; CSBP, clinic systolic blood pressure; DHMS, dipping with high morning surge; HFPEF, heart failure with preserved ejection fraction; HFREF, heart failure with reduced ejection fraction; HR, hazard ratio; ND, nondipping. eccentric LV hypertrophy (HR: 4.11, 95% CI: ) but not concentric LV hypertrophy (HR: 1.78, 95% CI: ), asymptomatic LV systolic dysfunction (HR: 10.71, 95% CI: ), and clinic (HR: 1.17, 95% CI: , per 10 mm Hg increase), 24-hour (HR: 1.49, 95% CI: , per 10 mm Hg increase), daytime (HR: 1.48, 95% CI: , per 10 mm Hg increase), and nighttime systolic BP (HR: 1.32, 95% CI: , per 10 mm Hg increase), high MS in dippers (HR: 3.87, 95% CI: ) but not nondipping (HR: 1.54, 95% CI: ), and NFMI (HR: 4.57, 95% CI: ) occurred during follow-up were significantly associated with risk of future HFREF. Conversely, age (HR: 2.27, 95% CI: , per 10 years increase), diabetes (HR: 3.19, 95% CI: ), concentric LV hypertrophy (HR: 4.20, 95% CI: ) but not eccentric LV hypertrophy (HR: 1.74, 95% CI: ), and clinic (HR: 1.17, 95% CI: , per 10 mm Hg increase), 24-hour (HR: 1.65, 95% CI: , per 10 mm Hg increase), daytime (HR: 1.57, 95% CI: , per 10 mm Hg increase), and nighttime systolic BP (HR: 1.62, 95% CI: , per 10 mm Hg increase), nondipping (HR: 3.04, 95% CI: ) but not high MS in dippers (HR: 2.11, 95% CI: ), and AF (HR: 2.27, 95% CI: ) occurred during follow-up were significantly associated with risk of future HFPEF. The other variables were not significantly associated with outcome. We performed 4 multivariable analyses (2 models for each type of HF). In the first model, we included variables significantly associated with outcome in univariate analysis (diabetes, LV hypertrophy, asymptomatic LV systolic dysfunction, and NFMI occurred during follow-up for HFREF, and age, diabetes, LV hypertrophy, and AF occurred during followup for HFPEF) and clinic systolic BP, and in the second model, we included 24-hour systolic BP in place of clinic BP, and circadian BP subgroups. Results of multivariable analyses are reported in Figure 1. After adjustment for other covariates, clinic BP was not independently associated with risk of HFREF or HFPEF, whereas 24-hour BP was independently associated with risk of both HFREF and HFPEF, and high MS was independently associated with risk of HFREF and nondipping was independently associated with risk of HFPEF. Moreover, eccentric LV hypertrophy, asymptomatic LV systolic dysfunction, and NFMI resulted independently associated with HFREF, and 1004 American Journal of Hypertension 29(8) August 2016

5 Ambulatory BP and Heart Failure in the Elderly age, diabetes, and concentric LV hypertrophy resulted independently associated with HFPEF. We performed a subgroup analysis excluding 53 patients with asymptomatic LV systolic dysfunction at baseline. The population included 1,138 subjects of whom 40 had HFREF and 67 had HFPEF. Univariate analysis showed that clinic BP, eccentric LV hypertrophy, 24-hour systolic BP, and high MS in dippers were significantly associated with future risk of HFREF; multivariable analysis showed that clinic BP was not independently associated with outcome, whereas 24-hour BP (HR: 1.72, 95% CI: , per 10 mm Hg increase) and high MS in dippers (HR: 2.55, 95% CI: ) were independently associated with risk of HFREF. Analyses showed essentially the same results concerning risk of HFPEF. If we forced gender and body mass index in the models results remained substantially the same. DISCUSSION This is the first study, to our knowledge, showing that: (i) 24-hour BP is independently associated with both future HFREF and HFPEF, (ii) high MS is independently associated with HFREF, and (iii) nondipping is independently associated with HFPEF, in elderly treated hypertensive patients. The association of eccentric LV hypertrophy, asymptomatic LV systolic dysfunction, and myocardial infarction and that of age, diabetes, and concentric LV hypertrophy with HFREF and HFPEF, respectively, has been previously discussed and do not need further comments. 3 8,27 To the best of our knowledge, there is a single study in the literature specifically evaluating the influence of ambulatory BP and circadian BP changes on the occurrence of HF. 22 Ingelsson et al. studied 951 elderly men aged 70 years, 66% with clinic hypertension (50% of whom were treated), who underwent ambulatory BP monitoring to evaluate daytime, nighttime, and 24-hour BP and nondipping (defined as night-day systolic BP ratio 1). 22 During the follow-up (mean 9.1 years), 70 HFs (both HFREF and HFPEF) occurred with an incidence rate of 8.6 per 1,000 person-years. 22 After adjustment for various covariates, nighttime diastolic BP and nondipping were independently associated with increased risk of HF both in the global population (HR: 1.26, 95% CI: , for 1 SD increase in nighttime diastolic BP, and HR: 2.29, 95% CI: , for night-day systolic BP ratio 1) and in the subsample (819 subjects) without myocardial infarction at baseline and during the follow-up (HR: 1.48, 95% CI: , for 1 SD increase in nighttime diastolic BP, and HR 2.82, 95% CI , for night-day systolic BP ratio 1). 22 Our study differs from the aforesaid one 22 for some aspects: (i) we studied elderly treated hypertensive patients aged 60 years, (ii) nondipping was defined as nighttime BP reduction <10%, and (iii) we divided patients with HF into those with HFREF and those with HFPEF. Thus, these 2 studies are not entirely comparable, though both of them emphasize the association of ambulatory BP and circadian BP changes with HF in elderly subjects. It is tempting to speculate what are the mechanisms by which 24-hour BP and circadian BP changes could influence the occurrence of HFREF and HFPEF. Concerning HFREF, it has been reported that increased 24-hour BP load may lead to asymptomatic depressed myocardial function in hypertension, 28 and probably to overt systolic dysfunction during time. This aspect could be worsened by sudden increase of BP load in the morning in patients with high MS. In this context, in hypertension, it has been reported that MS of BP is independently associated with brain natriuretic peptide level, 29 which is a stronger predictor of HFREF than of HFPEF. 7 As regards HFPEF, it has been reported that it is characterized by LV diastolic dysfunction, including decreased relaxation or increased stiffness, LV hypertrophy (mainly concentric), and fibrosis. 8,30 33 It has been shown that LV diastolic dysfunction is more closely related to 24-hour than to clinic BP and that diastolic function is more impaired in nondippers than in dippers. 34,35 Moreover, it has been reported that 24-hour BP and nondipping are more closely associated with LV hypertrophy. 36 Finally, it has been suggested that nondipping could be associated with myocardial fibrosis. 37 Thus, 24-hour BP and nondipping could influence diastolic function by a continuous hemodynamic load which could affect the extent and rate of relaxation and by favoring LV hypertrophy and fibrosis which increase LV stiffness. At present, there are few data about the circadian variation of onset of HF. Manfredini et al. 38 observed that the majority of acute pulmonary edema events occurred at night, whereas Allegra et al. 39 reported higher incidence of emergency department visits for congestive HF between 8 am and 3 pm. Our results support both previous findings, 38,39 probably depending on the type of HF. This study has some limitations. First, we studied only Caucasian subjects and our results cannot be applied to other ethnic groups. Second, our data were obtained in elderly treated hypertensive patients and cannot be extrapolated to younger and untreated subjects. Third, the lack of association of HFREF or HFPEF with treatment strategy does not mean lack of efficacy of therapy because all subjects were treated with antihypertensive therapy, most of whom received multiple therapy, and patients were not randomized to antihypertensive or antiplatelet or statin therapy. Fourth, we adjusted analyses for available confounders but other potential confounders such as functional status, physical activity, health behavior, and adherence to therapy (though both baseline and follow-up therapy were reported) were not available. Fifth, beyond data on previous coronary events (42 (3.9%) in patients who did not develop HF, 2 (3.6%) in those who developed HFREF, and 2 (3.0%) in those who developed HFPEF), no other data were available on baseline coronary artery disease because patients had no specific symptoms or signs and were not studied for this aspect at baseline. Sixth, we did not specifically design a study to evaluate factors associated with future HFREF and HFPEF, but this study is part of a prospective assessment of the prognostic value of ambulatory BP parameters and other risk markers in our initially treated hypertensive patients. Seventh, data about LV diastolic function were not available in all the subjects and were not included in the analyses. Finally, some of our Cox models (multivariate analyses) had 7 8 events per variable and it has been suggested that there should be 10 events American Journal of Hypertension 29(8) August

6 Pierdomenico et al. per variable in this type of analysis to obtain reliable results; however, it has been shown that reliable results are also obtained with 5 9 events per variable. 40 In conclusion, in elderly treated hypertensive patients, 24-hour systolic BP is independently associated with both future HFREF and HFPEF, whereas high MS is independently associated with HFREF and nondipping is independently associated with HFPEF. These findings suggest to achieve strict 24-hour BP control, beyond clinic BP, possibly using therapeutic strategies that reduce MS of BP in patients with high MS and improves nighttime BP reduction in nondippers, to better prevent HFREF and HFPEF in elderly treated hypertensive patients. DISCLOSURE The authors declared no conflict of interest. REFERENCES 1. Roger VL. Epidemiology of heart failure. Circ Res 2013; 113: Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. 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