SACRAMENTO — UC Davis researchers have identified for the first time a biological pathway activated when blood sugar levels are abnormally high and causes irregular heartbeats.
That condition — cardiac arrhythmia — is linked with heart failure and sudden cardiac death.
Reported online earlier this month in the journal Nature, the discovery helps explain why diabetes is a significant independent risk factor for heart disease.
“The novel molecular understanding we have uncovered paves the way for new therapeutic strategies that protect the heart health of patients with diabetes,” said Donald Bers, chair of the UCD department of pharmacology and senior author of the study.
While heart disease is common in the general population, the risk is up to four times greater for diabetics, according to the National Institutes of Health. The American Heart Association estimates that at least 65 percent of people with diabetes die from heart disease or stroke.
Through a series of experiments, the UCD team and its collaborators at the Johns Hopkins University School of Medicine showed that the moderate to high blood glucose levels characteristic of diabetes caused a sugar molecule in heart muscle cells to fuse to a specific site on a protein known as CaMKII.
CaMKII has important roles in regulating normal calcium levels, electrical activity and pumping action of the heart, according to Bers.
Its fusion with the sugar molecule, however, led to chronic overactivation of CaMKII and pathological changes in the finely tuned calcium signaling system it controls — triggering full-blown arrhythmias in just a few minutes.
The arrhythmias were prevented by inhibiting CaMKII or its union the sugar molecule.
The research encompassed detailed molecular experiments in rat and human proteins and tissues, calcium imaging in isolated rat heart muscle cells exposed to high glucose and assessing whole heart arrhythmias with optical mapping in isolated hearts and in live diabetic rats.
This allowed Bers and his team to identify the specific site of sugar attachment to CaMKII, along with how that attachment activated CaMKII and caused calcium-dependent arrhythmias.
In an additional experiment, the team found elevated levels of CaMKII modified by the sugar molecule in both hearts and brains of deceased humans who were diagnosed with diabetes. The highest levels were found in the hearts of patients who had both heart failure and diabetes.
Other UCD researchers on the study included lead author Jeffrey Erickson (now with the University of Otago in New Zealand), Laetitia Pereira, Lianguo Wang, Amanda Ferguson, Khanha Dao, Florin Despa (now with the University of Kentucky) and Crystal Ripplinger.
— UC Davis Health News Office