Transplanted Hearts Quickly Show Signs of Disease in Diabetes

Debra L Beck

March 23, 2020

A new study of heart transplant patients provides important mechanistic insights into the early pathogenesis of heart failure in diabetic patients.

"The question we asked is what changes occur in a healthy heart when it's placed in a diabetic patient," said Raffaele Marfella, MD, PhD, University of Campania, Naples, Italy, told theheart.org | Medscape Cardiology.

What Marfella and colleagues saw was that transplant recipients with diabetes, all of whom received hearts from nondiabetic donors, showed on serial endomyocardial biopsy (EBM) "relatively rapid progression of early signs of diabetic heart linked to lipid accumulation in cardiac cells that, ultimately, progressed to heart dysfunction." The same was not seen in heart recipients without diabetes (P = .019).

At 5- to 12-week follow-up, the EMBs in 11 diabetic recipients (28.6%), but not in nondiabetic heart recipients, showed cardiomyocyte lipid accumulation. Interestingly, only two diabetic recipients (5.7%) taking metformin showed signs of fat accumulation in the heart (= .0019).

The accumulation of myocardial lipid triglycerides in patients with diabetes was associated with cardiac dysfunction, independent of other risk factors, including body mass index, heart rate, and blood pressure.

"The opportunity to study serial cardiac biopsies demonstrated, in our experimental conditions, the relative rapid progression of early pathogenic events of [diabetic cardiomyopathy] linked to cardiac lipid accumulation," Marfella and colleagues write.

The Italian group published their findings in the March 24 issue of the Journal of the American College of Cardiology.

The DMCM-AHEAD study evaluated 158 first heart transplant recipients, 76 (48%) of whom had diabetes. Of those with diabetes, 35 (46%) were receiving metformin.

All transplanted patients undergo regular EMBs for about a year after transplant, affording the researchers the opportunity to use these tissues to see the effects of diabetes on "nondiabetic" hearts.

"The study Marfella and colleagues did was both elegant and really ingenious because you have to routinely get endomyocardial biopsies from these patients anyway, and it's a perfect opportunity to take a look at what's going on in these transplanted hearts," said Charles M. Alexander, MD, in an interview. Alexander, an endocrinologist in Gwenedd Valle, Pennsylvania, authored an editorial that accompanied the Marfella study.

Metformin Preventative?

Because metformin reduces ectopic fat accumulation in patients with diabetes, the investigators subcategorized the heart transplant recipients with diabetes according to metformin use. Those in the no-metformin group had never used the drug, and those in the metformin group with diabetes mellitus had used the drug for at least 6 months before transplantation.

Lipid accumulation was reduced in patients treated with metformin compared with those with diabetes not treated with metformin.

This may call for a re-evaluation of the use of metformin in these patients, because current guidelines do not encourage metformin use in diabetes or in diabetes with heart failure, said Alexander.

"Part of the reason that some patients aren't on metformin is the concern about lactic acidosis, especially in patients who have a reduced glomerular filtration rate. The other part of the problem is that these patients tend to have so many medical problems that they're on a boatload of medicines to begin with and if the doctors aren't seeing an elevated blood glucose, it may not be top of mind to use metformin or SGLT2 inhibitors, since we still think of these medicines as glucose-lowering medicines," said Alexander.

Of course, the metformin findings are from a nonrandomized subgroup and should be accepted with caution, he added.

Alexander would like to see another study that looks at combined and separate use of metformin and SGLT-2 inhibitors, which have in DAPA-HF and other studies been found to reduce the risk for cardiovascular death or hospitalization for heart failure.

Marfella said he is also intrigued by the possibility that the use of both metformin and SGLT-2 inhibitors could be an appropriate therapy to prevent the effects of diabetes on the heart.

Going one step further, however, he'd also like to see the model employed in this study used to study the effects of other chronic heart diseases — like hypertension and dyslipidemia — on the human heart. And even that might be just the beginning.

"Moreover, this model affords us the possibility, for the first time in humans, to evaluate the effects of drugs on heart cells. Practically, today we do not know what happens at a molecular level in human heart cells when we take aspirin or statins, for example. Everything we know comes from studies conducted on animals, but with this model we can evaluate this in humans," said Marfella.

Marfella and Alexander reported no relationships relevant to the contents of this paper to disclose.

J Am Coll Cardiol. 2020;75:1249-1262. Full text, Editorial

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