Ambulatory Pulse Pressure Predicts the Development of Left Ventricular Diastolic Dysfunction in Over 20 Years of Follow-up

Abstract

BACKGROUND

Ambulatory blood pressure (ABP) has been shown to have an association with left ventricular diastolic dysfunction (LVDD) in cross-sectional assessments. We evaluated the association between ABP measurement (ABPM) and the development of LVDD during over 20 years of follow up in 414 middle-aged subjects from OPERA cohort.

METHODS

ABPM, clinical, and anthropometric measurements were performed in baseline. Echocardiographic measurements were performed at baseline and during follow-up and E/E’ ≥15 was considered indicating significant LVDD.

RESULTS

Several baseline clinical characteristics (age, female gender, short stature, body mass index, prevalence of diabetes, in-office systolic BP (SBP), in-office pulse pressure (PP), N-terminal pro-atrial natriuretic peptide, and the use of antihypertensive therapy) were associated with the development of LVDD. Baseline 24-hour mean, daytime mean or nighttime mean SBP or diastolic BP were not associated with the development of LVDD, neither were different circadian BP profiles. Instead 24-hour mean, daytime mean and nighttime mean PP showed significant association with the development of LVDD (P from <0.001 to 0.001) even after adjustment with significant baseline clinical characteristics (P from 0.001 to 0.016).

CONCLUSION

These findings suggest that ambulatory PP has an independent predictive value in the development of LVDD during over 20 years of follow-up.

ambulatory blood pressure, blood pressure, hypertension, left ventricular diastolic dysfunction, pulse pressure

Hypertension is a common health problem concerning wide number of populations and a leading global risk factor for the burden of cardiovascular (CV) disease.¹ Hypertensive patients often have abnormalities in systolic function and left ventricular (LV) diastolic filling.² LV diastolic dysfunction (LVDD), also referred to as heart failure (HF) with a preserved LV ejection fraction (HFpEF), is associated with significant morbidity and mortality³ and it is predicted to become the most common type of HF.⁴ When compared to patients with HF with a reduced ejection fraction (HFrEF), patients with HFpEF are older, more often female, more often have hypertension, renal dysfunction, atrial fibrillation, and pulmonary disease.^5,6

Diagnosis and follow-up for high blood pressure (BP) relies mostly on office (clinical) BP values although several artifacts can affect office BP measurements (BPM). Ambulatory BPM (ABPM) is a method in which repeated BP readings take place while the patient undergoes normal daily activities. A 24-hour BP profile is detected for diagnosing hypertension. ABPM has proven to be a more accurate method than in-office BPM in CV risk determination⁷ and in controlling BP in treated hypertensive patients.^8,9 ABPM also correlates more closely to several measures of hypertensive end-organ damage¹⁰ and is superior in predicting CV morbidity and mortality when compared to in-office BPM.^7,11

There is evidence that average 24-hour ABPM is related to LV dysfunction^12,13 and also that ambulatory pulse pressure (APP)^14,15 and in-office PP¹⁶ show positive correlation with LVDD. The nondipping status seems to correlate with LVDD in hypertensives^17,18 and also in normotensives,¹⁹ but there is at least 1 study where the prevalence of LVDD did not differ among dipper and nondipper hypertensives.²⁰

In this prospective cohort study, our goal was to determine the association between ABPM and the development of LVDD in middle-aged subjects with over 20 years of follow-up time. The study population consists of 414 middle-aged (mean age 49.4) (during enrolment) subjects of the Oulu Project Elucidating Risk of Atherosclerosis (OPERA). To our knowledge, this is the first study to evaluate the predictive value of ABPM and the development of LVDD with such a long follow-up period.

METHODS

Subjects

The study population is from the OPERA project, which is a population-based, epidemiological study designed to address the risk factors and disease end-points of atherosclerotic CV diseases. The study population at baseline consists of a hypertensive cohort (300 men and 300 women) and a control cohort (300 men and 300 women) living in the city of Oulu and were 40–59 years old at the time of recruitment.²¹ The hypertensive cohort consist of randomly selected, age-matched (15 men and 15 women per year) patients from the Social Insurance Institute register for reimbursement of antihypertensive medication. They were entitled to a special refund (higher reimbursement class) of antihypertensive medication. For each hypertensive subject, an age- and sex-matched control was randomly selected from the national health register excluding subjects with the right to reimbursement for hypertension medication. They were recruited by an invitation letter during December 1990 to March 1993. Both the hypertensive and the control men were recruited during December 1990 to May 1992 and the women approximately a year later. A total of 520 men (86.7%) and 525 women (87.5%) participated: 259 control men (86.3%), 261 hypertensive men (87%), 267 control women (89%), and 258 hypertensive women (86%), the overall participation rate being 87.1%. The participating study subjects attended the research laboratory of the Department of Internal Medicine, University of Oulu.

After 20 years, the subjects were recruited for revisit. During the recruitment, 232 participants were deceased. Of the 813 survivors, 600 were available for re-examinations. The subjects who had ABPM at baseline and reliable echocardiographic measurements at follow-up were included in the present study. Excluding criteria included mitral regurgitation and/or LV ejection fraction <50%. Only 5 subjects were excluded because of LV ejection fraction ≤50%. A total of 414 subjects were included in this study. The mortality data were collected up to 2014 from the National Death Registry and by then 241 subjects were deceased; 7.8% of the subjects died of a CV disease event and 14,8% died of other causes. This study was approved by the Ethical Committee of the University of Oulu, and all the subjects volunteered to participate.

Clinical measurements

Extensive examinations were performed during enrolment 1990–1993 and at the end of the follow-up period in 2013–2014. At baseline weight, height, waist, and hip were measured and BPM were carried out at the visit. Body mass index was calculated as weight (kg) divided by height squared (m²), and body surface area was determined by the Dubois equation.²² Systolic BP (SBP) and diastolic BP (DBP) are the averages of the second and third measurements. PP was calculated reducing DBP from SBP.

At baseline, ABPM was recorded with a noninvasive fully automatic SpaceLabs90207 oscillometric unit (SpaceLabs, Redmond, WA). It was set to take a measurement every 15 minutes between 04:00 am to 12:00 pm and every 20 minutes between 12:00 PM to 04:00 AM. The British Hypertension Society and the US Association for the Advancement of Medical Instrumentation have previously settled the accuracy and reproducibility of the BP readings acquired with this device. The proper positioning of the cuff was ensured by means of the similarity (difference <5 mm Hg) between 4 SpaceLabs BPMs and 4 auscultatory readings using a Y-connector, and the patients were instructed to relax their arm during the measurement. Values of SBP less than 70 or more than 250 mm Hg, DBP less than 40 or more than 150 mm Hg, and heart rate less than 40 or more than 150 beats/min were automatically excluded from the analysis. Less than 3% of the BP readings were rejected as artifacts on the basis of these criteria.²³ During the follow-up period, the ABPM was recorded with Oscar 2 oscillometric ambulatory blood pressure monitor (SunTech Medical).²⁴ AccuWin Pro V3 software was used in the analysis of ABPM data.

All the laboratory analyses were acquired after an overnight fast. Venous blood was drawn into EDTA sample tubes. Plasma was separated by centrifugation at 2,000–2,600 rounds per minute for 10 minutes and held at 4 °C until further analyses, which were done, if possible, within 2 days after the blood samples had been drawn. Otherwise, plasma was stored at −20 °C to −70 °C for coming analyses. The routine clinical laboratory tests were carried out in the Central Laboratory of the Oulu University Hospital. Concentrations of N-terminal pro-atrial natriuretic peptide were measured as described previously²⁵

Echocardiographic measurements

The baseline echocardiographic measurements were performed by the same experienced cardiologist blinded to the patients’ clinical data with a Hewlett-Packard ultrasound color system Sonos 500 (Hewlett-Packard Company, MA). M-Mode, 2-dimensional, and Doppler examinations were performed.²⁶ The left ventricular mass (LVM) was calculated using the formula of Devereux et al.²⁷ and the LVM index ( by dividing the difference between LVM values by body surface area. At follow-up visit, the study subjects underwent an echocardiographic examination in a core laboratory using a GE Healthcare Vivid E 9 version 110. x.x ultrasound system (General Electric Company, Fairfield, CT). Standard and modern parameters including tissue Doppler-based measurements were determined according to the American Society of Echocardiography recommendations.²⁸E wave in the pulsed Doppler registration depicts the early mitral inflow in diastole, and E’ in the tissue Doppler registration measures the mitral annular longitudinal motion during early diastole.²⁹ The ratio of E to E’ (E/E’) is considered to be one of the best echocardiographic measurements of diastolic dysfunction.³⁰

Statistical methods

The 1-way analysis of variance was used to assess whether continuous variables differed statistically significantly between the subjects divided in 3 subgroups based on E/ E’. A χ²-test was carried out to assess the frequency differences. The power of different factors to predict E/E’ was assessed in the general linear multivariate model after adjusting with other relevant univariate predictors. An E/E’ value ≧15 was used as a criterion for LVDD. To determine correlations between the change in 24-hour mean ABPM and the change in echocardiographically measured parameters Pearson’s coefficient of correlation was used. All calculations were made with the SPSS (version 21; SPSS) statistical package. A P value <0.05 was considered to be statistically significant.

RESULTS

The study population was divided into 3 subgroups according to follow-up E/E’. The first subgroup (E/E’ ≤ 8) consisted of 78, the second subgroup (8 < E/E’ < 15) of 303, and the third subgroup (E/E’ ≥ 15) of 33 subjects. E/E’ ≥15 indicates significant LVDD.

Association of baseline characteristics and E/E’ subgroups at follow-up

Several baseline clinical variables differed significantly among the E/E’ subgroups after over 20 years of follow-up (Table 1). Baseline factors of higher age (P = 0.005), female gender (P = 0.003), the proportion of diabetics (P = 0.001), shorter height (P < 0.001), larger body mass index (P = 0.028), higher in-office SBP (P = 0.001), higher in-office PP (P < 0.001), higher level of NT-proANP (P < 0.001), fasting plasma glucose (P = 0.001), and the use of antihypertensive therapy (P = 0.017) were associated with the development of LVDD. In contrast to those mentioned previously, waist circumference, waist/hip ratio, DBP, heart rate, estimated glomerular filtration rate, low-density-lipoprotein-cholesterol, high-sensitivity C-reactive protein, LV internal diameter in diastole, fractional shortening, LVM index, left atrial diameter, or E/A integral were not significantly different between the E/E’ subgroups in the univariate analysis. These general characteristics of the study population are shown in the Table 1.

Table 1.

Association of baseline characteristics according to echocardiographically measured diastolic dysfunction after over 20 years of follow-up

Baseline variables	E/E’ ≤ 8 (N = 78)	8 > E/E’ < 15 (N = 303)	E/E’ ≥ 15 (N = 33)	P value
Age, years	48.7 ± 5.8	49.4 ± 5.3	52.4 ± 6.4	0.005
Gender, female	37 (47.4%)	160 (52.8%)	27 (81.8%)	0.003
Diabetics	6 (7.7%)	14 (4.6%)	7 (21.2%)	0.001
Height, cm	169.8 ± 9.5	168.2 ± 8.7	162.3 ± 6.6	<0.001
Body mass index, kg/m2	26.2 ± 3.9	27.5 ± 4.7	28.3 ± 4.5	0.033
Waist, cm	87.5 ± 13.1	89.5 ± 12.5	88.3 ± 11.1	0.398
Waist/hip ratio	0.85 ± 0.10	0.86 ± 0.08	0.84 ± 0.07	0.458
Systolic BP, mm Hg	139.8 ± 18.3	143.8 ± 18.8	155.2 ± 21.3	0.001
Diastolic BP, mm Hg	85.4 ± 10.3	88.0 ± 11.4	89.5 ± 10.5	0.114
Pulse pressure, mm Hg	54.4 ± 12.3	55.8 ± 12.6	65.7 ± 17.2	<0.001
Heart rate, beats/min	71.2 ± 8.6	69.9 ± 9.0	69.9 ± 10.1	0.515
eGFR, ml/min/1.73 m2	83.5 ± 13.9	82.1 ± 15.7	77.4 ± 15.8	0.159
NT-proANP, pmol/l	225.7 ± 89.5	256.7 ± 135.1	339.9 ± 231.1	<0.001
Fasting plasma glucose, mmol/l	4.4 ± 0.6	4.5 ± 1.0	5.2 ± 2.8	0.001
LDL-cholesterol, mmol/l	3.4 ± 0.9	3.5 ± 0.9	3.5 ± 0.9	0.892
hs-CRP, mg/l	2.1 ± 2.9	3.5 ± 8.7	3.5 ± 9.2	0.223
LVIDD, mm	51.4 ± 3.9	51.3 ± 4.7	49.7 ± 5.2	0.171
FS, %	35.0 ± 5.8	34.9 ± 5.6	36.1 ± 5.3	0.546
LVMI, g/m2	124.8 ± 31.5	124.8 ± 33.7	125.2 ± 46.7	0.998
LAD, mm	37.9 ± 5.0	38.7 ± 5.0	37.4 ± 4.1	0.246
E integral/A integral	1.78 ± 0.52	1.74 ± 0.47	1.73 ± 0.65	0.804
Antihypertensive therapy	29 (37.2%)	143 (47.2%)	22 (66.7%)	0.017
Betablockers	13 (16.7%)	81 (26.7%)	14 (42.4%)	0.016
ACE-inhibitors	11 (14.1%)	59 (19.5%)	6 (18.2%)	0.550
Diuretics	5 (6.4%)	42 (13.9%)	9 (27.3%)	0.013
Ca-channel blockers	6 (7.7%)	24 (7.9%)	5 (15.2%)	0.353
Other antihypertensive Medication	1 (1.3%)	7 (2.3%)	3 (9.1%)	0.050

The values are mean ± SD or percentage of patients. E wave in the pulsed Doppler registration describes the ejection phase of mitral flow in early diastole and E’ in the tissue Doppler registration measures the mitral annulus movement in early diastole, the ratio of E to E’ is one of the best echocardiographic measurements of diastolic dysfunction; E integral = the area of the E wave, A wave describes the atrial booster in mitral flow in late diastole measured by pulsed Doppler, A integral = the area of the A wave, the ratio of E integral and A integral describes diastolic function. Significant P values are bolded. Abbreviations: ACE, angiotensin-converting enzyme, BP, blood pressure, eGFR, estimated glomerular filtration rate; FS, fractional shortening; hs-CRP, high-sensitivity C-reactive protein; LAD, left atrial diameter; LDL-cholesterol, low-density-lipoprotein-cholesterol; LVIDD, left ventricular internal diameter in diastole; LVMI, left ventricular mass index, NT-proANP, N-terminal pro-atrial natriuretic peptide.

Baseline ABPMs according to E/E’ at follow-up

None of the continuous systolic or diastolic ABPM (24-hour mean, daytime mean, or nighttime mean) predicted the development of LVDD. Twenty-four-hour mean, daytime mean, and nighttime mean PP (P < 0.001) showed significant association with E/E’ in the univariate analysis. The data are shown in Table 2 before and after adjustments. The PP measurements (PPM) were tested on at a time in the multivariate general linear model using the statistically significant baseline clinical variables (age, sex, diabetic status, height, in-office SBP, in-office PP, NT-proANP, and the use of antihypertensive therapy) as confounding factors. Twenty-four-hour mean PP was also adjusted with 24-hour mean DBP, daytime mean PP with daytime mean DBP and nighttime mean PP with nighttime mean DBP. All of the PPM (24-hour mean (P = 0.001), daytime mean (P = 0.016), nighttime mean (P = 0.015)) predicted the development of LVDD after over 20 years of follow-up even after relevant adjustments. We also tested the results including the 5 excluded subjects with LV ejection fraction ≤50%, but this had no effect in the predictive value of PPM in the development of LVDD.

Table 2.

Association of baseline ambulatory blood pressure measurements according to echocardiographically measured diastolic dysfunction after over 20 years of follow-up

Ambulatory blood pressure baseline variables	8 ≤E/E’ (N = 78)	8 < E/E’ < 15 (N = 303)	E/E’ ≥ 15 (N = 33)	P valuea	P valueb
24-hour mean SBP (mm Hg)	125.8 ± 12.3	127.7 ± 11.6	131.5 ± 12.8	0.065
24-hour mean DBP (mm Hg)	79.7 ± 7.7	81.2 ± 7.9	78.2 ± 7.7	0.056
Daytime mean SBP (mm Hg)	130.5 ± 12.5	132.2 ± 12.1	136.6 ± 13.2	0.054
Daytime mean DBP (mm Hg)	83.7 ± 7.4	85.3 ± 8.6	82.3 ± 8.2	0.077
Nighttime mean SBP (mm Hg)	112.5 ± 12.7	114.3 ± 12.7	118.5 ± 14.6	0.070
Nighttime mean DBP (mm Hg)	68.5 ± 8.5	70.2 ± 9.1	67.3 ± 8.2	0.102
24-hour mean PP (mm Hg)	46.0 ± 7.5	46.5 ± 7.0	53.4 ± 9.3	<0.001	0.001c
Daytime mean PP (mm Hg)	46.8 ± 8.1	47.0 ± 8.3	54.3 ± 9.4	<0.001	0.016d
Nighttime mean PP (mm Hg)	44.0 ± 7.0	44.2 ± 7.8	51.2 ± 10.4	<0.001	0.015e

The values are mean ± SD. E/E’ was divided to 3 subgroups (subgroup 1: E/E’ ≤ 8, subgroup 2: 8 < E/E’ < 15, subgroup 3: E/E’ ≥ 15 indicating significant diastolic dysfunction). Abbreviations: ANCOVA, analysis of covariance; DBP, diastolic blood pressure; PP, pulse pressure; SBP, systolic blood pressure.

^aUnadjusted.

^bANCOVA analysis with adjustments for age, sex, height, body mass index, diabetic status, in-office systolic blood pressure, in-office pulse pressure, N-terminal pro-atrial natriuretic peptide, and the use of antihypertensive therapy.

^cAlso adjusted with 24-hour mean DBP.

^dAlso adjusted with daytime mean DBP.

^eAlso adjusted with nighttime mean DBP.

Association of circadian BP profiles and E/E’ at follow-up

We also considered different circadian BP profiles and their relation to E/E’. Depending on the size of nighttime BP fall (NF), patients were categorized into 4 groups: dippers (NF by 10–20%), nondippers (NF by 0–10%), extreme dippers (NF by >20%), and risers (no NF). These 4 groups were considered separately in SBP, DBP, and PP parameters. None of the circadian BP profiles predicted the development of LVDD in our study (data not shown).

The change in ABPMs according to E/E’ at follow-up

ABPM was also recorded at follow-up from a total of 381 subjects. Seventy-three of the subjects were in subgroup 1, 280 in subgroup 2, and 28 in subgroup 3. The whole study group (N = 381) was observed to experience an increase in all of the SBP and PP measurements and a decrease in all of the DBP measurements (Table 3). The purpose of this analysis was to determine the change in ABPM during the 20 years of follow-up. A substantial increase in PPM was observed in every subgroup during the 20-year follow-up period (P from<0.001 to 0.001). The increase in 24-hour mean, daytime mean, and nighttime mean PP was discovered to be the highest among those who developed LVDD (E/E’ ≥ 15) compared to those whose E/E’ <15 (P from <0.001 to 0.001).

Table 3.

Ambulatory blood pressure measurements according to echocardiographically measured diastolic dysfunction after over 20 years of follow-up

Ambulatory blood pressure variables	E/E’ ≤ 8 (N = 73)	8 > E/E’ < 15 (N = 280)	E/E’ ≥ 15 (N = 28)	P value
24-hour mean SBP
Baseline	125.6 ± 12.7	127.5 ± 11.6	129.2 ± 11.9	0.331
Follow-up	130.6 ± 12.7	132.1 ± 13.6	143.0 ± 14.6	<0.001
Change	5.0 ± 15.7	4.6 ± 16.6	13.9 ± 17.9	0.018
24-hour mean DBP
Baseline	79.7 ± 7.8	81.3 ± 8.1	77.0 ± 7.6	0.012
Follow-up	73.0 ± 8.2	72.5 ± 7.7	69.7 ± 7.0	0.146
Change	−6.7 ± 9.4	−8.8 ± 9.7	−7.3 ± 10.3	0.206
Daytime mean SBP
Baseline	130.3 ± 12.9	132.1 ± 12.1	134.1 ± 11.9	0.338
Follow-up	132.5 ± 12.5	133.6 ± 13.8	144.4 ± 14.2	<0.001
Change	2.1 ± 15.9	1.5 ± 16.9	10.2 ± 17.8	0.033
Daytime mean DBP
Baseline	83.6 ± 7.5	85.4 ± 8.8	80.9 ± 7.7	0.012
Follow-up	74.5 ± 8.3	73.8 ± 7.9	70.8 ± 7.0	0.107
Change	−9.2 ± 8.3	−11.7 ± 10.2	−10.1 ± 10.4	0.141
Nighttime mean SBP
Baseline	112.4 ± 12.9	114.1 ± 12.1	116.8 ± 14.8	0.283
Follow-up	120.0 ± 16.3	124.3 ± 17.0	136.5 ± 22.3	<0.001
Change	7.6 ± 17.8	10.2 ± 19.0	19.8 ± 27.5	0.019
Nighttime mean DBP
Baseline	68.5 ± 8.6	70.3 ± 9.3	66.7 ± 8.7	0.066
Follow-up	64.6 ± 9.1	65.7 ± 10.0	63.1 ± 8.7	0.320
Change	−3.8 ± 10.0	−4.5 ± 12.0	−3.5 ± 12.4	0.847
24-hour mean PP
Baseline	46.0 ± 7.7	46.2 ± 6.7	52.2 ± 9.2	<0.001
Follow-up	57.6 ± 8.8	59.6 ± 10.5	73.4 ± 13.5	<0.001
Change	11.6 ± 9.2	13.4 ± 10.0	21.2 ± 11.6	<0.001
Daytime mean PP
Baseline	46.7 ± 8.3	46.7 ± 8.2	53.3 ± 9.2	<0.001
Follow-up	58.0 ± 8.9	59.8 ± 10.6	73.6 ± 12.9	<0.001
Change	11.3 ± 9.5	13.1 ± 11.2	20.3 ± 11.0	0.001
Nighttime mean PP
Baseline	44.0 ± 7.1	43.8 ± 7.5	50.1 ± 10.7	<0.001
Follow-up	55.4 ± 10.7	58.6 ± 11.6	73.4 ± 20.3	<0.001
Change	11.4 ± 11.0	14.8 ± 12.0	23.3 ± 20.2	<0.001

The values are mean ± SD. E/E’ was divided to three subgroups (subgroup 1: E/E’ ≤ 8, subgroup 2: 8 < E/E’ < 15, subgroup 3: E/E’ ≥ 15 indicating significant diastolic dysfunction). Abbreviations: DBP, diastolic blood pressure; PP, pulse pressure; SBP, systolic blood pressure.

The results are presented in Table 3.

ABPM changes and the correlation with echocardiographically measured parameter changes

We also evaluated the correlation coefficients between the change in 24-hour mean ABPM and the change in echocardiographically measured parameters (Table 4). The change in 24-hour mean DBP correlated with the change in E/A integral (r = −0.220, P ≤ 0.001), and the change in 24-hour mean PP correlated with the change in left ventricular diameter in diastole (r = 0.113, P = 0.034).

Table 4.

Partial correlation coefficients (r) with P values for 24-hour mean ambulatory blood pressure measurement changes with echocardiographically measured parameter changes

	LAD		E/A integral		IVS		PVW		LVIDD
	r	p	r	p	r	p	r	p	r	p
24-hour mean SBP	0.19	0.712	−0.096	0.070	0.101	0.060	0.088	0.099	0.055	0.301
24-hour mean DBP	−0.62	0.236	−0.220	<0.001*	0.082	0.127	0.095	0.076	−0.25	0.645
24-hour mean PP	0.090	0.086	0.050	0.348	0.088	0.101	0.055	0.303	0.113	0.034*

All parameters are changes measured within 20 years. E/A integral = E integral = the area of the E wave, A wave describes the atrial booster in mitral flow in late diastole measured by pulsed Doppler, A integral = the area of the A wave, the ratio of E integral and A integral describes diastolic function. Abbreviations: DBP, diastolic blood pressure; IVS, intraventricular septum; LVIDD, left ventricular internal diameter in diastole; PP, pulse pressure; PVW, posterior ventricular wall; SBP, systolic blood pressure.

*Statistically significant P value.

DISCUSSION

Since the outcome of several trials addressing the management of HFpEF to date has been poor,³¹ it is important to further understand the mechanisms and risk factors underlying this problem. The present follow-up study showed that APP measurement (APPM) had an association with the development of LVDD over 20 years of follow-up among middle-aged subjects. To our knowledge, this is the first study to suggest the predictive value of APPM in the development of LVDD with a follow-up period of over 20 years, even though the group with severe diastolic dysfunction is quite small. These findings suggest that APPM has an independent predictive value in the development of LVDD.

Perkiömäki et al., 2016, suggested that a high in-office PP is an independent predictor of the development of LVDD during 20 years of follow-up.³² This study, as ours was a part of the OPERA cohort consisting of the same study population. The prognostic value of in-office PP and APP can be different, mainly because the statistic strength of the BPM (more numerous during ABPM) could provide a more significant linkage with future CV events.⁴ Therefore, we wanted to address APP and its predictive value in the development of LVDD. In some prior cross-sectional studies, the association between APP and LVDD has been discovered. Rizzo et al., 2004, suggested that APP >60 mm Hg in a sample of 108 untreated middle-aged subjects was related to impaired diastolic function.¹⁴ Whereas Trika et al., 2004, found out among 198 subjects that in elderly hypertensive patients without LV hypertrophy, a large PP at night may serve as an independent predictor of abnormal LV diastolic filling.¹⁵

In our study, higher age, female gender, higher prevalence of diabetes, shorter stature, heavier weight, higher in-office SBP and PP, and higher NT-proANP were associated with LVDD during a long-term follow-up. In previous studies, the risk factors have been shown to be similar. Owan et al., 2006, showed that the patients with HFpEF were older, more often female and had higher body mass index compared with those with HFrEF.⁶ Also a substantial proportion of these patients have been shown to have diabetes³³ and they tend to have higher levels of ANP (atrial natriuretic peptide).³⁴ Short stature is considered an independent risk factor of LVDD,³⁵ and Perkiömäki et al., 2016, discovered the association independently of gender.³² So it is highly likely that shorter stature is an actual risk factor among both genders.

LVDD is often the consequence of hypertension.^6,36 Elevated BP increases LVM,^36,37 which favor the development of LVDD. In our study, baseline in-office SBP and PP were associated with LVDD at follow-up indicating their predictive value in risk determination. The increased baseline NT-proANP concentrations provide evidence for compromised pump function of the heart even at this early stage. Although systolic ABPM at baseline did not predict the development of LVDD, a minor trend was discovered. Most importantly, APPM did in fact predict the development of LVDD at follow-up even after adjustment with relevant risk indicators. Increased PP may contribute to cardiac structural changes possibly through the pulsatile load on the heart,³⁸ and large arterial stiffness may increase the workload on the heart, leading to LV hypertrophy and cardiac dysfunction.³⁹ Arterial stiffness increase during aging and it is considered a risk marker for CV morbidity and mortality.⁴⁰ In our study, those who developed LVDD were older and had a higher in-office PP at baseline, which is in alignment with the findings in previous studies. Unfortunately, any measurements indicating arterial stiffness in our study were not available.

During aging, SBP increases as a result of hardening of the arteries, which was also seen in our study population. A decrease in DBP was seen in our study population. Therefore, a significant increase in APP was observed in every subgroup, although the increase was observed to be the highest among the subjects who developed LVDD (E/E’ ≥ 15). The subjects who developed LVDD seemed to have more severe hypertension compared to those whose E/E’ <15.

As we did not have reliable echocardiographic parameters to evaluate LVDD in the early 1990’s, therefore, we were unable to evaluate the actual development of LVDD. In the early 1990s, E/A-ratio was used as an indicator of LVDD. E/A-ratio is inversely associated with LVDD and it did not present any difference at baseline between the 3 E/E’ subgroups in our study. It can be speculated that our study group did not present significant LVDD at baseline, even though E/A-ratio is not considered a reliable parameter indicating diastolic dysfunction.

In conclusion, APPM is an independent risk factor in the development of LVDD during later life-course. Further studies are needed to verify this finding.

DISCLOSURE

The authors declared no conflict of interest.

ACKNOWLEDGMENTS

We acknowledge the excellent technical assistance of Mrs Saija Kortetjärvi and Mrs Heidi Häikiö. This study was supported by the Finnish Foundation for Cardiovascular Research.