The connection between heart failure and diabetes has long puzzled researchers, but a recent study may shed light on this. The research team delved into data spanning 18 years and found compelling evidence linking diabetes to changes in heart function. However, the increased filling pressures in the heart did not lead to higher mortality rates among patients with diabetes. These findings challenge previous theories and call for further investigation into the mechanisms behind the poor outcomes of people with heart failure and diabetes.
Previous research has shown that people being treated for heart failure are much more likely to die if they also have diabetes, even after adjusting for other risk factors. This is a dramatic difference in outcomes without a clear explanation – a source of considerable frustration to doctors such as Finn Gustafsson, a cardiologist at Denmark’s largest hospital who treats patients with advanced heart failure.
For decades, Gustafsson explains, researchers have debated whether diabetes could somehow remodel or rewire the heart in a unique diabetic cardiomyopathy. “There are several mechanisms by which diabetes can induce a failing heart in animal models,” he says. “But it has been much more difficult to establish this cause–effect relationship among humans.”
To prove the connection, Gustafsson and his team at Rigshospitalet would have to dig deep inside the human heart – literally.
Inside the motor
The researchers combed through 18 years of data to find nearly 600 people with heart failure who had undergone right heart catheterisation at Rigshospitalet.
“The catheterisation of the right side of the heart was developed by Werner Forssmann more than a century ago,” Gustafsson says. “He was a German radiologist who claimed that he could catheterise the right heart, and his colleagues did not believe him. So he took a Foley catheter – a urinary bladder catheter – inserted it in his own arm, ran it to the heart and took a chest X-ray.” Now this is a standard screening for people with heart failure to determine their eligibility for transplantation or a mechanical heart.
In modern right heart catheterisation, a much smaller, thinner tube than a Foley catheter (patients will be relieved to hear) is inserted through either the jugular vein in the neck or the femoral artery near the groin and guided directly into the right chamber of the heart and the pulmonary artery. A tiny balloon at the tip of the catheter enables doctors to measure changes in pressure and blood flow.
Gustafsson and his team were interested in three key metrics to “really know exactly how the motor is functioning”: wedge pressure, a measurement of pressure in the left atrium; central venous pressure, which is how the right heart fills and also serves as a measure of how much extra liquid is being carried in the body; and the cardiac index, or “how much blood the heart injects indexed to the body surface area,” he says. “Really big people need a larger resting cardiac output, and small people, less so.”
The researchers also used information from follow-up care to track outcomes – whether death, a heart transplant, the installation of a device to help the heart pump blood or a fully artificial heart.
There but not to blame
By comparing these three key metrics among patients with heart failure with and without diabetes, the researchers found compelling evidence that diabetes is associated with changes in heart function, Gustafsson says.
“The filling pressures differ, and this could be part of diabetic cardiomyopathy,” he explains. But patients without diabetes who happened to have similar filling pressures did not share the bleak mortality rates. In other words, “It was not the increased pressures in the heart that eventually killed the patient.”
If these results are confirmed in studies with larger sample sizes, researchers may have to look elsewhere to explain why people with diabetes fare so poorly in heart failure.
Of the people included in the study, “patients with diabetes had almost three times as high mortality as people without diabetes,” Gustafsson says. “This was still the case when we adjusted for wedge pressure, cardiac index and central venous pressure.” Although the filling pressures are not the smoking gun they hoped to find, “I think this should inspire us and other researchers to look for mechanisms in diabetes,” he says.
What does surviving a failing heart mean?
Gustafsson says a real challenge in studying this population is deciding how the various outcomes should be compared – how do you account for radical differences in treatment? “Some patients were transplanted, some got a mechanical heart and some were denied transplantation and died,” he explains. Does it really make sense to say that a person who died on the waiting list for a donated heart fared worse than a person who survived because of a match?
Another wrinkle is that people in heart failure may also be diagnosed with diabetes solely because of the heart failure itself. Doctors track levels of HbA1c – a form of haemoglobin attached to glucose – over time to measure blood sugar and eventually diagnose diabetes.
“Many of these patients have progressive circulatory failure, leading to poor muscle perfusion, which then leads to impaired glucose tolerance,” Gustafsson says. “Sometimes patients develop elevated HbA1c very close to the time when they are referred to us for advanced evaluation, simply because their muscle perfusion is poor.” These high HbA1c readings could just reflect how advanced the heart failure is. To tease that out, researchers will need additional information on when these patients were diagnosed with diabetes. The closer the diagnosis is to the onset of heart failure, the more likely it is to be connected.
For the moment, Gustafsson’s group is looking inside heart tissue for alternative explanations for the high morbidity rate. “We are now examining heart biopsies and the proteins they produce among patients with diabetes to understand how this compares with other patients with heart failure.”
The team also hopes to study people in earlier stages of heart failure to “see whether we can find similar or even different signals that would point in the direction of what early mechanisms might be involved in this,” he says. It is vital to “understand whether there could be potential targets for treatment in this group, which has their mortality tripled,” Gustafsson adds.