Functional capacity in a rat model of heart failure: impact of myocardial infarct size

Abstract

What is the central question of this study? To the best of our knowledge, no studies have evaluated oxygen uptake, carbon dioxide production and exercise tolerance in rats that have undergone myocardial infarction classified by myocardial infarct (MI) size. What is the main finding and its importance? Oxygen uptake and exercise intolerance are MI size dependent, and classification based on MI size can distinguish rats with functional capacity impairment. Rats with a large MI (>40% of the left ventricle) might provide a good model for the testing of new therapies that have the potential to modify the variables of functional capacity. Oxygen uptake (V̇O2) and exercise tolerance in rats classified by myocardial infarct (MI) size are underexplored. The aim of this study was to evaluate V̇O2, carbon dioxide production (V̇CO2) and exercise tolerance in rats that had undergone myocardial infarction. Fourteen weeks after myocardial infarction or sham surgery, rats underwent an integrated approach to evaluation of left ventricular function and V̇O2/V̇O2V̇CO2V̇CO2, exercise tolerance and skeletal muscle weight. Based on determination of MI size, rats were assigned to sham-operated controls (Sham, n = 12), small myocardial infarction (SMI, n = 8) and large myocardial infarction (LMI, n = 5) groups. The LMI rats showed lower systolic (ejection fraction and fractional shortening) and diastolic (E/A ratio) left ventricular function compared with SMI. Maximal V̇O2 (∼24%, P < 0.05), V̇O2 reserve (∼30%, P < 0.05), time to exhaustion (∼36%, P < 0.05) and maximal velocity (∼30%, P < 0.05) were lower in LMI compared with sham-operated control animals, with no difference between SMI rats and sham-operated controls. Maximal V̇CO2 and respiratory exchange ratio showed no significant difference between MI rats and sham-operated control rats. The LMI rats demonstrated lower gastrocnemius weight (∼12%, P < 0.05) and soleus weight (∼19%, P = 0.07) compared with sham-operated control rats. Significant correlations between MI size, left ventricular end-diastolic pressure, right ventricle hypertrophy, pulmonary congestion, ejection fraction and fractional shortening with maximal V̇O2 and distance run were observed. Oxygen uptake and exercise intolerance are MI size dependent.

Discovery of Aficamten (CK-274), a Next-Generation Cardiac Myosin Inhibitor for the Treatment of Hypertrophic Cardiomyopathy

“…Reduction of fractional shortening by greater than 50% has been shown to exhibit a heart failure phenotype in preclinical models and was used to define an excessive reduction in cardiac function. 24 The IC 10 value determined in the echo study represented our estimation of a beneficial in vivo effect that was later confirmed in human testing. 10 Aficamten had a shallow concentration−response profile with an IC 50 /IC 10 ratio of 9.9×, whereas mavacamten had a steeper concentration−response profile with an IC 50 /IC 10 ratio of 2.8×.…”

“…The therapeutic window was defined by the IC 50 /IC 10 ratio in the echocardiography experiment and corresponded to compound concentrations that reduced FS by 50% (IC 50 ) and 10% (IC 10 ), with a higher IC 50 /IC 10 ratio predictive of a greater therapeutic window. Reduction of fractional shortening by greater than 50% has been shown to exhibit a heart failure phenotype in preclinical models and was used to define an excessive reduction in cardiac function . The IC 10 value determined in the echo study represented our estimation of a beneficial in vivo effect that was later confirmed in human testing .…”

Long noncoding RNA MALAT1 downregulates cardiac transient outward potassium current by regulating miR‐200c/HMGB1 pathway

“…[9][10][11] In brief, rats were anesthetized by intraperitoneal injection of 2% pentobarbital sodium (2 mL/kg) for left thoracotomy and pericardiotomy. [9][10][11] In brief, rats were anesthetized by intraperitoneal injection of 2% pentobarbital sodium (2 mL/kg) for left thoracotomy and pericardiotomy.…”

“…Establishment of MI model was carried out as described. [9][10][11] In brief, rats were anesthetized by intraperitoneal injection of 2% pentobarbital sodium (2 mL/kg) for left thoracotomy and pericardiotomy. Under aseptic conditions, skin preparation was carried out first.…”