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Heart rate variability and target organ damage in hypertensive patients

  • Paolo Melillo1Email author,
  • Raffaele Izzo2,
  • Nicola De Luca2 and
  • Leandro Pecchia3
BMC Cardiovascular Disorders201212:105

DOI: 10.1186/1471-2261-12-105

Received: 23 August 2012

Accepted: 8 November 2012

Published: 15 November 2012

Abstract

Background

We evaluated the association between linear standard Heart Rate Variability (HRV) measures and vascular, renal and cardiac target organ damage (TOD).

Methods

A retrospective analysis was performed including 200 patients registered in the Regione Campania network (aged 62.4 ± 12, male 64%). HRV analysis was performed by 24-h holter ECG. Renal damage was assessed by estimated glomerular filtration rate (eGFR), vascular damage by carotid intima-media thickness (IMT), and cardiac damage by left ventricular mass index.

Results

Significantly lower values of the ratio of low to high frequency power (LF/HF) were found in the patients with moderate or severe eGFR (p-value < 0.001). Similarly, depressed values of indexes of the overall autonomic modulation on heart were found in patients with plaque compared to those with a normal IMT (p-value <0.05). These associations remained significant after adjustment for other factors known to contribute to the development of target organ damage, such as age. Moreover, depressed LF/HF was found also in patients with left ventricular hypertrophy but this association was not significant after adjustment for other factors.

Conclusions

Depressed HRV appeared to be associated with vascular and renal TOD, suggesting the involvement of autonomic imbalance in the TOD. However, as the mechanisms by which abnormal autonomic balance may lead to TOD, and, particularly, to renal organ damage are not clearly known, further prospective studies with longitudinal design are needed to determine the association between HRV and the development of TOD.

Keywords

Heart Rate Variability Target organ damage Hypertension

Background

Cardiovascular (CV) diseases are one of the most leading causes of morbidity and mortality in high developed countries [1]. A number of prospective population or cohort studies, such as the Atherosclerosis Risk in Communities Study [2], the Rotterdam Study [3], the Cardiovascular Health Study [4], and the Carotid Atherosclerosis Progression Study [5], have shown that asymptomatic organ damage is significantly related to incident CV events. If CV involvement is early detected by physicians, it is possible to influence the progression or regression of the disease by the therapy [6]. Although there is still a little information on the specific causes of these pathologies, a recent review by Thayer suggested that autonomic imbalance may be a final common pathway to increased morbidity and mortality from a host of conditions and pathologies, including CV diseases [7]. Analysis of heart rate variability (HRV) on the basis of routine 24-hour Holter recordings has been shown to provide a sensitive measurement of cardiac control by the autonomous nervous system (ANS) [8, 9]. HRV is a non-invasive measure reflecting the variation over time of the period between consecutive heartbeats (RR intervals) [8]. In fact, heart rate (HR), which continuously fluctuates over time, is under the influence of control mechanisms aimed at maintaining a dynamic stability called homoeostasis [10]. In this equilibrium, the sympathetic stimulation causes acceleration in HR by increasing the firing rate of pacemaker cells in the heart’s sino-atrial node, while the parasympathetic system causes deceleration in HR by decreasing of the firing rate of pacemaker cells [8]. Clinical studies have shown reduced HRV in patients with congestive heart failure [1116], diabetes [17], and white coat hypertension [18]. Moreover, decreased HRV measures have been shown to be a risk factor for mortality in chronic haemodialysis patients [19] and for progression to end-stage renal disease [20, 21]. Furthermore, several studies have shown that incidence of CV events can be reduced by therapeutic correction of any modifiable risk factors, such as hypertension, abnormal cholesterol, diabetes, smoking habit or physical inactivity. As noted and shown in the review by Thayer [7], there is at least some data to suggest that each of these risk factors is associated with decreased HRV. Regarding hypertensive patients a sympatho-vagal imbalance as evaluated by HRV with increased sympathetic activity and reduced vagal tone has been reported [22] and a recent paper by Garcia-Garcia [23] investigate the correlation between heart rate and the parameters that assess vascular, renal and cardiac target organ damage (TOD). However, only two HRV measures were selected in the study by Garcia-Garcia [23]. The aim of the current study was to evaluate the association between linear standard HRV measures with the vascular, renal and cardiac TOD in hypertensive patients registered in the Campania Salute network. The Campania Salute network is an open registry collecting information from a network of general practitioners and community hospitals networked with the centre, and providing a centralised database including demographics and clinical information of the patients.

Methods

Population study

For the present study, among the initial cohort of 12,000 patients registered in the database of the Campania Salute Network, we selected all the hypertensive subjects who underwent at least one visit in the Outpatient Hypertension Clinic of the University of Naples “Federico II” from 2000 to 2010 and were evaluated by a cardiac and carotid ultrasonography and by a 24h Holter ECG. The ECG Holter was performed after a one-month antihypertensive therapy wash-out. Details on this cohort have been previously reported [24, 25]. Exclusion criteria for the present analysis were: diagnosis of secondary resistant and/or uncontrolled hypertension, prevalent CV disease, clinical history of cancer, liver cirrhosis and/or failure, narcotics abuse, lifestyle changes in the last 12 months. Moreover, patients with atrial fibrillation and frequent ectopic beats as assessed by Holter were excluded. Prevalent CV disease was defined as history of previous myocardial infarction or angina or procedures of coronary revascularization, stroke or transitory ischemic attack, congestive heart failure, chronic kidney disease more than grade 3 (eGFR by MDRD < 30mL/min/1.73m2) at the time of the first examination in the outpatient clinic. Prevalent CV disease was excluded by an ad-hoc committee in the Hypertension Centre, based on patients’ history, contact with the referring general practitioner and clinical records documenting the occurrence of disease. In the sub-cohort of 10254 patients with arterial hypertension, 4257 patients were excluded for diagnosis of secondary resistant and/or uncontrolled hypertension, prevalent CV disease, clinical history of cancer, liver cirrhosis and/or failure, narcotics abuse, lifestyle changes in the last 12 months; 1814 for chronic kidney disease more than grade 3 (eGFR by MDRD < 30mL/min/1.73m2); 2556 for missing data (i.e. ultrasonography, holter ECG); 942 for atrial fibrillation and 485 for frequent ectopic beats.

Ethical issues

All the data of the patients (i.e. medical history, physical examination, routine laboratory tests and other diagnostic procedures) were stored in the computerised database of Campania Salute Network. The database generation of the Campania Salute Network was approved by the Federico II University Hospital Ethic Committee. All the participants signed informed consent to use data for scientific purposes.

Protocol

At the first visit all patients were given a detailed questionnaire inquiring about specifics lifestyle behaviours and smoking habit. In the current study they were categorised as non-smokers, ex-smokers or smokers. During the visits, blood pressure (BP), lipid and glucose profiles were measured for each patient by standard methods. Diagnosis and stratification of essential hypertension was performed according to the criteria established by the Guidelines for the Management of Arterial Hypertension [26]: systolic and diastolic BP were measured by a standard aneroid sphygmomanometer after 5 min rest in the supine position, according to the current guidelines [26]. Three BP measurements were obtained at 2-min intervals. The averages of these measurements were used for the analysis. Glomerular filtration rate (eGFR) was estimated by the Modification of Diet in Renal Disease (MDRD) formula [27]. Diabetes was defined as a fasting blood glucose ≥126 mg/dL or active glucose-lowering therapy [28].

Echocardiography

Two-dimensional-guided M-mode echocardiograms were performed using a dedicated ultrasound machine (SONOS 5500, Philips) with an ultrasound transducer of 2.5 MHz. The examinations were recorded on a digital recorder and analysed by three independent, trained and experienced physicians. The parameters relative to the left ventricle (LV) were measured in the parasternal long-axis view and obtained, according to the criteria of the American Society of Echocardiography [29], as an average of at least three measurements, as also performed in previous studies [30, 31]. LV mass was determined by using the formula developed by Devereux [32] as recommend by American Society of Echocardiography (ASE) [33] and divided by the body surface area to calculate LV mass index (LVMi, g/m2). Intraoperator and interassay variability were 5% and 6%, respectively [34].

Carotid ultrasound

B-mode ultrasonography of carotid arteries was performed with patients in the supine position with the neck extended in mild rotation. The scanning protocol was performed with an ultrasound device (SONOS 5500, Philips) equipped with a 7.5-MHz high-resolution transducer with an axial resolution of 0.1 nm. Examinations were recorded on S-VHS videotapes. All measurement were analysed by three different trained experienced physicians. An average of two readings was considered for subsequent calculations. The accuracy of determinations was evaluated as previously described by Lembo et al. [35]: the variability of measurements to evaluate intrasonographer and intersonographer reproducibility was 0.01 and 0.03 mm, respectively. The maximum arterial intima media thickness (IMT) in up to 12 arterial walls, including the right and the left, near and far distal common carotid (1 cm), bifurcation, and proximal internal carotid artery was estimated offline with an image processing workstation with the software COMPACS (Rev. 10.5.8, Medimatic, Genoa, Italy).

Assessment of TOD

Cardiac Involvement was evaluated as Left Ventricular Hypertrophy (LVH) which was diagnosed if LVMi exceeded 110 g/m2 in female and 125 g/m2 in male [36]. Vascular involvement was assessed as carotid artery atherosclerosis shown by increased IMT in B-mode ultrasonography. IMT values between 1.0 and 1.3 mm were defined as "thickening" and those higher than 1.3 mm as “plaque”. Chronic kidney disease was assessed by eGFR and involvement was quantified as follows:
  1. 1.

    group 1: increased or normal eGFR (eGFR ≥ 90 mL/min/1.73 m2)

     
  2. 2.

    group 2: mild eGFR (60 < eGFR < 90 mL/min/1.73 m2)

     
  3. 3.

    group 3: moderate eGFR (eGFR ≤ 60 mL/min/1.73 m2) [37]

     

Processing 24-hour holter recordings

On 2 consecutive days, patients underwent a 24-hour ECG Holter recording. The recorders were applied between 9 and 11 AM on a working day, and the patients were asked to follow as closely as possible their usual daily activities during each monitoring session. They were asked to stay in bed from 11 PM to 7 AM, and all reported to have slept normally during the nights they were monitored. The series of normal to normal (NN) beat intervals were obtained from ECG recordings using OSAS, an open-source software for QRS detection and beat classification [38]. Standard long-term HRV analysis on nominal 24-h recordings according to International Guidelines was performed [8]. The HRV analysis was performed using PhysioNet's HRV Toolkit [39]. We chose this toolkit as it is an open source and a rigorously validated package. All the computed basic time- and frequency-domain HRV measures were widely used in the literature [8]. A number of standard statistical time-domain HRV measures are calculated: Average of all NN intervals (AVNN), standard deviation of all NN intervals (SDNN), standard deviation of the averages of NN intervals in all 5-min segments of a 24-h recording (SDANN), mean of the standard deviations of NN intervals in all 5-min segments of a 24-h recording (SDNN IDX), square root of the mean of the sum of the squares of differences between adjacent NN intervals (RMSSD), percentage of differences between adjacent NN intervals that are longer than 50 ms (pNN50). The frequency-domain HRV measures rely on the estimation of power spectral density (PSD) computed, in this work, by Lomb-Scamble periodogram [40]. After PSD estimation, six standard frequency-domain HRV measures were calculated: total spectral power of all NN intervals up to 0.4 Hz (TOTPWR), between 0 and 0.003 Hz (ULF), between 0.003 and 0.04 Hz (VLF), between 0.04 and 0.15 Hz (LF), and between 0.15 and 0.4 Hz (HF), ratio of low to high frequency power (LF/HF).

Statistical analysis

Data were analysed by the use of PASW Statistics 18 software (Release 18.0; SPSS IBM, Chicago, IL, USA). Univariate differences were analysed using Kruskal-Wallis and Wilcoxon test for HRV measures, ANOVA and t-test for the other continuous variables (for instance age, IMT, etc.) and χ2 test for the categorical variables (for instance sex, smoking). For each HRV measure, which differs significantly among the three groups, an adjusted model was proposed by performing a binary or multinomial logistic regression, as appropriate. For each factor or covariate, the coefficient of the estimated regression model (β), the corresponding statistical significance (p), the odds ratio (OR) and the confidence interval for OR at 95% are presented. A p-value less than 5% was considered statistically significant.

Results

200 patients were analysed (127 male and 73 female). Demographic, clinical and laboratory characteristics of the study sample are shown in Table 1. Table 2 shows the characteristic of the study sample of patients categorised by eGFR. The moderate eGFR group is significantly older than the others and has a significantly higher proportion of patients taking diuretics. Systolic BP and Pulse Pressure values were significantly higher in mild decreased eGFR group (compared to normal eGFR group), where IMT values were significantly lower in normal eGFR group (compared to moderate decreased eGFR group). Table 3 shows the descriptive statistics of HRV measures in the groups stratified by eGFR. The three groups differed significantly in LF/HF. Table 4 shows the characteristic of the study sample of patients categorised by IMT. The Plaque group is significantly older than the others. LVMi values were significantly lower in the normal group compared to the Plaque group and the proportion of patients with LVH was significantly lower. A significantly higher proportion of patients with family history of hypertension was assessed in the Thickening group. A significant difference in the proportion of patients taking beta-blockers was observed. Table 5 shows the descriptive statistics of HRV measures in the three groups according to IMT. The three groups differed significantly in SDNN, SDANN, SDNN IDX TOTPWR, LF, and LF/HF. Table 6 shows the characteristic of the study sample of patients categorised by LVH. The LVH group is significantly older than the group without LVH. IMT values were significantly higher in the LVH group and the proportion of patients with vascular abnormalities was significantly higher. A significantly higher proportion of patients taking diuretics was assessed in LVH group. The values of Systolic BP and Pulse Pressure were significantly higher in the LVH group. Table 7 shows the comparison of HRV measures in the patients with and without LVH. The two groups differed significantly in LF/HF. Most differences persisted even in the adjusted models, which are reported in Table 8. As concerns renal TOD, the multinomial logistic regression selected age, family history of hypertension and systolic BP. Higher values of LF/HF are associated with an increased probability that a subject belongs to normal or mild eGFR groups rather than to moderate group (OR 2.718 and 2.637, respectively). Older age is associated with a decreased probability of being in normal or mild decreased eGFR groups (OR 0.897 and 0.943, respectively). The absence of family history of hypertension is associated with an increased probability of belonging to normal eGFR group (OR 2.951). Elevated systolic BP seems to be associated with a slightly increased probability of belonging to mild decreased eGFR group (OR 1.024). As regards vascular TOD, the adjusted models confirmed the differences in the values of SDNN and SDANN. In fact, higher values of SDNN and SDANN are associated with an increased probability that a subject had no vascular alterations rather than plaque. Moreover, this model confirms that older age is associated with vascular alterations. As regards cardiac TOD, the binomial logistic regression did not confirm the difference in LF/HF and showed that other variables are associated with LVH such as age, systolic BP, cholesterol, and diuretics.
Table 1

Characteristics of the study sample of patients

Characteristic

Value

Age (years)

62.5 ± 12.1

Sex (male/female, %)

63.5/36.5

Family history of hypertension (yes/no, %)

56.5/43.5

Family history of stroke (yes/no, %)

19.5/80.5

Smokers (yes/ex/no, %)

17.5/21/61.5

Diabetes (yes/no, %)

10/90

Diastolic BP (mmHg)

75.6 ± 12.0

Systolic BP (mmHg)

133.2 ± 22.6

Pulse pressure (mmHg)

57.6 ± 17.8

Fasting blood glucose (mmHg)

102.7 ± 24.1

Total Cholesterol (mg/dl)

185.8 ± 40.6

BMI (kg/m2)

27.7 ± 4.6

Beta-blockers (yes/no, %)

33.5/66.5

Alphabeta-blockers (yes/no, %)

10.5/89.5

Alpha-blockers (yes/no, %)

8/92

Diuretics (yes/no, %)

43.5/56.5

ACE inhibitor (yes/no, %)

37.5/62.5

Dihydropyridine (yes/no, %)

26/74

eGFR (mL/min/1.73 m2)

77.0 ± 18.9

Kidney Involvement (group 1/ 2 /3 %)

24/59.5/16.5

IMT (mm)

2.24 ± 1.56

Vascular abnormalities (no/ thickening/plaque, %)

13/11/78

LVMi g/m2

130.5 ± 31.0

Left Ventricular hypertrophy (no/yes, %)

40/60

Data are expressed as mean and standard deviation for continuous variables (i.e. age) and as percentage of patients per each group for categorical variables (i.e. gender).

Table 2

Characteristics of the study sample of patients stratified according to the eGFR

 

Normal eGFR (group 1)

Mild decreased eGFR (group 2)

Moderate decreased eGFR (group 3)

P Values

    

ANOVA or χ2

group 1 vs group 2

group 1 vs group 3

group 2 vs group 3

Age (years)

56 ± 11.5

63,0 ± 11.7

70.0 ± 9.4

<0.001

0.001

<0.001

0.05

Gender (male/female)

31/17

76/43

20/13

0.928

   

Family history of hypertension (yes/no)

25/23

69/50

19/14

0.778

   

Family history of stroke (yes/no)

11/37

22/97

6/27

0.790

   

Smokers (yes/ex/no)

13/8/27

8/27/7

27/75/21

0.379

   

Diabetes (yes/no)

5/43

11/108

4/29

0.883

   

Diastolic BP (mmHg)

73.2 ± 14.0

77.3 ± 11.5

73.0 ± 9.8

0.048

0.129

1

0.185

Systolic BP (mmHg)

124.5 ± 23.3

137.5 ± 20.0

130.2 ± 27.3

0.002

0.002

0.754

0.286

Pulse pressure (mmHg)

51.3 ± 14.1

60.1 ± 16.9

57.3 ± 23.3

0.014

0.010

0.396

1

Fasting blood glucose (mmHg)

99.7 ± 32.2

102.8 ± 20.0

106.7 ± 23.9

0.432

1

0.589

1

Total Cholesterol (mg/dl)

178.9 ± 36.4

187.7 ± 40.8

189.0 ± 45.8

0.395

0.610

0.817

1

BMI (kg/m2)

27.4 ± 5.2

28.1 ± 4.6

26.7 ± 3.5

0.261

1

1

0.379

Beta-blockers (yes/no)

15/33

41/78

11/22

0.924

   

Alphabeta-blockers (yes/no)

5/43

14/105

2/31

0.639

   

Alpha-blockers (yes/no)

3/45

8/111

5/28

0.252

   

Diuretics (yes/no)

17/31

49/70

21/12

0.03

   

ACE inhibitor (yes/no)

16/32

48/71

11/22

0.604

   

Dihydropyridine (yes/no)

12/36

30/89

10/23

0.826

   

eGFR (mL/min/1.73 m2)

101.9 ± 12.0

74.3 ± 8.8

50.6 ± 8.0

<0.001

<0.001

<0.001

<0.001

IMT (mm)

1.8 ± 0.76

2.23 ± 1.21

2.91 ± 2.85

0.007

0.282

0.005

0.81

Vascular abnormalities (no/ thickening/plaque)

33/6/9

91/13/15

28/3/2

0.502

   

LVMi g/m2

124.3 ± 26. 2

133.0 ± 32.3

130.4 ± 32.1

0.258

0.301

1

1

Left Ventricular hypertrophy (no/yes)

24/24

44/75

12/21

0.268

   

Data are expressed as mean and standard deviation for continuous variables (i.e. age) and as number of patients per each group for categorical variables (i.e. gender).

The p-values refer to ANOVA and post-hoc comparisons with Bonferroni corrections for continuous variables, to χ2 for categorical variables.

Table 3

Comparisons of HRV measurement in patients stratified by eGFR

 

Normal eGFR (group 1)

Mild decreased eGFR (group 2)

Moderate decreased eGFR (group 3)

P-values

 

Mean

St. Dev.

Quartiles

Mean

St. Dev.

Quartiles

Mean

St. Dev.

Quartiles

 
   

1st

2nd

3rd

  

1st

2nd

3rd

  

1st

2nd

3rd

 

AVNN

859.7

109.4

784.1

848.9

916.8

867.8

136.4

774.9

853.5

954.4

884.4

119.0

793.6

875.4

963.4

0.525

SDNN

125.7

30.2

101.9

119.5

146.1

119.4

38.8

92.2

111.1

140.1

116.6

36.1

94.7

113.6

141.1

0.280

SDANN

113.4

32.5

90.1

108.6

137.0

106.6

38.7

78.0

99.4

129.1

105.2

36.1

81.2

104.0

132.4

0.308

SDNN IDX

51.9

11.8

43.2

51.4

58.9

51.2

16.5

40.7

47.4

61.1

45.4

13.7

36.2

44.3

58.3

0.168

RMSSD

32.6

12.5

24.4

30.1

38.1

35.7

18.9

22.6

30.7

42.3

35.6

14.3

24.4

33.5

42.1

0.602

pNN50

8.8

6.6

3.8

7.7

11.9

11.2

10.4

2.8

7.9

17.8

11.5

11.0

4.1

9.7

12.9

0.714

TOTPWR

18224

8902

11002

16124

23743

17498

12477

8919

13736

21744

17099

10273

9648

14338

24713

0.354

ULF

14919

8093

8797

12379

18709

14098

10139

7083

10675

18458

14311

8999

7867

11539

20217

0.368

VLF

1815

843

1184

1592

2384

1872

1417

961

1471

2416

1368

835

780

1254

1959

0.071

LF

861

522

481

711

1108

823

795

368

601

922

660

460

344

543

925

0.123

HF

629

502

293

471

743

705

715

205

496

815

760

602

251

527

1230

0.626

LF/HF

1.74

0.92

1.17

1.44

2.11

1.48

0.90

0.91

1.25

1.75

1.00

0.47

0.71

0.85

1.25

<0.001

St. Dev. standard deviation.

The p-values refer to Kruskal-Wallis test.

Table 4

Characteristics of the study sample of patients stratified according to IMT

 

Normal

Thickening

Plaque

P Values

    

ANOVA or χ2

Normal vs Thickening

Normal vs Plaque

Thickening vs Plaque

Age (years)

47.3 ± 13.3

57.0 ± 9.6

65.9 ± 9.8

<0.001

0.004

<0.001

0.001

Sex (male/female)

16/10

10/12

101/51

0.157

   

Family history of hypertension (yes/no)

16/10

18/4

79/73

0.026

   

Family history of stroke (yes/no)

4/22

6/16

29/123

0.564

   

Smokers (yes/ex/no)

4/3/19

6/2/14

25/37/90

0.242

   

Diabetes (yes/no)

2/24

1/21

17/135

0.572

   

Diastolic BP (mmHg)

76.5 ± 10.8

73.4 ± 18.6

75.8 ± 11.1

0.643

1

1

1

Systolic BP (mmHg)

131.5 ± 19.2

124.1 ± 33.2

134.8 ± 21.1

0.106

0.768

1

0.113

Pulse pressure (mmHg)

55.0 ± 14.9

50.6 ± 19.9

59.0 ± 17.8

0.086

1

0.856

0.117

Fasting blood glucose (mmHg)

98.0 ± 20.7

95.7 ± 22.0

104.5 ± 24.7

0.154

1

0.601

0.321

Total Cholesterol (mg/dl)

182.0 ± 38.0

192.0 ± 39.1

185.6 ± 41.4

0.687

1

1

1

BMI (kg/m2)

28.8 ± 5.4

27.3 ± 3.7

27.6 ± 4.6

0.395

0.747

0.596

1

Beta-blockers (yes/no)

15/11

6/16

46/106

0.019

   

Alphabeta-blockers (yes/no)

1/25

3/19

17/135

0.465

   

Alpha-blockers (yes/no)

1/25

2/20

13/139

0.702

   

Diuretics (yes/no)

9/17

8/14

70/82

0.429

   

ACE inhibitor (yes/no)

10/16

8/14

57/95

0.989

   

Dihydropyridine (yes/no)

7/19

4/18

41/111

0.675

   

eGFR (mL/min/1.73 m2)

84.1 ± 17.5

81.2 ± 17.8

75.2 ± 19.1

0.045

1

0.077

0.479

Renal involvement

9/15/2

6/13/3

33/91/28

0.502

   

IMT (mm)

0.89 ± 0.11

1.19 ± 0.08

2.62 ± 1.61

<0.001

1

<0.001

<0.001

LVMi g/m2

109.6 ± 19.0

126.7 ± 33.2

134.6 ± 30.9

<0.001

0.149

<0.001

0.744

Left Ventricular hypertrophy (no/yes)

20/6

11/11

49/103

<0.001

   

Data are expressed as mean and standard deviation for continuous variables (i.e. age) and as number of patients per each group for categorical variable (i.e. gender).

The p-value refers to ANOVA and post-hoc comparison with Bonferroni corrections for continuous variables and to χ2 for categorical variables.

Table 5

Comparisons of HRV measurement in the group of patients stratified by IMT

 

Normal IMT

Thickening

Plaque

P-value

 

Mean

St. Dev.

Quartiles

Mean

St. Dev.

Quartiles

Mean

St. Dev.

Quartiles

 
   

1st

2nd

3rd

  

1st

2nd

3rd

  

1st

2nd

3rd

 

AVNN

830.0

123.5

749.2

821.6

916.2

842.3

141.8

746.7

820.5

957.3

879.0

124.7

797.1

864.8

952.0

0.116

SDNN

140.1

48.8

105.3

132.3

171.3

121.7

34.3

94.2

115.3

147.2

116.9

33.3

93.3

111.6

136.9

0.049

SDANN

128.4

49.7

88.2

124.8

157.9

110.8

34.7

81.0

102.2

138.3

104.1

33.5

80.3

98.5

124.1

0.046

SDNN IDX

58.9

19.0

44.4

55.2

73.1

50.7

13.8

43.0

48.9

56.5

49.0

14.2

38.8

47.4

59.5

0.042

RMSSD

36.9

13.5

26.8

32.2

42.6

30.7

11.7

22.1

29.7

34.0

35.2

17.9

22.7

30.5

41.7

0.216

pNN50

12.5

9.1

5.9

8.2

16.5

9.2

9.1

2.8

6.1

11.3

10.6

10.0

3.1

8.3

15.5

0.195

TOTPWR

24209

16727

12113

19664

31647

17583

10891

9798

14497

22534

16480

9863

9300

13860

21255

0.049

ULF

19550

13805

9436

16075

25947

14453

9137

7958

11822

18562

13420

8327

7216

10942

17851

0.092

VLF

2590

1944

1113

2117

3172

1746

1101

1091

1514

1862

1640

1027

960

1325

2251

0.052

LF

1255

1040

471

1006

1863

819

627

493

688

934

726

595

357

568

934

0.009

HF

813

685

305

542

1299

566

517

178

499

617

694

661

229

477

914

0.376

LF/HF

1.78

0.98

1.05

1.53

2.25

2.02

1.25

1.14

1.55

2.71

1.33

0.75

0.82

1.13

1.68

0.002

St. Dev. standard deviation.

The p-values refer to Kruskal-Wallis test.

Table 6

Characteristics of the study sample of patients with and without LVH

 

LVH

P values

 

Patient Group with LVH

Patient group without LVH

 

Age (years)

56.8 ± 12.1

66.3 ± 10.6

0.001

Sex (male/female)

49/31

78/42

0.589

Family history of hypertension (yes/no)

48/32

65/55

0.415

Family history of stroke (yes/no)

15/65

24/96

0.827

Smokers (yes/ex/no)

17/18/45

18/24/78

0.404

Diabetes (yes/no)

2/78

18/102

0.004

Diastolic BP (mmHg)

73.8 ± 12.1

76.8 ± 11.8

0.094

Systolic BP (mmHg)

126.1 ± 25.3

137.9 ± 19.4

0.001

Pulse pressure (mmHg)

52.3 ± 18.0

61.1 ± 16.8

0.001

Fasting blood glucose (mmHg)

99.8 ± 23.6

104.7 ± 24.3

0.161

Total Cholesterol (mg/dl)

191.0 ± 38.6

182.3 ± 41.7

0.132

BMI (kg/m2)

27.2 ± 4.3

28.0 ± 4.8

0.235

Beta-blockers (yes/no)

31/49

36/84

0.199

Alphabeta-blockers (yes/no)

7/73

14/106

0.510

Alpha-blockers (yes/no)

5/75

11/109

0.456

Diuretics (yes/no)

25/55

62/58

0.004

ACE inhibitor (yes/no)

25/55

50/70

0.136

Dihydropyridine (yes/no)

17/63

35/85

0.211

eGFR (mL/min/1.73 m2)

79.9 ± 17.9

75.1 ± 19.5

0.071

Kidney Involvement (1/2 /3)

24/44/12

24/75/21

0.268

IMT (mm)

1.82 ± 0.93

2.52 ± 1.82

<0.001

Vascular abnormalities (no/ thickening/plaque)

20/11/49

6/11/103

<0.001

LVMi g/m2

105.0 ± 13.8

147.5 ± 27.3

<0.001

Data are expressed as mean and standard deviation for continuous variables (i.e. age) and as number of patients per each group for categorical variable (i.e. gender).

The p-values refer to t-test for continuous variables and χ2 for categorical variables.

Table 7

Comparisons of HRV measurement in the group of patients with and without LVH

 

Patients with LVH

Patients without LVH

P values

 

Mean

St. Dev.

Quartiles

Mean

St. Dev.

Quartiles

 
   

1st

2nd

3rd

  

1st

2nd

3rd

 

AVNN

846.9

121.8

772.6

829.5

916.8

883.1

129.2

789.9

863.7

963.8

0.071

SDNN

123.5

37.0

101.5

118.3

142.3

118.4

36.0

91.8

112.7

142.4

0.247

SDANN

111.2

37.6

88.0

106.7

128.7

105.9

36.3

79.4

99.0

129.5

0.304

SDNN IDX

51.9

15.0

42.7

49.5

60.8

49.5

15.2

38.5

47.8

58.4

0.127

RMSSD

32.8

14.5

22.9

29.2

36.4

36.4

18.1

23.1

32.4

42.3

0.123

pNN50

9.9

10.3

3.2

7.1

11.9

11.2

9.4

3.4

9.2

17.0

0.163

TOTPWR

18472

12108

10873

15952

21928

17029

10776

8958

14057

22697

0.288

ULF

15018

10082

8177

12029

18491

13872

9043

7093

11412

18656

0.347

VLF

1892

1255

1074

1668

2393

1697

1206

923

1336

2086

0.105

LF

896

782

429

704

1092

744

619

369

556

912

0.072

HF

666

694

210

483

757

716

622

261

502

965

0.316

LF/HF

1.74

0.99

1.03

1.60

2.08

1.28

0.74

0.81

1.03

1.51

<0.001

St. Dev. standard deviation.

The p-values refer to Wilcoxon test.

Table 8

Multinomial or binary logistic regression models

Compared groups

HRV measure, factor or covariate

β

p

OR

95% CI of OR

Normal eGFR versus Moderate decreased eGFR

Intercept

5.971

0.021

    
 

LF/HF

1.000

0.038

2.718

1.057

to

6.984

 

Systolic BP

−0.003

0.779

0.997

0.974

to

1.020

 

Age

−0.109

<0.001

0.897

0.847

to

0.948

 

Absence of family history of hypertension

1.082

0.047

2.951

1.014

to

8.588

Mild decreased eGFR versus Moderate decreased eGFR

Intercept

0.527

0.819

    
 

LF/HF

0.969

0.034

2.637

1.075

to

6.465

 

Systolic BP

0.024

0.027

1.024

1.003

to

1.046

 

Age

−0.058

0.020

0.943

0.898

to

0.991

 

Absence of family history of hypertension

0.710

0.122

2.034

0.827

to

5.001

Normal IMT group versus Plaque group1

Intercept

5.552

0.002

    
 

SDNN

0.018

0.024

1.018

1.002

to

1.033

 

Age

−0.169

<0.001

0.844

0.796

to

0.896

 

Absence of family history of hypertension

0.347

0.532

1.415

0.476

to

4.211

Thickening group versus Plaque group1

Intercept

2.688

0.101

    
 

SDNN

0.005

0.446

1.005

0.992

to

1.019

 

Age

−0.080

0.001

0.923

0.879

to

0.970

 

Absence of family history of hypertension

−1.072

0.071

0.342

0.107

to

1.096

Normal IMT group versus Plaque group1

Intercept

5.777

0.001

    
 

SDANN

0.017

0.021

1.017

1.003

to

1.032

 

Age

−0.169

<0.001

0.845

0.797

to

0.696

 

Absence of family history of hypertension

0.357

0.523

1.429

0.478

to

4.270

Thickening group versus Plaque group1

Intercept

2.626

0.101

    
 

SDANN

0.006

0.351

1.006

0.993

to

1.020

 

Age

−0.080

0.001

0.923

0.879

to

0.970

 

Absence of family history of hypertension

−1.059

0.075

0.347

0.108

to

1.112

group with Hypertrophy versus group without Hypertrophy2

Intercept

−5.240

0.004

0.005

   
 

LF/HF

−0.155

0.528

0.856

0.563

to

1.302

 

Age

0.068

<0.001

1.071

1.036

to

1.107

 

Cholesterol

−0.006

0.141

0.994

0.986

to

1.002

 

Diuretics

−0.854

0.011

0.426

0.220

To

0.823

β: regression coefficient.

p: p-value referred to each variable in the regressions (multinomial or binary logistic).

OR: odds ratio, which is exp(β).

95% CI: 95% confidence interval.

1 multinomial logistic regression.

2 binary logistic regression.

Discussion

To our knowledge, the current study is the first one to investigate standard linear HRV measures, both in time and in frequency domains, in hypertensive patients, categorised by severity of TOD at different levels (cardiac, vascular and renal) and considering adjusted models for age and other clinical parameters (such as gender, metabolic variables). Time and power spectral analysis of 24-hour electrocardiographic monitoring was performed in 200 hypertensive patients in basal conditions. At these same times, patients underwent echocardiographic and carotid ultrasonography study evaluations and routine laboratory evaluations in order to assess TOD at different level. The data of the current study showed that significantly lower values of some HRV measures were found in patients with CV involvement at different levels. Particularly, decreased LF/HF, which is a marker of sympatho-vagal balance, was found in the patients with moderate decreased eGFR, the highest grade of kidney involvement considered in this study. Similarly, depressed values of indexes of the overall ANS modulation on the heart, such SDNN and SDANN, were found in patients with plaque compared to patients with a normal IMT. These associations remained significant after adjustment for other factors known to contribute to the development of TOD, including diabetes, hypertension, and metabolic variables. Moreover, depressed LF/HF was found also in patients with LVH but this association was not significant after adjustment for other factors. As stated in a recent paper by Garcia-Garcia [23] the association between HRV and the development of TOD or vascular alterations has not been clearly established. Garcia-Garcia [23] investigated the association between 24-hours heart rate and IMT, LVMi, and eGFR, by performing a cross-sectional study including 360 hypertensive patients without heart rate lowering drugs, aged 30–80 years. We underline that they computed only two HR parameters: the mean HR and the standard deviation of HR (which are similar to AVNN and SDNN computed in the current study, respectively), while in this study almost all the linear HRV measures were computed as recommended and standardised in International Guidelines [8] and confirmed by recent literature [9]. Moreover, we proposed a larger number of covariates than Garcia-Garcia [23] in the adjusted model, for instance, the familiarity for hypertension or stroke. They found no association between AVNN and SDNN with LVH, consistently with our results. Moreover, they found associations between AVNN and SDNN with respect to IMT and eGFR, but these were lost after adjusting for age. Our results were coherent with these findings, even if in our studies the association of SDNN with IMT was significant also after adjustment. However, the patients in the study by Garcia-Garcia [23] were younger (56 ± 11 years versus 62 ± 12 years) and with a lower percentage of heart (18% vs 60%), and vascular (23% vs 75%) TOD. Moreover, the HRV analysis in this study was performed after a one-month antihypertensive therapy wash-out while many patients in the sample studied by Garcia-Garcia received drug therapy (not HR lowering drugs). We underline that the therapy before ECG holter measurement among selected groups was comparable as no significant differences occurred. The only exception was represented by diuretics, as a larger proportion of patients in the moderate eGFR group assumed diuretics compared with the other two groups (mild and normal eGFR) and a larger proportion of patients in the hypertrophy group assumed them compared to the group without hypertrophy. This difference was due to the fact that the antihypertensive treatment of patients with moderate decreased eGFR or with hypertrophy was based on the combination of diuretics with other drugs (i.e. Beta-blockers, ACE inhibitor, AT1 Antagonist and Dihydropyridine) which were usually prescribed also in the other groups of patients. We underline that the association of diuretics with a lower HRV has been already shown by the ARIC study [41] in 3577 hypertensive patients and by a recent study [42] in general male population, for that reason we performed the HRV analysis after a drug washout. The comparison of our results with those by Garcia-Garcia re-enforces the importance of computing several HRV parameters, especially the frequency-domain measures, such as LF/HF, which is considered as a non-invasive marker of the sympatho-vagal balance. However, the plausible mechanisms by which abnormal autonomic balance may lead to TOD and, particularly, renal organ damage one are not clearly known. Our results were consistent with two recent studies [20, 21], investigating HRV and kidney disease, which concluded that lower HRV (particularly, frequency domain measures) was associated with higher risk of progression to end-stage renal disease and suggested that autonomic imbalance may lead to kidney damage. For that reason, prospective longitudinal studies are needed to evaluate a causal effect between HRV and TOD. In future studies, additional HRV measures, derived from nonlinear [43] and/or point process time-frequency [44] analysis, could be selected either in short-term recordings under standardised conditions [45] or in long-term continuous monitoring [46]. Moreover, other non-invasive parameters related to ANS activity, such as pupillometric features [47, 48], could be adopted to provide additional information on autonomic cardiac control. As regards the other factors which entered the adjusted models, the age is the most significant variable, confirming that cardiac, vascular, and renal abnormalities increase progressively with age [49, 50]. The absence of hypertensive familiarity seems to be associated with no renal involvement. Significantly higher systolic BP values were found in the mild decreased eGFR group, maybe because the blood pressure values are controlled in patients with moderate renal eGFR by the (significantly higher) use of diuretics. Higher systolic BP values were associated with LVH, coherently with the fact that it is an established cardiac manifestation of chronic hypertension [51]. Moreover, other factors associated with LVH are higher assumption rate of diuretics and higher values of cholesterol. Although previous studies have shown that gender influences HRV parameters both in healthy subjects [52] and hypertensive patients [53], this factor entered no final adjusted models. This means that within the selected sample of patients the gender-related differences in HRV were smaller than differences related to other factors and covariates, in particular age or progression of TOD. We consider in any case that the main limitations of this study were the inherent ones of observational and cross-sectional design, which precludes longitudinal analysis between HRV and TOD.

Conclusions

In conclusion, depressed HRV appeared to be associated with vascular and renal TOD. In particular, depressed values of indexes of the overall ANS modulation on heart were found in patients with plaque compared to those with a normal IMT. These associations remained significant after adjustment for other factors known to contribute to the development of TOD. Moreover LF/HF, a marker of sympatho-vagal balance, was significantly decreased in the groups with mild and moderate decreased eGFR, confirming the involvement of autonomic imbalance in TOD. However, as the mechanisms by which abnormal autonomic balance may lead to TOD are not clearly known, we suggested that further prospective studies with longitudinal design would be performed to investigate HRV in the early stages of hypertension and of TOD development.

Authors’ information

PM and LP are biomedical engineers with research interest in biomedical signal processing for cardiologic risk assessment, particularly, by Heart Rate Variability analysis and using artificial intelligence methods. PM acquired ECTS-credits in the field of medicine, particularly cardiology. Moreover, PM and LP got their Ph.D. at the Faculty of Medicine of the University of Naples Federico II (in partnership with the Department of Biomedical, Electronic and Telecommunication Engineering of the same University). RI is a researcher in cardiologic science. NDL is an associate professor in cardiologic science.

Abbreviations

AVNN: 

Average of all NN intervals

BP: 

Blood Pressure

CI: 

Confidence Interval

CV: 

Cardiovascular

ECG: 

Electrocardiogram

eGFR: 

estimated Glomerular Filtration Rate

HF: 

Spectral power of all NN intervals between 0.15 and 0.4 Hz

HR: 

Heart Rate

HRV: 

Heart Rate Variability

IMT: 

Maximum arterial Intima Media Thickness

LF: 

Spectral power of all NN intervals between 0.04 and 0.15 Hz

LF/HF: 

Ratio of low to high frequency power

LV: 

Left Ventricle

LVH: 

Left Ventricular Hypertrophy

LVMi: 

LV Mass index

MDRD: 

Modification of Diet in Renal Disease

OR: 

Odds Ratio

pNN50: 

Percentage of differences between adjacent NN intervals that are longer than 50 ms

PSD: 

Power Spectral Density

RMSSD: 

Square root of the mean of the sum of the squares of differences between adjacent NN intervals

SDANN: 

Standard deviation of the averages of NN intervals in all 5-min segments of a 24-h recording

SDNN: 

Standard deviation of all NN intervals

SDNN IDX: 

Mean of the standard deviations of NN intervals in all 5-min segments of a 24-h recording

TOD: 

Target Organ Damage

TOTPWR: 

Total spectral power of all NN intervals up to 0.4 Hz

ULF: 

Spectral power of all NN intervals between 0 and 0.003 Hz

VLF: 

Spectral power of all NN intervals between 0.003 and 0.04 Hz.

Declarations

Acknowledgements

The study was conceived and designed in the framework of the research project Remote Health Monitoring (R.H.M.), involving all the authors, and funded by the Regione Campania and of the Ph.D. Scholarship by PM. Moreover, the current work was supported by Italian Ministry of Education, University and Research with the project Smart Health and Artificial intelligence for Risk Estimation (SHARE). LP acknowledges support of this work through the MATCH Programme (EPSRC Grant EP/F063822/1) although the views expressed are entirely his own. The funding bodies have no role in design, in the collection, analysis, interpretation of data, in the writing of the manuscript, or in the decision to submit the manuscript for publication.

PM and LP thanks Prof. Marcello Bracale for his scientific leadership (technological issues) in the research project R.H.M.

Authors’ Affiliations

(1)
Multidisciplinary Department of Medical Sciences, Second University of Naples
(2)
Departments of Clinical Medicine, Cardiovascular and Immunological Sciences, Federico II University Hospital
(3)
Electrical Systems and optics research division, Faculty of Engineering, University of Nottingham

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