Heart rate variability and dysglycemia: natural history and intervention

The promise and unknowns of HRV measurements.

Increased risk of heart disease
People with impaired glucose metabolism and diabetes have an increased risk of cardiovascular disease.

Heart rate variability (HRV) is a non-invasive, easily obtainable and sensitive marker of cardiac autonomic function, shown to predict cardiovascular and all-cause mortality. HRV is affected in diabetic cardiac autonomic neuropathy (CAN), a common diabetic complication.

The use of HRV measurements holds great potential in cardiovascular risk assessment, treatment monitoring and early assessment of cardiac autonomic neuropathy, but current knowledge about the natural development of HRV indices and how adverse changes in these indices can be avoided or attenuated is sporadic.

HRV unknowns
Little is known about the development of adverse HRV changes over time in individuals with normal glucose status, pre-diabetes and diabetes.

It is also unclear whether lifestyle intervention can improve HRV indices in individuals with pre-diabetes and how changes in glycaemic state affect HRV indices in individuals with newly diagnosed diabetes.

The metabolite Methylglyoxal (MG) has been suggested to play an important role in the formation of advanced glycation end products (AGEs) and could thereby act as a strong mediator of diabetic complication. MG has been demonstrated to be a causative factor in painful diabetic peripheral neuropathy, and could therefore be an important factor in the development other diabetic neuropathies such as CAN. 

Design and method
We base our thesis on the hypotheses that:
- changes in HRV outcomes over time are associated with changes in glucose metabolism in non-diabetic, pre-diabetic and diabetic individuals,
- lifestyle intervention in pre-diabetics and multifactorial intervention in newly diagnosed individuals can affect HRV indices, and
- MG could be involved in the pathogenesis of diabetic neuropathy.

Thus, this thesis has four aims

  • examine the natural development of HRV indices in non-diabetic, pre-diabetic and diabetic individuals over 10 years and evaluate if a changing glycaemic state has a modifying effect on HRV development,
  • investigate how changes in HbA1c over a six-year follow-up period of an multifactorial intervention trail affect HRV indices in newly diagnosed type II diabetes patients
  • investigate whether increased accumulation of MG and MG-derived AGEs are associated with decreased HRV indices and CAN in patients with newly diagnosed type II diabetes participating in a multifactorial intervention trail
  • investigate if lifestyle intervention can improve HRV in pre-diabetic individuals.

Target group
The research project includes healthy individuals, people with pre-diabetes and patients with type 2 diabetes.

Expected outcome
The project will generate new knowledge about changes in HRV in people with dysglycemia and will demonstrate whether adverse changes in HRV indices can be limited by changes in lifestyle or glucose metabolism in people with pre-diabetes and diabetes, respectively. We will expose the potential link between MG and CAN.

The long-term aim of this project is to generate results that can contribute to more accurate understanding of the natural history of heart rate variability, which is crucial for the ability to distinguish between natural and detrimental HRV measures.

Additionally we seek to demonstrate how HRV indices can be improved. In turn, this could prove to contribute to a reduction in cardiovascular risk and the development of CAN.

MG could prove to be a tool for risk stratification in the development of CAN, or even a target for novel pharmaceutical intervention.

Planned publications
Fall 2013:  “Natural history of heart rate variability in individuals with impaired glucose metabolism and diabetes”

Vinter 2014 “The effect of lowering HbA1c on heart rate variability in individuals with newly diagnosed type 2 diabetes.”

Spring 2014 “The association between levels of methylglyoxal and the development of diabetic cardiovascular autonomic neuropathy.”

Spring 2015 “The effect of a multifactorial lifestyle intervention on heart rate variability in people with impaired glucose metabolism.”


Funding
The project is partially funded by the Danish Ministry of Science, Innovation and Higher Education.

Collaborators
Jan Skov Jensen MD, PhD, DMSc, professor at the Institute of Surgery and Internal Medicine, at the Faculty of Health and Medical Sciences, Copenhagen University. Jan has extensive experience in clinical cardiovascular and epidemiological research and has published over 125 articles in peer-reviewed scientific journals.

Jesper Fleischer, M.Sc.BME., PhD, Jesper has published several articles in peer-reviewed scientific journals regarding HRV and has developed the Vagustm device.
 

Inspirational articles
Vinik AI, Ziegler D. Diabetic cardiovascular autonomic neuropathy. Circulation 2007 January 23;115(3):387-97.

Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, Pop-Busui R et al. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev 2011 June 22.

Diakakis GF, Parthenakis FI, Mavrakis HE, Patrianakos AP, Zacharis EA, Nyktari EG, et al. Association of impaired glucose tolerance with increased heart rate and subclinical inflammation. Hellenic J Cardiol 2005;46(6):394-401.

Thornalley PJ. Pharmacology of methylglyoxal: formation, modification of proteins and nucleic acids, and enzymatic detoxification--a role in pathogenesis and antiproliferative chemotherapy. Gen Pharmacol 1996 June;27(4):565-73.

Desai K, Wu L. Methylglyoxal and advanced glycation end products: new therapeutic horizons? Recent Pat Cardiovasc Drug Discov 2007 June;2(2):89-99.

Article in Dagens Medicin 2011 (only in Danish)

Sidst opdateret 24-07-2015

Christian Stevns Hansen
PhD-student
Clinical Epidemiology Research