September 1, 2022 | Impaired heart metabolism, signaled by low adenosine triphosphate (ATP) levels detected by an MRI test, may be able to predict future sudden cardiac death, according to T. Jake Samuel, Ph.D., fellow in cardiology at John Hopkins Medicine. If so, the measurement would help answer the million-dollar question of who needs an implantable cardioverter defibrillator (ICD) to monitor and treat life-threatening electrical problems with the heart.
Currently, patients are judged to be at risk for heart arrhythmias and thus candidates for an ICD based on having a low ejection fraction, an indication that their heart is not effectively pumping out blood. As demonstrated in the early 2000s, ICDs improve survival rates in a sizable population of patients with reduced left ventricular function and are unquestionably of clinical value, says Samuel.
The other reality, however, is that the devices implanted based on low ejection fraction alone often never discharge to save a life and sometimes fire inappropriately, he adds. The battery life of an ICD is typically no longer than seven years, by which time only 30% to 40% of these devices deliver an appropriate electric shock to restore a regular heart rhythm.
ATP concentration may be a useful barometer of ICD need, as suggested by a study that published recently in JCI Insight (DOI: 10.1172/jci.insight.157557) where Samuel was the first author. People with low cardiac ATP levels were found to have a three-fold higher risk of sudden cardiac death compared to those with normal ATP metabolism—and this was still the case when adjusted for low left ventricular ejection fraction.
An ICD was never needed in roughly 80% of those with normal ATP levels over the 10-year study period, Samuel notes.
ICD implantation is a costly procedure (typically well over $30,000) and comes with a roughly 4% per year complication rate, he says. “And we’re showing that over a 10-year follow-up those individuals with normal cardiac ATP levels have a low risk of developing an arhythmic event, so a lot of these individuals may never gain any benefit from having the [device].”
One day, perhaps fewer such people will have the device implanted in the first place and be spared the expense, inconvenience, and potential complications of the procedure, he says. “We think this could be a good screening tool in the future for deciding who gets and who doesn’t get an ICD.”
Patients in the study received follow-up visits every three to six months over a decade to determine if they had appropriate ICD firings for life-threatening arrhythmias, giving the researchers confidence in the results, says Samuel. Still, only 46 patients were enrolled so the findings need to be confirmed in a larger, ideally multicenter clinical trial, he adds.
The study suggests the potential of drugs that improve heart metabolism may be useful in the prevention of sudden cardiac death, Samuel says. Emerging evidence indicates that metabolic modulators such as SGLT2 inhibitors, prescribed for type 2 diabetes, reduce arrhythmias in animal models (Cardiovascular Diabetology, DOI: 10.1186/s12933-021-01392-6) and sudden cardiac death risk in patients with reduced ejection fraction (Heart Rhythm, DOI: 10.1016/j.hrthm.2021.03.028).
According to the American Heart Association, sudden cardiac death accounts for 50% of all cardiovascular deaths in the United States, claiming more than 300,000 lives annually.
Patients in the trial agreed to undergo an MRI test to measure their ATP concentration before a clinically indicated ICD implantation. The phosphorus magnetic resonance spectroscopy (MRS) technique was first developed in the 1990s at Johns Hopkins Medicine by Paul Bottomley, Ph.D., one of the study co-authors, Samuel says.
The technique uses a specialized coil that tunes to phosphorus, producing signals from metabolites in the area being imaged—in this case, the heart. From a metabolic standpoint, ATP is the energy molecule for living cells and includes three phosphate molecules, he explains.
In the study, researchers used the MRS method to measure both the concentration of ATP and other key metabolites such as phosphocreatine in the heart and the flux between them, which is driven by the creatine kinase enzyme, says Samuel. “But when we ran our analysis, the concentration of ATP came out as a predictor, not phosphocreatine and not the flux between those two metabolites.”
The MRS technique has become increasingly available at Johns Hopkins and elsewhere, which is not to say it is simple to do, Samuel says. “If you have a phosphorus coil, technically anybody can do this.” Adoptees include research teams across the world.
Among the challenges is that ATP concentrations are much lower than those of water or fat detected with a regular MRI hydrogen coil and the phosphorus coils have limited depths of penetration in the body, Samuel continues. Analysis and processing are also a bit cumbersome, although Hopkins researchers plan to develop the technique to have greater “click-and-play” functionality in the clinic.
The only other noninvasive option for measuring heart metabolism is a PET scan, which involves either a contrast agent or consumption of a radiotracer that come with a risk of ionizing radiation, he says. “You could [also] biopsy the tissue and then do an analysis but that is highly invasive and a very last resort.”
Among new MRI techniques on the horizon are chemical exchange saturation transfer (CEST) imaging, which measures creatine and phosphocreatine levels in the heart, says Samuel. It capitalizes on the magnetic exchange between these molecules and a water signal, providing a new contrast mechanism for studying molecular processes and properties such as metabolite concentrations.