Diabetic Cardiac Autonomic Neuropathy: Link between Heart Rate Variability, Violated Blood Pressure Pattern, and Pulse Wave Velocity

Abstract

Abnormalities in heart rate (HR) variability (HRV) and blood pressure (BP) variability may increase the risk of cardiovascular diseases. A well-known risk factor for cardiovascular morbidity, such as arrhythmias, stroke, congestive heart failure, heart attacks, and sudden death syndrome, is cardiac autonomic neuropathy (CAN). It has been claimed that chronobiologically evaluating HRV and BP and optimizing timed treatment efficacy can significantly lower the risk of cardiac or stroke death. Physiological cardiovascular activities are under the control of the cardiac autonomic nervous system. Damage of the autonomic nerves leads to dysfunction in HR control and vascular dynamics, notably to CAN. For people with diabetes mellitus (DM), metabolic abnormalities and significant morbidity and mortality are caused by an autonomic imbalance between the sympathetic and parasympathetic nervous systems, which regulate cardiovascular function. There is a strong correlation between changes in neuroendocrine sleep architecture, circadian clock oscillations, glucose metabolism, autonomic function, and diurnal profiles of BP and HR, and there has been evidence of circadian rhythm misalignment in DM patients. The purpose of the chapter is to analyze the current state of the problem in the relationship between DM and circadian rhythm disorders, HRV, and arterial stiffness.

1. Introduction

Many biological activities rely on the circadian clock as the main regulator of metabolism and energy homeostasis. Dyslipidemia (DLP), insulin resistance (IR), and hyperglycemia are all seen in animal models, where the suprachiasmatic nucleus (SCN) of the hypothalamus has been altered. Circadian disorders, such as a decline in the sleep-wake cycle brought on by insufficient sleep, shift work, and social jet lag, have been linked to symptoms of the metabolic syndrome (MeTs) such as impaired glucose tolerance (IGT), insulin sensitivity, hypertriglyceridemia, an increase in body mass index (BMI), and mean arterial blood pressure (BP) [1, 2]. Taken together, these studies suggest that autonomic nervous system (ANS) dysfunction could play a role in the pathogenesis of glucose dysregulation [3]. According to physiological principles, insulin is directly secreted from β-cells under the control of the parasympathetic nervous system (PNS), and the body’s glucose levels are managed by the ANS [4]. Although autonomic dysfunction is linked to an increased risk of cardiovascular diseases (CVDs), the specific mechanism by which autonomic dysfunction is linked to CVDs is uncertain [5, 6]. Reduced heart rate variability (HRV) and reduced baroreflex sensitivity (BRS) are early indicators of cardiac autonomic dysfunction [6, 7, 8, 9], cardiac attacks, congestive cardiac failure, stroke, and sudden arrhythmic death are all very susceptible to cardiac autonomic neuropathy (CAN).

In the latter, hypertension (HTN) is followed by structural remodeling of the myocardium, including fibrosis and hypertrophy.

This remodeling is accompanied by changes in the extracellular matrix composition, as well as changes in the expression, distribution, and function of cell membrane ion channels, Ca2-cycling proteins, and intercellular gap junction connexin-43 channels [8, 9, 10].

Several epidemiological studies have found that greater arterial stiffness, independent of other cardiovascular risk factors, predicts mortality and morbidity. Diabetes can aggravate arterial stiffness by causing pathological changes in the vascular bed, such as changes in the type or structure of collagen and/or elastin in the arterial wall, decreased nitric oxide (NO) bioavailability, chronic low-grade inflammation, increased oxidative stress (OS), and increased sympathetic tone [11].

Hyperglycemia, which is linked to the activation of pro-inflammatory transcription factors and an increase in OS, which results in vasculopathy, is responsible for many of the pathophysiological mechanisms underlying vascular dysfunction in diabetes mellitus (DM). Elevated levels of advanced glycation end products (AGEs) may affect the molecular matrix of the vessel wall.

According to certain research, type 2 diabetes (T2DM) may reduce endothelial NO bioavailability and attenuate vascular smooth muscle cells (VSMCs) response to NO by causing endothelium and VSMC to malfunction in diabetics compared to controls. All of these mechanisms are implicated in mediating hyperglycemia-induced arterial stiffness.

When compared to healthy, age- and sex-matched controls, patients with primary autonomic failure who do not have DM had stiffer aortas.

According to these findings, there is a pathophysiological link between arterial stiffness and cardiac autonomic dysfunction, and ANS is critical for preserving the elastic characteristics of the arteries [12].

Advanced glycation end products (AGEs) production, protein kinase C activation, low-grade inflammation, and endothelial dysfunction are all shared pathogenetic pathways that link arterial stiffness with cardiac autonomic dysfunction [13, 14]. It is still unknown whether increased arterial stiffness causes impaired cardiac autonomic function or whether impaired cardiac autonomic function causes arterial stiffness, as well as the pathophysiological relationship between arterial stiffness and autonomic dysfunction.

2. Type 2 diabetes mellitus

Diabetes and changes in cardiac autonomic control have a well-established link. This includes individuals with IR and children of T2DM patients who have never had diabetes or HTN, where the mean values of HRV are reduced. In healthy individuals, low HRV is linked to a rise in the occurrence of this illness. Numerous research findings suggest a tight connection between T2DM and autonomic neuropathy. Increasing research suggests that CAN is widespread in people with IGT. A metabolic insult and obesity may trigger the onset of CAN. In addition, individuals with IGT frequently experience autonomic symptoms. In addition to CAN, people with IGT have abnormalities in endothelium peripheral vasoreactivity and sudomotor function [15].

Liu et al. retrospectively reviewed 104 patients with T2DM and coronary heart disease (CHD) medical records. Correlation analyses were carried out between HRV measures, clinical parameters, and the severity of coronary lesions. The Gensini scores and the number of damaged arteries were used to determine the severity of coronary lesions. According to Spearman’s correlation analysis, there is a substantial negative association between the standard deviation of 5-min mean intervals of NN (SDANN) scores, a component of HRV, and Gensini scores, which remained significant after adjustment for clinical covariates. The research has demonstrated that in patients with T2DM the overall connection between CAN and coronary lesions may exist independently of established variables in the etiology of vascular endothelial damage and atherosclerosis [16, 17]. These findings suggest that endothelial dysfunction and cardiac autonomic nervous dysfunction are related pathophysiologically in T2DM [18]. Reduced HRV values are related to the severity of coronary artery lesions among persons with stable angina pectoris [19]. Liu et al. indicated that CAN might reflect the progression of coronary atherosclerosis in persons with T2DM. According to the authors, CAN may be associated with the degree of coronary atheromatous burden in T2DM patients. The combination of cardiac autonomic nervous function testing and plaque enhancement may improve CHD risk classification in T2DM patients [16].

CAN results from impaired autonomic function and subsequent nervous system imbalance of the cardiovascular system that occurs due to diabetes [20]. CAN can also result from metabolic disturbances in prediabetes and MeTs, which are conditions before established diabetes [8]. If a person develops type 1 diabetes (T1DM), hyperglycemia affects several cellular pathways, leading to microvascular problems, including Cardiac autonomic neuropathy (CAN) [6]. A complicated link between rising IR and developing autonomic dysfunction leads to CAN in prediabetes, MeTs, and T2DM [21]. Diabetes patients who have high blood glucose have the following changes: positive regulation of the hexosamine pathway, which leads to an increase in N-acetyl glucosamine and, consequently, the induction of OS; exacerbation of OS due to lipid peroxidation and reduction of glutathione levels and enzymes involved in antioxidant defense; increase in sorbitol, whose intracellular increase promotes osmotic stress and greater electrolyte output from the cell, which causes impairment of Schwann cells from peripheral neurons [22]. The primary driver for CAN development in T1DM is hyperglycemia compared with the multifactorial pathogenesis of CAN in T2DM. In early CAN, IR directly promotes sympathetic predominance [21]. T2DM patients have a variety of vascular risk factors, including DLP and HTN, which can lead to microvascular disease [9]. Diabetes patients with low HRV have an increased risk of complications and mortality compared to those with normal HRV values. SampEn (a nonlinear measure used to evaluate the regularity of a time series) and high-frequency (HF) power of HRV, among other metrics, are superior discriminators for detecting autonomic dysfunction [23]. People with diabetes had a lower amplitude of day-night fluctuations in HRV from a circadian standpoint. These data support using HRV as a risk indicator in T2DM [10, 24].

3. The circadian rhythms and heart rate variability

Circadian rhythms are controlled by circadian clocks, which control day-night oscillations for ~24 hours. The molecular mechanism of the circadian clock is based on a negative feedback loop, which includes four main transcription factors of the helix-loop-helix or per-arnt-sim domain: CLOCK, BMAL1, PER, and CRY3 [25]. The SCN clock controls the circadian rhythm of the heart rate (HR) through circadian changes in the autonomic tone of the sinus node, particularly increased vagal tone at night.

The SCN regulates the diurnal release of other neurohumoral substances, but its effect on the HR’s circadian rhythm is unknown. Two mechanisms are responsible for the circadian rhythm of HR: the central circadian clock in the SCN of the hypothalamus can directly influence the electrophysiology of the heart and arrhythmogenesis through various factors, including the ANS and a local circadian clock within the heart (albeit controlled by a central clock) can regulate the circadian rhythm of ion channel expression in the heart. The ANS can play a unique role as a bridge between clocks. In particular, the ANS is capable of synchronizing the local clock in order to effectively control fluctuations in the expression of ion channels [25].

The ANS reacts to internal and external stimuli and maintains the organism’s homeostasis. The autonomic background of the cardiac periodicity control is important for the interpretation of HRV measurements. Under physiologically normal conditions, the respiratory rate is in the HF range, which relates the HF components to the vagal modulations of the heart period. At the same time, the low-frequency (LF) power of HRV modulations reflects a combined vagal and sympathetic control [26]. Because the sympathetic and vagal systems induce different frequencies of cardiac periodicity modulation, the HRV is an appropriate approach for analyzing the relative strength of modulations by both limbs of the autonomic system. The latter makes it possible to assess the relationship between sympathetic and vagal control using the LF/HF ratio or the so-called normalized LF and HF components (excluding very low-frequency components) [26]. Because of the relationship between cardiac ANS status and spectrum components of HRV (and other analogs of measurement), HRV analysis is useful for diagnosing autonomy, which is defined by a lack of autonomic response. Numerous studies have demonstrated the clinical utility of HRV in the early diagnosis and type classification of diabetic neuropathy [26, 27].

The clinical significance of HRV is determined by the following provisions [28]:

• First, HRV can detect early subclinical manifestations of autonomic dysfunction, which could be useful from a therapeutic standpoint in understanding the subject’s risk and subsequent care. In other words, having knowledge into HRV could influence the aggressiveness of the treatment and the choice of treatment when dealing with hyperglycemia and complications, as well as recognizing possible hazards that are not visible (e.g., CAN).

• Second, T2DM management must be comprehensive and include preventive intervention.

• Third, a better understanding of interventions that could improve HRV may allow guiding the patient toward lifestyle changes that can improve HRV parameters and, therefore, quality of life.

4. Autonomic nervous system and heart rate variability

It is common knowledge that the ANS is a component of the peripheral nervous system that regulates involuntary physiologic processes, including HR, BP, respiration, digestion, and sexual arousal [29]. The ANS regulates cardiac function by balancing the effects of sympathetic and parasympathetic nervous system impulses on the heart. These autonomic signals are integrated by intrinsic cardiac neurocircuits to fine-tune cardiac regulation, and sensory feedback loops regulate autonomic transmission in response to external stimuli [13]. The sympathetic nervous system (SNS) is responsible for activating activity and attention: the “fight or flight” response. During this process, BP and HR rise, glycogenolysis occurs, etc. Almost every living tissue in the body is innervated by the SNS. The PNS encourages “rest and digest” processes, HR and BP drop, gastrointestinal peristalsis, etc. The ANS swiftly governs and modifies BP and HR interaction through the arterial baroreflex. A negative feedback loop buffers change in HR and BP to maintain them under various situations in daily life [29, 30]. The ANS dynamically controls the heart. Control of chronotropy, lusitropy, dromotropy, and inotropy is handled by a hierarchical neural network. Intrinsic autonomic dysfunction is caused by disorders that directly impact the autonomic nerves, such as DM and primary autonomic failure syndromes. Extrinsic autonomic dysfunction reflects alterations in autonomic function caused by cardiac or other illness. Therefore, these two types of autonomic dysfunction can be associated with diabetes [31].

Strong physiological connections link the ANS with glucose metabolism. A network of autonomic nerve fibers surrounds pancreatic islet cells and their blood vessel supply. In healthy individuals, parasympathetic nerve signaling triggers the early release of insulin from the pancreatic β-cells (e.g., first-phase insulin release) in response to sensory signals [32].

In rodent models, PNS increases β-cell proliferation [33]. In response to hypoglycemia, sympathetic nerve transmission modulates glucagon secretion by islet α-cells and suppresses insulin secretion [4, 9]. β-adrenoceptors expressed in α-cells and α2-adrenoceptors expressed in β-cells are responsible for these two SNS actions. The ANS also innervates the liver, adipose tissue, and smooth muscle tissue, whose effects on glucose metabolism are related to insulin sensitivity [3, 34].

Autonomic dysfunction, as measured by decreased HRV, has also been linked to calcification of the coronary arteries [35, 36]. Whether dysfunction of the ANS contributes to the development of atherosclerosis, it will significantly impact our understanding of the pathogenesis of coronary atherosclerosis in patients with diabetes. A direct effect of autonomic disorders on atherosclerosis is plausible. Sympathetic denervation may result in VSMCs dedifferentiation and a shift to a phenotype associated with extracellular matrix synthesis and migration to the intima, and changes seen in atherosclerosis [37].

5. Heart rate variability and arterial stiffness

In T2DM, cardiac autonomic dysfunction induces HR increase, resulting in diastole shortening; however, it appears that independent of the effect on HR, cardiac autonomic dysfunction can shorten diastole duration (DD). Because DD has a significant impact on subendocardial myocardial viability (SVI) and cardiac autonomic dysfunction, in addition to arterial stiffness, plays a main role in SVI impairment and may thus affect cardiovascular prognosis.

In T2DMs, cardiac autonomic dysfunction causes HR to accelerate, resulting in diastole shortening; however, it appears that cardiac autonomic dysfunction may decrease DD regardless of the effect on HR. Since DD strongly influences SVI, cardiac autonomic dysfunction plays a primary role in addition to arterial stiffness in the impairment of SVI and as a result, the cardiovascular prognosis may worsen [38, 39].

Reduced HRV in uncomplicated diabetics indicates an obscure process of autonomic neuropathy in diabetic patients, which occurs even before clinical atherosclerotic CVD is manifested. Surrogate atherosclerosis indicators have also been linked to lower HRV, and higher carotid intima-media thickness (CIMT) in T2DM patients has been linked to lower HRV, independent of conventional cardiovascular risk factors. As a result, the existence of CAN should be considered quite early in the course of diabetes rather than after clinical CVD develops [40, 41].

Chorepsima et al. discovered that, in addition to BP, decreased cardiac autonomic function as measured by HRV was a significant predictor of abnormal pulse wave velocity (PWV) in T2DM patients. Moreover, lower HRV values were independently related to higher PWV [12]. A decrease in HRV has been associated to an increased risk of death in people with CHD or diabetes. HRV can also be used to detect BRS control, specifically vagal control. As a result, vascular stiffness may influence BRS and, as a result, HRV. Increased arterial stiffness, as assessed by PWV and/or the ambulatory arterial stiffness index, has been associated to coronary atherosclerosis and a worse cardiovascular prognosis in both the general population and specific disease groups, most notably DM.

Reduced HRV in uncomplicated patients with DM reveals the enigmatic process of CAN in diabetic patients, which begins prior to clinical atherosclerotic CVDs manifest. Surrogate atherosclerosis indicators have also been linked to reduced HRV and greater CIMT has been associated to reduced HRV in T2DM patients, independent of conventional cardiovascular risk factors. As a result, rather than waiting until clinical CVDs have developed, the occurrence of CAN should be evaluated much earlier in the course of DM [40, 42].

Based on Bagherzadeh et al. findings and previous works, one could suggest that atherosclerosis, both due to diabetes and increased age, is influenced by the CAN, resulting in an increased risk of CVD and related mortality in T2DM patients. Compared with normal controls, Bagherzadeh et al. observed increased arterial stiffness and decreased HRV in uncomplicated T2DM patients. The association between HRV indices and PWV was significant after diabetes adjustment; however, this impact was abolished following adjustment for confounders. Based on the findings of this study, it appears that there is a connection between HRV and arterial stiffness as a measure of atherosclerosis in diabetic patients, albeit the influence of confounding factors should be considered [40].

Technically, baroreceptor/reflex sensitivity parameters quantify the HRV change concerning BP variability. BRS represents the ability of carotid sinus and aortic arch baroreceptors to detect changes in aortic distention and communicate them to brainstem nuclei responsible for cardiac autonomic regulation [43]. Parasympathetic discharge is controlled by the nucleus of tractus solitary, while sympathetic outflow is controlled by the rostral ventrolateral medulla [44]. In actuality, the intensity of the link between changes in BP and reflex modulation of HR can be determined by two checkpoints mediated by the status of baroreceptors. The first corresponds to the physical features of the vascular system, which transports pressure signals to baroreceptors, while the second represents the ANS’s primary effector. The latter is known as neuronal BRS, whereas the former is known as mechanical BRS. Autonomic neuropathy, rather than carotid stiffness, has been found to be a greater predictor of BRS in T2DM patients [44]. To this end, different studies have focused on characterizing changes in the different ganglia and nuclei in the cardiac neural network in MeTs, prediabetes, and T2DM [10].

Arterial stiffness is a marker of subclinical vascular disease that has been documented among young patients with T1DM. The exposure of blood vessels to the continuous harmful effects of hyperglycemia may result in the early development of arterial stiffness in these patients. Medial arterial calcification (MAC), a complicated dynamic process influenced by multiple molecular signaling pathways, causes peripheral arterial stiffness. Despite peripheral arterial stiffness is known to be linked to peripheral artery disease (PAD) [45], the impact of MAC on peripheral vascular beds is poorly understood, despite the fact that advanced stages of MAC, which are characterized by loss of elasticity in arterial walls, are associated with worse tissue perfusion, ultimately leading to arterial flow stasis. MAC was formerly thought to be a harmless illness, despite the presence of associated PAD in a large fraction of patients, at least patients with T1DM. Arterial wall stiffness is now recognized as a key risk factor for cardiovascular death and morbidity, as well as a strong, independent predictor of all-cause mortality, and future CV events [45, 46].

Arterial stiffness is a significant risk factor for cardiovascular disease linked to isolated systolic HTN and elevated pulse pressure (PP) in target organ microvasculature [11]. Mechanotransduction, mitochondrial OS, DLP, a decreased elastin/collagen ratio, production of elastin cross-linking, reactive oxygen species (ROS)-induced inflammation, calcification, VSMC stiffness, endothelial dysfunction, genome mutations, and epigenetics all contribute to artery wall stiffening. Targeting these several biochemical pathways at various times of CVD risk factor exposure could be a novel approach to developing medicines that lower arterial stiffness without impacting artery strength or normal remodeling [47].

Lacolley et al. identify the following key provisions related to arterial stiffness:

• The connection between hemodynamics and mechanosensing is indicated by arterial stiffness.

• In recent years, the processes behind arterial stiffness have changed from elastin and collagen to VSMC phenotypic changes linked to metabolic, genetic, and epigenetic parameters, OS, and mechanotransduction.

• Different cardiovascular (CV) risk factors, such as aging, HTN, DM, and chronic kidney disease (CKD), as well as their various durations of exposure, share the processes that increase arterial stiffness to various levels.

• To combat or perhaps reverse this complex process, it is currently difficult to find medications that target either the early or late stages of arterial stiffness [47].

Numerous pathophysiological research have shown how arterial stiffness is affected by CV risk factors. The processes by which these CV risk factors harden the major arteries have been gradually uncovered [47, 48]. In particular, for people with essential HTN, significant arterial stiffness is raised in response to the biomechanical fatigue of the stiff wall materials, such as collagen, brought on by repetitive pulsatile stress and the increased loading of these materials by high blood pressure [49]. Furthermore, the activation of the renin-angiotensin-aldosterone pathway contributes to structural changes in the artery wall via VSMC proliferation, low-grade inflammation, increased collagen content, and AGE production. Another example is T2DM, which might harm the large artery wall due to its primary features, which include hyperglycemia and IR. Both variables may exert structural and functional effects via various methods. Chronic hyperglycemia stimulates VSMC proliferation and increases the generation of AGEs and collagen cross-linking, stiffening the arterial wall material. Moreover, the expression of matrix metalloproteinase-2 and -9, as well as angiotensin II receptors, is elevated in vascular tissue [47]. Insulin resistance stimulates collagen production and raises the expression of numerous inflammatory-related genes. Arterial stiffness is, thus, most likely a result of these alterations. The final example is CKD, which causes calcifications the large arteries wall. The sequence of molecular processes causing vascular calcification may start with the loss of expression by VSMCs of constitutive inhibitory proteins and end with expression by VSMCs and macrophages of osteoblastic, chondrocytic, and osteoclastic-associated proteins that orchestrate the calcification process [47, 50].

In a community-based cohort study, Zheng et al. discovered that arterial stiffness could be a risk factor for diabetes independent of established risk factors (e.g., age, BMI, BP, and alcohol use). The temporal analysis results, in particular, revealed that a change in arterial stiffness might precede a change in fasting blood glucose (FBG) rather than vice versa [49]. Increased arterial stiffness is a common sign of atherosclerotic vascular system involvement and is known to occur as a result of atherosclerotic risk factors such as aging, DLP, HTN, DM, and smoking. CHD, cerebrovascular disease, and PAD are all linked to increased arterial stiffness [38]. These findings indicate that diabetes candidates have endothelial dysfunction and inflammation as their blood glucose levels rise after being diagnosed with T2DM. Endothelial dysfunction is a well-known contributor to the macrovascular and microvascular consequences of diabetes. Endothelial dysfunction may precede diabetes by promoting IR and glucose dysregulation, eventually leading to diabetes. The precise importance of endothelial dysfunction for people with prediabetes and diabetes, however, is still being discussed [38].

According to several studies, increased big arterial stiffness appears as early as prediabetes. Carotid-femoral PWV (cfPWV) was higher in persons with impaired FBG or IGT compared to those with normal glucose metabolism in the ADDITION-Leicester cohort. The rise was identical to that seen in people with newly diagnosed T2DM. Carotid stiffness scores increased with FBG, insulin, and glycated hemoglobin A1c (HbA1c); cfPWV increased with HbA1c, FBG, homeostasis model assessment of IR (HOMA-IR) index, and HbA1c, as well as waist circumference, triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C), were all predictors of cfPWV following a 17-year follow-up. Finally, a recent study in middle-aged CVD-free patients found a link between cfPWV and telomere length (inverse) and the HOMA-IR index (direct), showing that IR associated with chronic inflammation may promote telomere shortening and vascular aging [51].

Cardiovascular autonomic dysfunction has been found in patients with T1DM and lower-extremity arterial calcification or markers of arterial stiffness. The Pittsburgh Epidemiology of Diabetes Complications study found that CAN, as defined by abnormal HRV after deep breathing, was linked with arterial stiffness regardless of traditional CV risk markers in a cohort of 144 individuals with childhood-onset T1DM. In addition, the SEARCH cardiovascular disease project used a cross-sectional design to investigate the correlations between HRV and multiple measures of arterial stiffness in young individuals with T1DM and healthy controls. CAN was linked to arterial stiffness in both the central and peripheral vascular beds, irrespective of other traditional CV risk factors as obesity-related parameters, blood pressure, lipid profiles, smoking, and microalbuminuria.

In addition, aberrant HRV during timed deep breathing was recently linked to aortic stiffness in a large sample of T1DM patients from the Steno Diabetes Center, even after controlling for gender, age, BP, glycemic management, diabetes duration, and renal function [45].

Some studies looked at arterial stiffness measurements in aged individuals and T2DM patients to support the use of these measurements as markers for primary prevention in target populations. A case-control research was carried out to examine PWV and the augmentation index (AIx) in two groups of cardiovascular patients: T2DM and CHD. After adjusting for gender and age, BP and HR discovered a strong link between CHD, PWV, and Aix. Interestingly, when the results of patients with T2DM were compared to healthy individuals, the elevated PWV values remained significant, implying that the outcomes depended on the methods used to quantify arterial stiffness.

A recent outstanding review detailed the potential clinical implications of arterial stiffness on the microvasculature. In summary, arterial stiffness may play a role in the development of numerous brain (e.g., dementia and cognitive impairment), heart (e.g., ischemia, myocardial dysfunction, and heart failure), liver (e.g., IR and nonalcoholic steatohepatitis) dysfunctions, CKD among other potential target organs with high-flow and low-resistance [36, 52].

6. Type 2 diabetes mellitus and cardiac autonomic neuropathy

Khandoker et al. conducted a comparative study of the characteristics of cardiac autonomic function alterations in patients with T2DM with diagnosed diabetic CKD, peripheral neuropathy (PN), and diabetic retinopathy. The results show that the entropy in patients, combining all complications, was significantly lower than the corresponding values for the control group. Odds ratios (OR) from entropy analysis also demonstrated a significantly higher association in patients with retinopathy and PN. Furthermore, the LF/HF ratio had a stronger connection with these diabetes-related complications, particularly in the group of patients who had all complications (OR: 4.92). The researchers suggest the type of microvascular or PN problem prevalent in T2DM persons affects HR entropy differently. In addition, attention is focused on implying that disorders of multi-organ connectivity are directly related to ANS dysfunction [42]. Barzilay et al. investigated whether measures of cardiovascular ANS function are linked with the incidence of diabetes and annual changes in FBG levels, as well as insulin sensitivity and secretion in older persons without diabetes. The mean annual unadjusted change in FBG was found to be 1 mg/dL. Higher detrended fluctuation analyses (DFA) values, averaged across 4–11 beats (DFA1), or 12–20 beats (DFA2), suggesting greater vs. less organization of beat-to-beat intervals, were related to reduced FBG increase with time. Higher SD of the N-N interval (SDNN) was related with decreased FBG rise with time in mutually adjusted analyses. Higher DFA1, DFA2, and SDNN levels were associated with increased insulin secretion and sensitivity but not with diabetes incidence. In individual and joint analyses, greater levels of specific cardiovascular autonomic factors linked with improved cardiovascular health are associated with a borderline decreased risk of diabetes incidents and significantly lower FBG level increases over time. These data support the concept that ANS function contributes to metabolic regulation [3].

7. Diabetic cardiac autonomic neuropathy and heart rate variability

Diabetic autonomic neuropathy, particularly CAN, is considered an important potential factor in circadian cardiovascular rhythms disruption [20, 53, 54]. The link between the symptoms of either greater sympathetic or decreased vagal activity and propensity for arrhythmogenesis has fueled efforts to establish quantitative autonomic activity markers [23, 55]. HRV is one of the most promising of these indicators [56]. The presence of CAN in diabetic patients is the strongest risk factor for early mortality and morbidity [20]. Landmark trials, such as the European Epidemiology and Prevention of Diabetes (EURODIAB) study, Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, and the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, have confirmed such an association. A cross-sectional investigation in T2DM conducted by Metelka et al. revealed severe autonomic dysfunction in the majority of patients studied, regardless of diabetes duration. It confirms the suggestion to test ANS integrity in T2DM patients at the time of diagnosis and during the early stages of the disease [57]. In this regard, the American Diabetes Association recommends screening for CAN in T2DM patients at the time of diagnosis [20].

A study conducted by Sethi et al. identified the prevalence of a very high proportion of CAN in T2DM, irrespective of the disease duration and glycemic control in asymptomatic patients. In addition, the obtained results indicate sympathetic and parasympathetic dysfunction, suggesting advanced CAN [58]. The results of the Verona newly diagnosed type 2 diabetes study showed that in 557 persons with newly onset T2DM, the prevalence of confirmed CAN was 1.8%, while the prevalence of early CAN was 15.3%. Therefore, it is likely that the pathophysiological disorders of metabolism are at an earlier stage, namely prediabetes [10].

Poor glycemic control in T1DM and a combination of HTN, obesity, DLP, and poor glycemic control in T2DM are established risk factors for CAN [20]. In patients with recent-onset diabetes, a lower vagus-mediated HRV has been shown to be associated with IR and reduced cardiorespiratory activity in both types of diabetes and hepatic steatosis [9] in T2DM. The obtained results indicate that these factors may contribute to the early development of CAN [59]. Kück et al. report that, unlike patients with new-onset T1DM, those with T2DM show early baroreflex dysfunction, likely due to IR and hyperglycemia [52]. Thus, dysglycemia is not the exclusive cause responsible for the initiation of CAN and its progression in T2DM. Obesity and its associated DLP, hyperinsulinemia, and HTN are additional risk factors for CAN in T2DM [44]. The Danish branch of the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION-Denmark) aimed to investigate the course of CAN and related cardiometabolic risk variables in T2DM patients. Risk factors related to CAN status, as determined by cardiovascular autonomic reflex tests (CARTs), were studied using multivariate logistic regression. The results of the study showed a progressive heterogeneous course of CAN. Risk factors for CAN include hyperglycemia, obesity, and hypertriglyceridemia. Furthermore, hyperglycemia and obesity had a negative impact on continuous CAN measurements, highlighting the importance of modifiable risk factors in the development of CAN [27].

There are no established reference values for HRV variables that can be used to diagnose CAN [6]. However, Breder and Sposito suggest that CAN can be diagnosed by obtaining abnormal results in at least two of the six parameters listed below: SDNN 50 ms, the root mean square of the sum of squared differences (RMSSD) between R-R intervals <15 ms, the proportion of NN50 divided by the total number of NN (R-R) intervals (PNN50) < 0.75%, LF < 300 ms², and HF < 300 ms² derived from 24-hour Holter ECG recording [54]. Nighttime HRV may be a more accurate technique for measuring CAN and, as a result, may enhance the prediction of CV events in low-risk T2DM patients [60]. The Copenhagen Holter study recruited 678 community-dwelling individuals aged 55–75 years with no history of CVD. Six hundred fifty-three participants had access to both day and nighttime HRV. The study involved 133 participants with newly diagnosed T2DM and well-controlled T2DM. CV events were defined as CV death, myocardial infarction, stroke, or coronary revascularization. In persons with T2DM, 24-hour HRV was related to all-cause mortality rather than CV events. To predict CV events in persons with T2DM, conventional risk variables exhibited a receiver operating characteristic (ROC) value of 0.704 (95% CI 0.602–0.806). The addition of nighttime SDNN enhanced the prediction of CV events by conventional risk variables in persons with T2DM. Consequently, decreased nighttime HRV predicts an increased risk of CV events in adults with well-controlled T2DM, suggesting that nighttime HRV may supplement established risk variables in predicting CV events in T2DM patients [60].

Reduced HRV is the first indicator of CAN, indicating reduced parasympathetic and sympathetic activity without clinical signs and symptoms [28]. T2DM decreases practically every HRV variable. A systematic review and meta-analysis of 25 studies on HRV in T2DM revealed an overall decrease in HRV in T2DM persons due to a loss in both sympathetic and parasympathetic nerve function [53]. Another systematic review found that continuous RR intervals ratio (SD1/SD2), SDANN, and HF had higher sensitivity and specificity in detecting autonomic dysfunction in diabetes patients, suggesting they might be better diagnostic markers [24]. Abnormal nonlinear HRV variables are associated with diabetes or increase the risk of developing T2DM [55]. Similarly, a review study found lower HRV variables in MeTs and T2DM, as measured by short-term and 24-hour ECG recordings [28].

Pop-Busui et al. evaluated whether HRV measurements obtained from normal ECG recordings accurately assess CAN. Participants in the diabetes control and complications trial/epidemiology of diabetes interventions and complications underwent standardized CARTs (R-R response to paced breathing, Valsalva, and postural shifts), as well as digitized 12-lead resting ECGs. It is established that participants with CARTs-defined CAN had significantly lower SDNN and RMSSD compared with those without CAN (P < 0.001). SDNN dominates in defining CAN, with an area under the curve of 0.73 indicating acceptable test performance. For the best cutoff point, the Kappa statistic for SDNN was 0.41 (95% confidence interval 0.30–0.51), indicating good agreement with CARTs-defined CAN. These are the first studies to show convergence between HRV indices derived from ECGs and the gold standard CARTs, suggesting that they could measure CAN in clinical studies and therapeutic care [61].

8. Possible pathogenic pathways binding CAN and atherosclerosis progression

The link between CAN and atherosclerosis is widely established [46]. The ANS controls heart rate and vascular tone, and its failure may lead to atherosclerosis and arterial stiffness in diabetics [62]. According to the SEARCH cardiovascular disease project, even young patients with T1DM may show evidence of early autonomic dysfunction. Similarly, in these participants, CAN and arterial stiffness were linked independently of other traditional CV risk variables. However, whether CAN is related to simultaneous asymptomatic PAD in patients with arterial stiffness is unknown. Nattero-Chávez et al. postulated that CAN was linked to both arterial stiffness as measured by an ankle-branchial index (ABI) greater than 1.2 and the presence of PAD [45].

Nattero-Chávez et al. investigated the relationship between CAN and arterial stiffness as indicated by an ABI ≥ 1.2 in T1DM patients while thoroughly screening for PAD with vascular sonography. The authors present evidence that peripheral artery compliance is associated with cardiovascular autonomic dysfunction in young adults with T1DM who maintain satisfactory glycemic control.

The results reported by the author additionally demonstrate that the prevalence of CAN is threefold higher in patients with arterial stiffness than in those with normal ABI values, with the highest incidence in the group of patients with both concomitant PAD and arterial stiffness; this connection maintained even after adjusting for the presence of PAD or other relevant CV risk factors.

Furthermore, peripheral arterial stiffness encourages the relationship between cardiovascular autonomic dysautonomia and atherosclerosis in a group of T1DM patients. Other evidence supports this bidirectional pathogenic pathway from cardiac autonomic dysfunction to arterial stiffness and atherosclerosis [45].

Autonomic neuropathy appears to be more than just a microvascular consequence, with various pathophysiological mechanisms involved in its development [46].

9. The interplay between arterial stiffness and cardiac autonomic neuropathy

Diabetes is associated with two types of autonomic dysfunction: intrinsic and extrinsic [31]. The first is caused by a direct insult to the autonomic nerves, whereas the second can be induced by cardiovascular dysfunction, such as aortic stiffness and dilated cardiomyopathy. Studies on the principal causes of cardiac autonomic dysfunction in T2DM have revealed that it is primarily intrinsic [14, 44].

Diabetes mellitus is characterized by chronic hyperglycemia and in T2DM by IR, that is, chronic hyperinsulinemia. Dysfunction of the endothelial system is one of the first vascular complications observed in diabetic patients. Endothelial dysfunction worsens faster in T2DM patients than in T1DM patients, most likely due to the toxic effect of hyperinsulinemia on the arterial wall.

Endothelial dysfunction causes increasing arterial stiffness over time [16, 51]. Endothelial function and arterial elasticity decline with age, and the effect is exacerbated when diabetes is present [50].

The bidirectional relationship between OS and low-grade inflammation is also responsible for the deterioration of arterial structure and function in aging diabetes arteries. The primary molecule, nuclear factor kappa-light-chain-enhancer of activated B cells, is indirectly impacted by chronic hyperglycemia via ROS [63]. This specific molecule enables a positive feedback relationship between aging and diabetes. Diabetes causes further damage to aged arteries by downregulating antioxidant and anti-inflammatory mechanisms.

OS and inflammation may be engaged differently in diabetes than in arterial aging, with IR activating them in diabetes and a defective genetic longevity pathway in arterial aging [50].

As a result, diabetes affects all of the aging mechanisms discussed above. It has been proposed that the effects of diabetes and aging (a) share the same mechanisms, and thus cause additional damage to the arterial wall or (b) that they act in concert to amplify the deterioration of arterial structure and function caused by aging, in addition to its deleterious mechanisms that directly affect the arterial wall. The second theory is more correct based on the available data [50].

As a result, in middle-aged or older persons, arterial aging acts as the primary arterial wall failure, and diabetes acts as the secondary arterial wall failure seeded in the aging milieu. In other words, basic cellular dysfunction is caused by aging and senescence, exacerbated by secondary damage induced by IR and hyperglycemia in diabetes, resulting in secondary cell dysfunction.

The scenario is reversed in younger patients. Diabetes causes primary cellular dysfunction, whereas aging causes secondary cellular dysfunction. Although it may appear arbitrary, these two circumstances most likely overlap extensively. Nonetheless, these assumptions enhance the likelihood of arterial wall failure related to aging in diabetic patients [50].

Youth with T2DM have accelerated vascular aging, making them vulnerable to cardiovascular problems in early adulthood. Jaiswal et al. investigated the link between increased arterial stiffness and decreased HRV in young people with T2DM. In the SEARCH study, which enrolled 193 youth with T2DM were assessed PWV (PWV carotid-femoral segment) and HRV parameters. It was found that the youth with increased arterial stiffness were older, had higher BP, BMI, and TG, and lower HDL-C. In linear regression analysis, increased PWV was associated with lower SDNN independent of age, gender, BP, and BMI. However, when TG was taken into account, the correlation was diminished and nonsignificant, implying that the interaction between arterial stiffness and HRV is partly mediated by DLP [64].

Univariate analysis of the results of a cross-sectional study of 26 patients with DM revealed a significant positive correlation between resting systolic BP (SBP) and Ewing’s score and an inverse correlation between the highest peak of volumes of O2 (VO2peak) and Ewing’s score. Multivariate linear regression found that a significant model incorporating resting SBP and VO2peak explained 93.8% of the variance in Ewing’s score. The author concluded that both factors were independent predictors of CAN in people with T2DM [62]. Thus, the current investigation demonstrated a moderate connection between high SBP and CAN, consistent with many prior studies. This link can be explained simply by the role of sympathetic activity dominance over parasympathetic activity in elevated BP.

The primary purpose of the ANS is to keep both arms of the ANS in balance. However, the equilibrium between the two arms is absent or decreased with CAN. This is indicated mainly by decreased parasympathetic activity and a dominating sympathetic impact over the heart and circulatory system, particularly the muscle tissue. Actually, sympathetic hyperactivity and higher sympathetic neural discharge are more prevalent in T2DM patients [65]. Moreover, in vitro investigations revealed that catecholamines (e.g., adrenalin and noradrenaline) promote vascular smooth muscle replication, which may lead to vascular wall hyperplasia and arterial stiffening [62].

Eleftheriadou et al.’s cross-sectional study’s major goal was to evaluate the association between PP amplification (PPA), HRV, and BRS in T2DM persons. Furthermore, the authors investigated the relationship between cardiac autonomic activity and central hemodynamic parameters influencing PPA such as aortic PWV, AIx, and common carotid artery stiffness distensibility coefficient. After correcting for age, duration of diabetes, height, waist circumference, aortic PWV, usage of β-blockers, and BRS-PPA was found to be substantially and independently linked with male gender, aortic SBP, HR, AIx, and HRV characteristics, such as total power of HRV.

No significant relationships were identified between HRV parameters or BRS and aortic PWV, AIx, or distensibility coefficient. Cardiovascular autonomic dysfunction was linked to increased PPA in T2DM patients. This connection was independent of the well-known influence of resting HR and standard CV risk or diabetes-related variables. Furthermore, it was not mediated by autonomic dysfunction’s effects on arterial stiffness or pressure wave reflections. These results imply cardiac autonomic dysfunction influences PPA via mechanisms other than resting tachycardia and arterial characteristics [41].

What are the possible processes that connect cardio-autonomic dysfunction, arterial stiffness, and atherosclerosis? Complex interactions control the physiologic equilibrium of peripheral vascular beds and heart autonomic innervation, including metabolic processes such as OS and inflammation, which are disrupted in diabetic patients. Although CAN can cause an inflammatory response, other mechanisms, such as BP dysregulation, might play a role in developing AS and atherosclerosis [46, 47, 51]. From the early stages of CAN, parasympathetic downregulation changes the physiologic decline in BP at nighttime (i.e., a so-called non-dipping pattern). In people with CAN, the relative sympathetic overload and exposure of the vascular bed to elevated BP values during sleep may, at least in theory, induce vascular damage, stiffening of the arteries, and atherosclerosis [45].

Alternatively, from the early stages of T1DM, autonomic dysfunction and a decrease in arterial elasticity may coexist [61]; however, their order of appearance and the potential involvement of causality in such an association are unsolved. Nattero-Chávez et al. indicated that the coexistence of arterial stiffness and PAD partly explained the association between CAN and arterial stiffness. The cross-sectional design, however, precludes any conclusions concerning causality [45].

In theory, arterial stiffness may lead to cardiovascular dysautonomia due to baroreceptor dysfunction; conversely, CAN may encourage arterial stiffness by increasing HR as an increase in HR results in arterial stiffening regardless of ANS activity changes [10]. Furthermore, cardiovascular dysautonomia may affect arterial wall elasticity by changing the vascular tone of large arteries [45].

CAN and arterial stiffness may develop in parallel due to aging in hyperglycemia rather than being directly connected. Hyperglycemia leads to atherosclerosis via various pathways, including endothelial dysfunction and hypercoagulability [48]. Chronic hyperglycemia enhances the accumulation of AGEs, which disrupt the adhesion capabilities of endothelial cells’ basement membranes and activate inflammatory cells in the arterial wall, favoring atherogenesis [48]. Similarly, AGEs cause collagen cross-linking within the vascular wall, losing collagen elasticity, and decreasing arterial and cardiac compliance [45].

10. Conclusion

CAN is one of the underdiagnosed microvascular complications of T2DM caused by hyperglycemia-induced neuronal damage [54]. The decline in HRV is seen even before manifesting signs and symptoms of diabetic CAN. As a result, there is strong evidence of decreased HRV in T2DM patients. HRV pattern analysis has the capacity to discover autonomic imbalance in the preclinical and asymptomatic stages. Both sympathetic and parasympathetic activity is reduced in T2DM persons, which can be explained by the negative effects of altered glucose metabolism on HRV [53, 54].

Arterial stiffness may be involved in developing several dysfunctions in the heart, brain, liver, kidney, and others. Arterial stiffness may contribute to cardiovascular dysautonomia by inducing baroreceptor dysfunction; conversely, CAN may favor arterial stiffness by increasing HR and impairing arterial wall elasticity. Both states may also develop in parallel due to aging in the presence of hyperglycemia.

The presence of CAN should be evaluated considerably earlier in the DM process, and reduced HRV is the earliest sign of CAN. Improvement of HRV may allow guiding the patients toward lifestyle changes and early management.

Given its promise as a noninvasive, reliable, and painless assessment, the benefits of an HRV evaluation in diagnosing and monitoring the severity of T2DM should be investigated further.

Conflict of interest

The authors declare no conflict of interest.