A nephroprotective iodinated contrast agent with cardioprotective properties: A pilot study

Abstract

Background and purpose: Evaluation and treatment of acute ischemic syndromes, in the heart and brain, require vessel visualization by iodinated X-ray contrast agents. However, these contrast agents can induce injury, in both the kidneys and target organs themselves. Sulfobutylether beta cyclodextrin (SBECD) added to iohexol (SBECD-iohexol) (Captisol Enabled-iohexol, Ligand Pharmaceuticals, Inc, San Diego, CA) is currently in clinical trials in cardiovascular procedures, to determine its relative renal safety in high-risk patients. Preclinical studies showed that SBECD-iohexol reduced contrast-induced acute kidney injury in rodent models by blocking apoptosis. The current study was undertaken to determine whether SBECD-iohexol is also cardioprotective, in the male rat ischemia-reperfusion model, compared to iohexol alone.

Methods: After anesthesia, the left coronary artery was ligated for 30 min and the ligation released and reperfusion followed for 2 h prior to sacrifice. Groups 1-4 were injected in the tail vein 10 min prior to ischemia with: (1) vehicle; (2) iohexol; (3) SBECD; and (4) SBECD-iohexol. Infarct size, hemodynamics, and serum markers were measured.

Results: An eight-fold increase in serum creatine kinase in the iohexol-alone group was observed, compared with no increase in the SBECD-iohexol group. The mean arterial pressure and rate pressure product were depressed in the iohexol-alone group, but not in the SBECD-iohexol group, or controls. No difference in infarct size or serum creatinine among the groups was observed.

Conclusion: The results of this study suggest that SBECD-iohexol is superior to iohexol alone, for both the preservation of cardiomyocyte integrity and preservation of myocardial function in myocardial ischemia.

Keywords: cardiotoxicity of contrast; contrast for interventional procedures; iodinated contrast safety; protection from contrast; safe.

FIGURE 1

Mean arterial pressure (MAP) (A) and rate pressure product (RPP) (B) in the rat model of ischemia/reperfusion (30 min/2 h) injury. Rats were treated with vehicle (saline, Group 1; n = 4), iohexol (1500 mg/kg, Group 2; n = 4), sulfobutylether beta cyclodextrin (SBECD) (225 mg/kg, Group 3; n = 3), or a combination of SBECD‐iohexol (1500–225 mg/kg, Group 4; n = 6). Animals in Groups 1–4 received an intravenous infusion of either vehicle or test article into the tail vein over a 2‐min period after the baseline (BL) period. Animals were monitored for the duration of the study. Values are expressed as mean ± standard deviation

FIGURE 2

Effect of iohexol (1500 mg/kg, Group 2), sulfobutylether beta cyclodextrin (SBECD) (225 mg/kg, Group 3), or a combination of SBECD‐iohexol (1500–225 mg/kg, Groups 4 and 5) on the circulating levels of creatine kinase (A) and creatinine (B) after ischemia/reperfusion (30 min/2 h) injury in the rat. Animals in Groups 1–4 received an intravenous infusion of either vehicle or test article into the tail vein over a 2‐min period after the baseline period; animals were then monitored for an additional 8 min. Animals in Group 5 received an intravenous infusion of the test article into the tail vein over a 2‐min period at the beginning of reperfusion. Values are expressed as mean ± standard deviation. n = number of animals in each group

FIGURE 3

Myocardial infarction in the rat model of ischemia/reperfusion (30 min/2 h) injury. (A) Area at risk (AAR; % of left ventricle [LV]) and (B) infarct size (IZ, % AAR) in rats treated with vehicle (saline, Group 1), iohexol (1500 mg/kg, Group 2), sulfobutylether beta cyclodextrin (SBECD) (225 mg/kg, Group 3), or a combination of SBECD‐iohexol (1500–225 mg/kg, Groups 4 and 5). Animals in Groups 1–4 received an intravenous infusion of either vehicle or test article into the tail vein over a 2‐min period after the baseline period; animals were then monitored for an additional 8 min prior to initiation of ischemia. Animals in Group 5 received an intravenous infusion of the test article into the tail vein over a 2‐min period at the beginning of reperfusion. Values are expressed as mean ± standard deviation. n = number of animals in each group