Author + information
- Clyde W. Yancy, MD, MSc⁎ ( and )
- Daniel C. Lee, MD, MS
- ↵⁎Reprint requests and correspondence:
Dr. Clyde W. Yancy, Northwestern University, Feinberg School of Medicine, Division of Cardiology, 676 North St. Clair, Suite 600, Chicago, Illinois 60611
As we pursue the high bar of optimal quality of care for patients with heart failure by targeting appropriate patients with all indicated evidence-based, guideline-driven interventions, we are disquieted not only by the cost implications but also by the stark awareness that for some of our patients, many of our therapies are likely minimally efficacious if not frankly nonefficacious and all that is really gained is exposure to harm. Remarkably, after decades of investigation, we have no more specific indication for evidence-based beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, or aldosterone antagonists than left ventricular ejection fraction measurements and New York Heart Association classification—crude indicators at best (1). And for the single indicated therapy with a more precise descriptor of responsiveness, isosorbide dinitrate plus hydralazine for African-American patients with heart failure, that treatment has failed to experience any significant use for indicated patients (2).
Differential responses to medical therapies as a function of race, ethnicity, and sex, and possibly similar differential response to device therapy as a function of sex, have been well documented (3). Certain genetic predilections may explain some of this heterogeneity, but a more pragmatic answer may be that the acquisition of the data suggesting differential responsiveness was flawed. Clearly race and/or ethnicity represent poor proxies for anything physiologic, and sex is only slightly better. A more favorable scenario would be care that is guided by much more precise indications for therapy, clear avoidance of harm, and accurate predictors of response. This is the promise of personalized medicine—a promise that has not yet been delivered despite this prolific era of biomarkers and an assortment of “-omics.”
In this issue of iJACC, Dilsizian et al. (4) have reported a novel strategy that identifies up-regulation of myocardial ACE in laboratory animals using a targeted imaging agent, techentium-99m labeled lisinopril (Tc-99m-Lis). Based on the observation that myocellular ACE activity is up-regulated in human and animal models of heart failure, the authors tested the feasibility of using Tc-99m-Lis to distinguish the hearts of ACE-1 over-expressing transgenic rats from those of wild-type control rats. Quantification of Tc-99m-Lis activity in explanted hearts by gamma-well counting demonstrated a nonsignificant increase of Tc-99m-Lis uptake (expressed as percent injected dose per gram) in transgenic versus control hearts at 10 min after injection (0.48 ± 0.29% vs. 0.19 ± 0.10%, p = 0.171) and a significant increase in Tc-99m-Lis uptake in transgenic versus control hearts at 30 min after injection (0.74 ± 0.13% vs. 0.17 ± 0.03%, p = 0.028). Pre-treatment with unlabeled lisinopril substantially reduced Tc-99m-Lis uptake, demonstrating specificity of the Tc-99m-Lis radiotracer.
In vivo imaging was also performed utilizing a small-animal imaging system with combined single-photon emission computed tomography and computed tomography capability (micro SPECT/CT). Three representative images acquired in vivo were presented to highlight the potential of Tc-99m-Lis as an imaging agent. Mirroring the ex vivo data, the control rat demonstrated minimal myocardial Tc-99m-Lis signal, the transgenic rat demonstrated robust myocardial Tc-99m-Lis signal, and pre-treatment of a transgenic rat with unlabeled lisinopril resulted in minimal signal within the myocardium and lungs.
Biochemical assays confirmed that ACE-1 enzyme activity was higher in transgenic animals whereas control animals and animals pre-treated with unlabeled lisinopril demonstrated the expected low levels of ACE activity. The implication is that those phenotypes with evidence of high tissue ACE-1 activity would be especially good candidates for ACE inhibition.
Do these data get us closer to personalized medicine? Are we able to extrapolate that for patients with heart failure in whom ACE activity is up-regulated and maladapted, ACE inhibitor therapy would be of greatest benefit? Older data from a RAND Corporation meta-analysis of available clinical trials suggested that women receive no demonstrable benefit from ACE inhibitors (5). Similarly, post-hoc analyses from the SOLVD (Studies of Left Ventricular Dysfunction) trials suggested that African Americans respond less well to ACE inhibitors (6). Withholding evidence-based therapies on the basis of sex, race, or ethnicity is categorically untenable, but it is possible that not every woman or African American receiving an ACE inhibitor is deriving a benefit. A better approach is needed. Is an assessment of ACE-1 activity the answer for ACE inhibitor therapy?
The current data are certainly intriguing; however, several questions give us pause and demonstrate how far we must go to acquire a precise marker that will guide the use of evidence-based therapy, in this case for heart failure. How accurately does the over-expression of ACE-1 in transgenic animals correlate with up-regulated ACE-1 in clinical heart failure? The over-expression of ACE-1 in transgenic animals by 30-fold compared to controls may not only be significantly different from human heart failure but may also represent the magnitude of difference required for accurate imaging. Would Tc-99m-Lis image a lesser level of increased ACE-1 activity with a similar degree of certainty? That large differences in uptake can be appreciated by ex vivo quantification is promising, but future studies will be necessary to define the accuracy with which in vivo imaging can discriminate graded differences in ACE activity. This task will be more difficult in vivo, where high Tc-99m-Lis uptake in the lungs (which was >50-fold higher than the heart in this study) may compromise precise assessment of myocardial ACE activity. Furthermore, translation of high-resolution small-animal micro SPECT/CT findings to patients raises additional challenges, such as reduced resolution and increased soft tissue attenuation.
The activity of ACE-1 in heart failure cleaves angiotensin I, yielding angiotensin II, and acts on angiotensin 1-7 (Ang 1-7), a peptide that has antithetical properties compared to angiotensin II (7). Will Tc-99m-Lis imaging provide any insight regarding ACE-1 activity on Ang 1-7? A well-known variation of the ACE gene has a 287 base pair Alu insertion in intron 16. The presence or absence of this insertion yields 3 genotypes—II, DD, and DI—of which the DD or dual deletion genotype is associated with a greater cardiovascular disease burden, especially hypertension. How will Tc-99m-Lis imaging detect these genetic variations of ACE?
The renin-angiotensin-aldosterone system is complex. It is well documented that within weeks after initiation of ACE inhibitor therapy, angiotensin II levels return to pre-treatment thresholds. This verifies that generation of angiotensin II occurs by non-ACE enzymatic activity. This observation almost assuredly dismisses chronic suppression of ACE-1 as the mechanism of clinical benefit for ACE inhibitors. This and other candidate mechanisms of action, for example, suppressing kininase activity or increasing Ang 1-7 levels, may remain quite important in determining clinical benefit of ACE-I therapy even if upregulated tissue ACE-1 activity per se is not the predominant finding. Thus, how important is it to image ACE-1 activity in vivo?
The work done by Dilsizian et al. (4) is commendable and represents a step closer to more precise identification of phenotypes that may predict a better responsiveness to ACE-inhibitor therapy. However, the focus of this field might merit a more measured thought process. Perhaps the quest here is not to identify the patients for whom the response would be optimal but rather the patient for whom either the risk would be great or the benefit nil. Certainly, if the risk of angioedema due to an ACE inhibitor, or hyperkalemia due to an aldosterone antagonist, or bronchospasm due to a beta-blocker could be predicted by assessment with a radio-labeled tracer, then arguably it might be of more clinical utility than another positive indication for therapy.
Thus, meaningful research focused on increasing our precision in the prescription of evidence-based medical therapies for heart disease should continue. But personalized medicine remains an unfulfilled hope. For now, we should continue to advocate the use of evidence-based, guideline-driven therapy for heart failure per current indications for all appropriate patients.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
↵⁎ Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
- American College of Cardiology Foundation
- Hunt S.A.,
- Abraham W.T.,
- Chin M.H.,
- et al.
- Taylor A.L.,
- Ziesche S.,
- Yancy C.W.,
- et al.
- Barsheshet A.,
- Brenyo A.,
- Goldenberg I.,
- Moss A.J.
- Dilsizian V.,
- Zynda T.K.,
- Petrov A.,
- et al.
- Shekelle P.G.,
- Rich M.W.,
- Morton S.C.,
- et al.