A roadmap to screen, diagnose and treat diabetes: Author's Addendum.

Background

The aim of the reviewed guidelines on screening, diagnosis and treatment of diabetes is to provide clinicians with a comprehensive means to approach patients with suspected or diagnosed diabetes in daily clinical settings: Guidelines tell us what we should or could do in different clinical settings.
We seek to achieve an individual approach to each individual patient based on clinical experience and knowledge of the latest recommendations to offer the best possible care. This addendum gives information regarding additional clinically useful recommended methods for a patient's cardiovascular risk assessment.

I - Heart rate variability 

In patients with diabetes and cardiovascular disease, heart rate variability (HRV) provides a powerful means of observing the interplay between the sympathetic and parasympathetic autonomic nervous systems (ANS).
The ANS plays an important role, both in physiological situations and in various pathological conditions such as diabetic neuropathy, myocardial infarction (MI) and congestive heart failure. Heart rate variability has a high association with the risk for sudden cardiac death, and arrhythmic complications. The characterisation of HRV in a large number of diseases, suggests that this parameter can be a possible marker of homeostasis loss. The cost-effectiveness in the application of the technique and ease of data acquisition makes HRV an option for the evaluation of ANS and a promising clinical tool to assess and identify impairments on health in many clinical scenarios.

Indexes

For HRV analysis, indexes obtained by linear methods, time and frequency domain and HRV with deep breathing and nonlinear methods can be used. The records for analysis of HRV indexes by linear methods can be obtained for short periods (2, 5, 15 minutes) or long periods (24 hours) - which is what is more common in clinical practice. Nonlinear behavior is predominant in human systems, because of its dynamic nature complex, which cannot be described adequately by linear methods. The obtained data from time and frequency techniques are currently used as a noninvasive marker of the activity of the autonomic nervous system. There are commercially available noninvasive, fully automated computer-based systems that provide HRV and Pulse Wave Velocity (PWV) analysis for a quantitative assessment of the ANS and autonomic balance (sympathetic and parasympathetic). New methods for estimation and quantification of HRV are also available, performed by extensive research and analyses by Conti and co-workers (1,2). The guidelines evaluating the clinical usefulness and comparison of various studies of HRV have been established by the Task force of ESC and NPSE (2). For detailed information’s on HRV measurement and applications please refer to references below (1-4).

Clinical applications

A reduced HRV has been identified as a strong indicator of risk related to adverse events in both healthy individuals and patients with a large number of diseases, which intimates to the vital role that ANS plays in maintaining health. Heart rate variability indexes have been used to better understand diseases such as coronary artery disease, cardiomyopathy, arterial hypertension, myocardial infarction, sudden death, chronic obstructive pulmonary disease, renal failure, heart failure, diabetes, and various neurological disease as well (5). Clinicians caring for patients with ischemic heart disease, especially following acute events are always interested in predicting risk of developing major and life-threatening complications. Risk models should include clinical, imaging, and biomarkers data of prognostic value. Indeed, understanding biological behavior signals might represent a fundamental step toward better care. The main advantage of signals such as HRV indexes is that they can be calculated in real time and in a noninvasive manner.
In hypertension, acute myocardial infarction, coronary artery disease, diabetes and atherosclerosis, HRV indexes are reduced. Increase in parasympathetic modulation induces an electrical stability of the heart, while the high sympathetic activity increases the vulnerability of the heart and the risk of cardiovascular events. There is a large body of evidence linking altered HRV with mortality, particularly in deaths due to arrhythmia. Numerous studies have demonstrated a link between HRV and poor prognosis after myocardial infarction. Data reported from the Framingham Heart Study found that in this large community-based study population, decreased HRV correlated significantly with increased risk of major cardiac events at a mean follow-up of 2.5 years, even after adjusting for other known cardiovascular risk factors. The prognostic value of HRV for sudden cardiac death may be improved by combining HRV measure with other parameters, such as heart rate turbulence and neurohormonal activation (5,6).

Assessment of Diabetic Neuropathy

Cardiac autonomic impairment appears to be present at early stages of diabetic metabolic impairment, and it is a frequent cause of morbidity and mortality among diabetic individuals. Its clinical manifestations include functional impairment such as postural hypotension, persistent tachycardia, gustatory sweating, gastroparesis, bladder atony, and nocturnal diarrhea. Once clinical manifestations of diabetic autonomic neuropathy (DAN) are manifested the estimated 5-year mortality is approximately 50%. Thus, early subclinical detection of autonomic dysfunction is important for risk stratification and subsequent management (6). Analyses of short-term and/or long-term HRV have been proven useful in detecting DAN. In diabetic patients without evidence of autonomic neuropathy, reduction of the absolute power of LF and HF during controlled conditions was also reported. However, when the LF/HF ratio was considered or when LF and HF were analysed in normalised units, no significant difference in comparison to normal subjects was present. Thus, the initial manifestation of this neuropathy is likely to involve both efferent limbs of the autonomic nervous system. Insulin Resistance Atherosclerosis Study found a direct association between heart rate and fasting insulin. (7-9) Combined abnormalities of autonomic reflex function and autonomic tonic activity identifies diabetic post infarction patients with very poor prognoses. In diabetic post-MI patients, severe autonomic failure (SAF) was strongly associated with 5-year mortality and can be affected by sequelae of diabetes, by sequelae of MI, or by a combination of both (10). Patients with SAF should receive intensive cardiac therapy based on a multifactorial approach including tight ambulatory monitoring, regular screening for progression of coronary artery disease, optimum medical therapy of heart failure, and finally prophylactic implantation of a cardioverter defibrillator.
For the patient presenting with a real or suspected DAN, there are three HRV methods which can be used: 1) simple bedside RR interval methods, 2) long-term time domain measures that are more sensitive and more reproducible than the short-term tests, and 3) frequency domain analysis performed under short-term steady state conditions, which is useful in separating sympathetic from parasympathetic abnormalities. The following abnormalities in frequency HRV analysis are associated with DAN: 1) reduced power in all spectral bands, which is the most common finding; 2) failure to increase LF on standing, which is a reflection of impaired sympathetic response or depressed baroreceptor sensitivity, 3) abnormally reduced total power with unchanged LF/HF ratio, and 4) a leftward shift in the LF central frequency, the physiological meaning of which needs further elucidation.
Combined abnormalities of autonomic reflex function and autonomic tonic activity identifies diabetic post infarction patients with very poor prognoses. In diabetic post-MI patients, severe autonomic failure (SAF) was strongly associated with 5-year mortality and can be affected by sequelae of diabetes, by sequelae of MI, or by a combination of both (10). Patients with SAF should receive intensive cardiac therapy based on a multifactorial approach including tight ambulatory monitoring, regular screening for progression of coronary artery disease, optimum medical therapy of heart failure, and finally prophylactic implantation of a cardioverter defibrillator.

HRV-indexes future studies should be aimed at evaluating how HRV is affected by known cardiovascular risk factors and to find a standard of measurement of different indexes, comparing healthy and disease states and investigating the risk of major cardiovascular events.

II - Aortic Pulse Wave Velocity 

Aortic stiffness, and specifically aortic pulse wave velocity (aPWV), has been increasingly recognised as a valuable biomarker for CV risk prediction. Indeed, aPWV has strong pathophysiological links with the pathogenesis of arteriosclerosis, atherosclerosis, cardiac function and coronary blood flow. aPWV integrates and reflects the long-term effect of the established, and new risk factors on the arterial wall, together with the genetic predisposition of the patients. It can be measured with reliable and reproducible non-invasive techniques, and importantly, normal values validated in large populations are now available (11,12).
Arterial stiffness increases with age and hypertension and is also enhanced in subjects with diabetes mellitus, atherosclerosis, peripheral vascular disease, cerebrovascular disease, abdominal aorta aneurysm and end-stage renal disease (13). High SBP and pulse pressure, low DBP, and increased pulse wave velocity (PWV) which are related to the increased aortic stiffness are independent markers of increased cardiovascular morbidity and mortality in the general population. PWV is a strong predictor of cardiovascular risks as determined by the Framingham equations. Furthermore, the presence of a PWV >13 m/s (a marker of arterial stiffness), taken alone, appeared as a strong predictor of cardiovascular mortality with high performance values (14).

Method

Arterial stiffness is determined via two systems: pulse wave velocity (PWV) (time from arrival of the pulse wave to the carotid artery and femoral artery) and applanation radial tonometric pulse wave analysis for calculating aortic pressure, as well as the relationships between the latter and the peripheral pressure values. PWV is measured by placing pressure sensitive transducers over different arteries (e.g., the right carotid and femoral arteries for carotid-femoral PWV). Dividing the distance separating the sensors by the time corresponding to the transmission time of the pulse wave (defined by the start of the rising phase of the pulse wave) from one site to the other determines the PWV (15). The consensus document of the Artery Society; European Society of Hypertension Working Group on Vascular Structure and Function; and the European Network for Noninvasive Investigation of Large Arteries, advises on the measurement procedures and provides arguments for the use of 80% of the direct carotid-femoral distance as the most accurate distance estimate. It also advises the use of 10 m/s as new cut-off value for carotid-femoral pulse wave velocity (16). It is a non-invasive, inexpensive, rapid measurement of arterial stiffness, now considered the gold standard for arterial stiffness assessment in daily practice.
Situations in which measurement of aortic PWV should not be performedare: arrhythmia, unstable clinical situation, high-grade stenosis of carotid artery and carotid sinus syndrome. Inaccuracy for an individual measurement can be introduced by central obesity or large breast size increasing the distance measured over the body surface. The use of calipers or infantometers for measurement in this situation has been recommended.

III - Asymptomatic organ damage and risk stratification

The latest European guidelines on management of hypertension points to the crucial role of asymptomatic organ damage (OD) evaluation to determine CV risk of individuals with and without hypertension. The observation that any of four markers of OD (microalbuminuria, increased PWV, left ventricular hypertrophy and carotid plaques) can predict CV mortality independently of SCORE stratification is a relevant argument in favor of using assessment of OD in daily clinical practice (12). The latest systematic review of the data from 16 studies with 17,635 participants aimed to determine whether aPWV improves prediction of cardiovascular disease (CVD) events beyond conventional risk factors concluded that aPWV reclassifies risk in models that include standard risk factors. This parameter may enable better identification of high-risk populations that might benefit from more aggressive CVD risk factor management (17).

Patient management

Based on the impact of an elevated PWV on CV prognosis, it is expected that reducing PWV, would significantly decrease CV events and mortality. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers are currently the drugs of choice for reduction of PWV in clinical practice despite little improvement in arterial compliance with short-term treatment (18). Administration of lipid-lowering agents and a type of oral hypoglycemic agent had a significant effect in reducing PWV in normolipidemic and normotensive individuals. Importantly, although PWV improves with hypertension treatment, the medication impact on PWV is apparently independent of blood pressure reduction (19).
Arterial stiffness is great and simple tool for improved risk stratification and optimal treatment of diabetic patients with cardiorenal disease.

Conclusions

Arterial stiffness is a great simple tool for improved risk stratification and optimal treatment of diabetic patients with cardiorenal disease.
Aortic stiffness measurement, which is a simple and safe noninvasive method, should be used for cardiovascular risk assessment of type 2 diabetic patients with high cardiovascular risk. Carotid-femoral PWV provides cardiovascular risk prediction independent of standard risk factors, glycaemic control, and ambulatory BPs in high-risk type 2 diabetes. Patients with increased aortic stiffness should have tight control of all cardiovascular risk factors as long as possible. 
Heart rate variability is a useful additional method for risk stratification of sudden cardiac death and arrhythmic complications in the diabetic patient.