Characterizing preclinical models of ischemic heart failure: differences between LAD and LCx infarctions

Abstract

Large animal studies are an important step toward clinical translation of novel therapeutic approaches. We aimed to establish an ischemic heart failure (HF) model with a larger myocardial infarction (MI) relative to previous studies, and characterize the functional and structural features of this model. An MI was induced by occluding the proximal left anterior descending artery (LAD; n ϭ 15) or the proximal left circumflex artery (LCx; n ϭ 6) in Yorkshire pigs. Three pigs with sham procedures were also included. All pigs underwent hemodynamic and echocardiographic assessments before MI, at 1 mo, and 3 mo after MI. Analyses of left ventricular (LV) myocardial mechanics by means of strains and torsion were performed using speckle-tracking echocardiography and compared between the groups. The proximal LAD MI approach induced larger infarct sizes (14.2 Ϯ 3.2% vs. 10.6 Ϯ 1.9%, P ϭ 0.03), depressed systolic function (LV ejection fraction; 39.8 Ϯ 7.5% vs. 54.1 Ϯ 4.6%, P Ͻ 0.001), and more LV remodeling (end-systolic volume index; 82 Ϯ 25 ml/m 2 vs. 51 Ϯ 18 ml/m 2 , P ϭ 0.02, LAD vs. LCx, respectively) compared with the LCx MI approach without compromising the survival rate. At the papillary muscle level, echocardiographic strain analysis revealed no differences in radial and circumferential strain between LAD and LCx MIs. However, in contrast with the LCx MI, the LAD MI resulted in significantly decreased longitudinal strain. The proximal LAD MI model induces more LV remodeling and depressed LV function relative to the LCx MI model. Location of MI significantly impacts the severity of HF, thus careful consideration is required when choosing an MI model for preclinical HF studies.anterior; posterior; remodeling; torsion; sphericity THE STATISTICAL REPORT FROM the American Heart Association revealed a decline in mortality attributable to cardiovascular diseases by 30.6% in the last decade. However, one out of three patients still die from cardiovascular diseases in the US and the mortality in heart failure (HF) patients remains high (31). Significant progresses in treatment devices as well as modern pharmacotherapy have improved prognoses, while efforts on greater improvements continue. Several novel treatments for HF including gene therapy and cell therapy, and novel pharmaceuticals show promising results in small animal experimental studies. However, structural and physiological differences between human and small animals (27) continue to limit their clinically relevant predictive value for translating to humans. Hence, the need for large animal studies is still required to validate the efficacy and safety of these novel treatments in more clinically relevant models of HF.There are several large animal models of HF using diverse species. Pigs, dogs, and sheep are frequently used animals in translational experimental studies of cardiovascular diseases (18). Among them, the pig is most common due to similar coronary anatomies to humans, lack of inherent coronary collaterals, and ease of handling (14). HF can be induced b...

Left Ventricular Unloading Using an Impella CP Improves Coronary Flow and Infarct Zone Perfusion in Ischemic Heart Failure

“…At 2 weeks after MI, end‐diastolic WT of the anterior wall (infarct zone) decreased significantly, whereas the remote myocardial WT remained unchanged (anterior: 7.2±0.9 to 6.3±1.0 mm [ P =0.03]; remote: 7.2±0.7 to 7.1±0.7 mm [ P =0.89], before MI to 2 weeks after MI, respectively). Infarct size measured by digital planimetry after heart explantation was 26.0±3.4% of the total LV. These data are consistent with previously published reports using a similar approach to induce ischemic HF .…”

“…Infarct size measured by digital planimetry after heart explantation was 26.0±3.4% of the total LV. These data are consistent with previously published reports using a similar approach to induce ischemic HF . At 2 weeks after MI, coronary angiograms revealed TIMI 2 flow in 8 animals and TIMI 3 flow in 2 animals (1 each in Impella and SNP groups) in the LAD.…”

“…We also used a transmural infarction model by injecting thrombus to induce more severe HF phenotype as those are the likely target patient population in clinic. Whether our findings apply to nontransmural infarction model, such as ischemia/reperfusion or chronic ischemia, needs to be addressed in the future studies. The coronary flow wire was removed after the measurements at 5 minutes and reintroduced at 120 minutes after Impella initiation.…”

Primary Effect of SERCA2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction

“…All animals underwent echocardiographic assessment, followed by hemodynamic measurements. All pigs were subjected to extensive anterior MI (procedure described below) and cage‐housed for 1 month to develop chronic HF with marked left ventricular (LV) dysfunction compared with control pigs as we have previous reported 8. Animal sera were collected at the time of MI to screen for neutralizing antibodies against AAV1 9.…”

Reply to “Letter to the editor: Characterizing preclinical model of ischemic heart failure: difference between LAD and LCx infarctions”

“…REPLY: We thank Dr. Katz and colleagues (7) for their interest and comments on our recent study (3). The study was conducted to develop and characterize a large animal model of chronic heart failure (HF) associated with large myocardial infarction (MI).…”