Molecular imaging is beginning to give cardiologists insight into biological processes behind heart failure, knowledge that may allow them to monitor disease progression and tailor therapies. But market realities still pose barriers.
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are among the most widely prescribed drugs in the U.S. In 2011, physicians wrote 164.8 million prescriptions for ACE inhibitors and 83.5 million for ARBs as treatments for hypertension, according to IMS Health.
But response to these drugs may be highly variable, with race, ethnicity, sex, age, comorbidities and other factors possibly contributing to differences. Who really benefits from these therapies? Molecular imaging, which allows physicians to peek into biological processes at the cellular and subcellular level, may provide some answers.
“This is a pivotal point in clinical molecular imaging,” says Eric A. Osborn, MD, PhD, of the Cardiovascular Research Center at Massachusetts General Hospital in Boston and co-author of a series of reviews of molecular imaging and cardiovascular disease. In their most recent state-of-the-art article, he and Farouk A. Jaffer, MD, PhD, detailed how novel imaging modalities contribute to drug development, monitoring of disease progression and tailored therapies (J Am Cardiol Imag 2013;6:1327-1341). Jaffer is also affiliated with the Cardiovascular Research Center. “We’ve seen the high trajectory that molecular imaging is taking. It is something clinicians need to pay attention to because it is coming to them in the near term.”
Homing in on heart failure
Early activation of the renin-angiotensin system and angiotensin II have been implicated in the development of interstitial fibrosis, cardiac remodeling and heart failure. The 2013 American College of Cardiology/American Heart Association guidelines recommend initiating ACE inhibitor treatment at a low dose in patients with current or prior heart failure symptoms and gradually increasing dosage if the drug is well tolerated to reduce mortality and morbidity risk. ARBs offer an alternative in patients who are ACE-inhibitor intolerant.
One of the beauties of molecular imaging is its ability to noninvasively study targets such as ACE activity and cardiomyocytes in living subjects, which potentially could be used to understand disease progression and guide treatment. Building on previous research based on explanted human hearts of transplant patients, Vasken Dilsizian, MD, of the diagnostic radiology and nuclear medicine department at the University of Maryland School of Medicine in Baltimore, and colleagues developed a strategy to track myocellular ACE up-regulation using hybrid micro SPECT-CT (J Am Cardiol Imag 2012;5:409-418). Their goals were to apply findings from this animal study to support imaging studies using SPECT in people with heart failure.
“Is it possible the enzyme activity itself can be modified and change with time? We can only answer with imaging,” Dilsizian says. “Otherwise we can only say the patient is less resistant or more resistant of the disease progressing.”
The researchers used technetium-99m-labeled lisinopril (Tc-Lis), which localizes in the lung and other tissues that express ACE, injected into 21 ACE-1 overexpressing transgenic rats and 18 wild-type control rats. They obtained images in vivo with a dual-head micro-SPECT gamma camera in combination with micro-CT (X-SPECT, Gamma Medica) at 10, 30, 60 and 120 minutes after the radiolabel was administered. Nine transgenic rats and eight control rates were pretreated with cold lisinopril. The rats’ hearts were explanted and imaged.
Control rats showed tracer uptake at 60 minutes after administration in the lungs but not the myocardium and transgenic rats had substantial uptake in the myocardium. Pretreatment with lisinopril substantially reduced uptake in transgenic rats, proof of its targeting specificity. ACE-1 enzyme activity was 30-fold higher in the myocardium of the transgenic rats compared with controls.
Dilsizian sees this as a potential strategy to monitor the progression of heart failure and identify who might or might not benefit from ACE inhibitor therapy. Given that response to medication can change over time, it also might help physicians calibrate and adjust dosage to maximize the drug’s effect.
“It is not just who benefits from it but how do you titrate the right dose to the right patient,” he says. “Obviously it has to be related to how the ACE activity or the ACE receptor itself is responding to the therapy. The only way you can do that is with imaging.”
From pigs to people
Other researchers have taken a different approach in an effort to use molecular imaging as a prognostic tool and a way to refine treatment in heart failure. While at Johns Hopkins University’s nuclear medicine division, Kenji Fukushima, MD, PhD, and colleagues conducted a study that targeted the angiotensin II type 1 receptor (AT1R) in cardiac tissue using hybrid PET-CT. The study was designed to establish the feasibility and safety of myocardial AT1R PET ligand C-11 KR31173 in pigs and healthy humans.
The animal study included nine pigs, four healthy and five with induced MI scanned by C-11 KR31173 dynamic PET-CT (GE Discovery Rx VCT, GE Healthcare) at three to four weeks after the event. The healthy pigs also were imaged. Additionally, four healthy men underwent AT1R PET ligand C-11 KR31173 imaging.
In the animal study, KR31173 was detectable and specific to AT1R in healthy pigs. Compared with healthy pigs, and one hour after administration, C-11 KR31173 was up-regulated in the myocardium of the infarcted pigs with greater retention in the infarct zone.
None of the volunteers reported symptoms after administration of the tracer. Retention was detectable, stable over time and regionally homogeneous. But retention was significantly lower than seen in healthy pigs and after pretreatment with an AT-1 blocker, 54 percent of receptors were blocked, which suggests limited specificity.
“This is a good combination of preclinical work in pigs that had heart attacks experimentally as well as volunteers showing on a proof-of-principal and pilot basis that you can image angiotensin receptors in patients,” Osborn says. “It is an important first step for utilizing this kind of imaging to tailor therapy for heart failure patients, which would be the logical next step to test with this agent.”
The two approaches touch different parts of the renin-angiotensin-system elephant but may prove complementary, according to the Fukushima team. Dilsizian points out ACE activity precedes angiotensin II, which he sees as an advantage.
The push for personalized medicine should give molecular imaging a boost as well, but it faces many challenges. Tc-Lis, for instance, is in limbo, the victim of a bankruptcy and a shift in company priorities, Dilsizian says. Osborn observes that much of the drive in molecular imaging in cardiovascular disease is fueled by work like his, which focuses on FDG-PET with FDA-approved tracers.
“You don’t see a lot of translation of newer agents for clinical testing because the regulatory framework for bringing those to market,” he says. Agents that get FDA-approved still might not be reimbursed by Medicare, Dilsizian adds.
The latest American Heart Association estimates place the number of adults in the U.S. with heart failure at 5.1 million with a projected increase of 46 percent by 2030. That alone might provide incentives to shift the focus toward preventive and tailored care. Failing to manage heart failure early on with medical therapy may lead to the need for expensive devices like implantable cardioverter-defibrillators and left ventricular assist devices.
“If you use imaging appropriately before the transition to end-stage cardiomyopathy occurs, patient lifestyle is better, morbidity and mortality is better and the healthcare costs downstream will be better,” Dilsizian reasons. “Everyone looks at the bottom line rather than the consequences. Obamacare is addressing prevention, and imaging is part of that, especially in heart failure patients.”