**4. HF ms2**

There are three main spectral components in an HRV spectrum named as high frequency (HF), low frequency (LF), and very low frequency (VLF) bands. The HF band represents the power in the frequency range between 0.15 and 0.4 Hz. HF power is generally believed to represent respiration-linked changes in heart rate and is generally accepted as a measure of respiratory sinus arrhythmia (RSA), or the parasympathetic contribution to HRV. RSA refers to the acceleration in heart rate that occurs during inspiration (due to the cardiovascular control center's inhibition of vagal outflow) and the subsequent heart rate deceleration that occurs during expiration, due to vagal restoration [13, 14].

Doheny et al. in 2015 [15], evaluated the possibility of using a non-invasive biomarker that allows early detection of patients at risk of necrotizing enterocolitis (NEC), that is an acute neonatal inflammatory disease that may lead to intestinal necrosis, multi-system failure and death. For that, they used the high frequency (HF) component of heart rate variability. They studied 70 stable preterm infants (gestational age 28-35 week). HF ms2 was 21.5 ± 2.7 ms2 in infants that remained healthy and 3.9 ± 0.81 ms2 in those that later developed stage 2 + NEC (P < 0.001). The cut-off value in the ROC curve was 4.68ms2 , predictive for developing NEC with sensitivity and specificity of 89% and 87%, and positive and negative predictive values of 50% and 98%, respectively. They concluded that HF ms2 may serve as a potential, non-invasive predictive biomarker of NEC-risk in infants.

In 2004, Abramkin et al. [16], studied 188 patients to compare the prognostic value of different noninvasive reflex tests on days 4-11 of myocardial infarction. The age varied from 34 to 75 years, 68% were men, and 93.6% were on beta-blockers, all without heart failure NYHA IV on the day of tests. HF power < 65 ms2 during active standing (OR 28.8, 95% CI 4.1-104.2; p = 0.001, positive predictive value 29.4%) was an independent predictor of sudden cardiac death.

In a meta-analytic study carried out in 2021 by Heimrich et al. [17], the objective was to verify whether the analysis of heart rate variability could indicate decreased parasympathetic tone in patients with Parkinson's disease. A total of 47 studies were evaluated, including 2772 individuals, 1566 of which had Parkinson's Disease (65.0 ± 0.6 years) and 1206 were healthy controls (62.6 ± 1.0 years). Based on 24 studies, it was possible to detect that the FH ms2 was significantly lower in the group of patients with the disease (145.2 ± 41.1 versus 219.4 ± 48.8 ms2; P = 0.002; heterogeneity 91%).

### **5. Objective**

Considering that the heart rate (HR), the root-mean-square of successive differences between adjacent normal RR intervals (RMSSD) and the HF band power in the frequency range between 0.15 and 0.4 Hz (HFms2), can help to differentiate the homeostatic level between individuals with severe impairment and high risk, and healthy individuals, we performed an intensive review of the literature by collecting published data involving the aforementioned variables, in search of a cutoff value for defining homeostatic reference levels and creating an individualized diagnostic coding.

### **6. Method**

Based on research projects linked to FAPESP - Brazil (2017/12529-7) and CNPq -Brazil (308,555/2018-0), studies involving the use of one or more of the *Heart Rate Variability as a Marker of Homeostatic Level DOI: http://dx.doi.org/10.5772/intechopen.102500*

three variables mentioned above were evaluated. In total, it was possible to analyze 164 studies involving the heart rate of individuals with importantly compromised homeostatic level (HL\_ic), 181 studies involving the heart rate of apparently healthy individuals (HL\_ah), 179 studies involving the RMSSD of individuals with HL\_ic, 221 studies involving the RMSSD from HL\_ah subjects, 125 studies involving the HF ms2 of subjects with HL\_ic and 155 studies involving the HF ms2 of HL\_ah subjects. Obviously, there were concurrent studies in certain situations. Due to a large number of references, they are cited separately and available in a *supplementary file*.

### **7. Statistical analysis**

Data were presented as mean and standard deviation, weighted mean, quantities, percentages and correlation coefficients. Comparisons between groups were made by analysis of variance or the Kruskal-Wallis test and its post-tests, according to the indication. Correlation graphs were constructed and Box-Whisker graphs were used for illustration. An alpha error of 5% was accepted, with P values less than or equal to 0.05 being considered significant. The statistical software used was StatsDirect version 3.3.5 (03/22/2021).

### **8. Results**

The total amount of data analyzed was extremely high. **Table 1** below indicates the amounts for each variable under conditions of significantly compromised and apparently healthy homeostasis, as well as the mean and standard deviation values for the age of the group, the mean and standard deviation of the variable, and the weighted mean of the variable.


### **Table 1.**

*Distribution of the number of studies included, amount of data per variable, according to homeostatic level (importantly compromised [HL\_ic] or apparently healthy [HL\_ah].*

As the behavior of heart rate variability is related to age, linear correlation calculations were made between age (predictor) and the variable to be predicted (HR, RMSSD or HFms2 ) in the HL\_ic and HL\_ah groups (**Table 2**; **Figures 1**–**6**).


### **Table 2.**

*Distribution of simple linear regression, correlation coefficients (r and r2 ) and two-sided P-values, by homeostatic condition.*

#### **Figure 1.**

*Correlation graphs (age x heart rate) in the groups of individuals with importantly compromised homeostatic level (HL-ic) and apparently healthy (HL\_ah).*

### **Figure 2.**

*Correlation graphs (age x RMSSD) in the groups of individuals with importantly compromised homeostatic level (HL-ic) and apparently healthy (HL\_ah).*

*Heart Rate Variability as a Marker of Homeostatic Level DOI: http://dx.doi.org/10.5772/intechopen.102500*

### **Figure 3.**

*Correlation graphs (age x HF ms2 ) in the groups of individuals with importantly compromised homeostatic level (HL-ic) and apparently healthy (HL\_ah).*

### **Figure 4.**

*Scattergram (HR in bpm) for the groups of individuals with importantly compromised homeostatic level (HL- ic; red circles) and apparently healthy (HL\_ah; blue squares).*

### **Figure 5.**

*Scattergram (RMSSD in ms) for the groups of individuals with importantly compromised homeostatic level (HLic; red circles) and apparently healthy (HL\_ah; blue squares).*

### **Figure 6.**

*Scattergram (HF in ms2 ) for the groups of individuals with importantly compromised homeostatic level (HL- ic; red circles) and apparently healthy (HL\_ah; blue squares).*

A moderate negative correlation was found between heart rate and age, both in cases with significant homeostatic impairment and in apparently healthy cases. There was also a moderate negative correlation between RMSSD and age, and between HFms2 and age in the apparently healthy group. The fact that there was only a weak negative correlation between HFms2 and age in the group with significant homeostatic impairment and also the absence of correlation between RMSSD and age in this impaired group, was noteworthy. This may suggest that RMSSD is a more effective or sensitive biological marker of homeostasis, revealing changes regardless of age.

It became also relevant to evaluate the data of the three selected variables, in the group composed of individuals named as being from the general population (HL\_gp). Thus, from the global data survey carried out, a number of 10,121,910 were obtained from individuals from the general population, in different age groups. The values of mean, standard deviation, weighted mean, mean age ± standard deviation and number of articles consulted are found in **Table 3** and **Figure 7**.

Comparative statistical analysis between the 3 groups (HL\_ah, HL\_ic and HL\_gp) for the three selected variables, using the Kruskal-Wallis test with post-test Dwass-Steel-Chritchlow-Fligner, showed a non-significant difference between HR HL\_ah versus HR HL\_gp (P = 0.6228); the statistically significant difference between HR HL\_ah versus HR HL\_ic (P < 0.0001); the statistically significant difference between HR HL\_gp versus HR HL\_ic (P < 0.0001).


### **Table 3.**

*Data and values were obtained in the assessment of the general population (HL\_gp).*

### **Figure 7.**

*Box-whisker graphs of the distributions of values for heart rate (A), RMSSD (B) and HF ms2 (C) variables, by the homeostatic level group.*

Regarding the variable RMSSD, there was a statistically significant difference between RMSSD HL\_ah versus RMSSD HL\_gp (P < 0.0001); the statistically significant difference between RMSSD HL\_ah versus RMSSD HL\_ic (P < 0.0001); the statistically significant difference between RMSSD HL\_gp versus RMSSD HL\_ic (P < 0.0001).

In the comparative analysis of the variable HF ms2, there was a statistically significant difference between RMSSD HL\_ah versus RMSSD HL\_gp (P < 0.0001); statistically significant difference between RMSSD HL\_ah versus RMSSD HL\_ic (P < 0.0001); statistically significant difference between RMSSD HL\_gp versus RMSSD HL\_ic (P = 0.0002).

Therefore, it is concluded that data from the so-called general population are not suitable to be considered as a normal condition and this must be taken into account when this group is used as a control group.

Finally, based on the weighted average of the results in **Table 1**, on the scatter plots involving the group of individuals with significant homeostatic impairment and the group of apparently healthy individuals, we propose a classification model for the individual homeostatic level. This classificatory model is a three-level, three-stage alphanumeric coding, designed as follows:

Level A: Heart Rate (bpm)

Stage A1: Heart Rate less than 70 bpm Stage A2: Heart Rate between 70 and 85 bpm Stage A3: Heart Rate above 85 bpm Level B: RMSSD (ms) Stage B1: RMSSD above 32 milliseconds. Stage B2: RMSSD between 32 and 28 milliseconds. Stage B3: RMSSD less than 28 milliseconds.

Level C: HF ms2

Stage C1: HF ms2 above 468 ms2

Stage C2: HF ms2 between 468 and 156 ms2 .

Stage C3: HF ms2 less than 156 ms2 .

Thus, a totally healthy individual, with an excellent Homeostatic Level and, therefore, with very low risk, would receive the A1B1C1 classification. An individual with a

**Figure 8.** *Set of possibilities in the alphanumeric classification of the individual homeostatic level (Created by the authors).*

high basal heart rate, a very low RMSSD value and a very low HF power value would be classified as A3B3C3 indicating high severity, low homeostatic level and, therefore, at high risk. Several intermediate combinations would be possible characterizing the current state of each case. The figure below illustrates the full set of possibilities (**Figure 8**).

In conclusion, the present analytical study, based on an extensive amount of data published in the literature (more than 10.5 million values), referring to three recognized variables of heart rate variability markers of the level of homeostasis, allowed us to define cut-off levels indicative of apparently healthy or with important homeostatic compromise. It was possible to conclude that values obtained in the general population are not equivalent to normal values, a fact that must be considered when this group is used as a control. It was also possible, to elaborate a very simple alphanumeric classification with practical applicability in the characterization of the individual homeostatic level.
