Although a precise definition of septic cardiomyopathy is still a matter of debate, cardiac dysfunction occurs in 40–60% of septic shock patients. It is entirely reversible in survivors within 10 days [
70], but the presence of sepsis-related cardiac dysfunction is associated with increased short-term mortality [
71‐
74]. Apart from causal treatments (antibiotics, surgical source control) and initial fluid resuscitation, no available treatment has been shown to improve the course of septic cardiomyopathy in humans [
75]. As myocardial tissue is not easy to obtain from critically ill patients, only a few studies displayed data on the cellular mechanisms of human septic cardiomyopathy from the left ventricle of patients who died from sepsis [
76‐
79]. To guide the understanding of the main causal mechanisms of human septic cardiomyopathy, most animal studies have used either endotoxin or fecal peritonitis models, with no or only limited resuscitation. Cecal ligation and puncture (CLP) models mimic the chronology of morphological features observed in human septic cardiomyopathy. Early in this model, prior to fluid resuscitation, animals show decreased cardiac output [
80] with normal cardiac contractile performances of isolated perfused hearts [
81]. At this stage, fluid resuscitation normalizes cardiac output, leading to the so-called hyperdynamic phase of sepsis [
82]. Later on, animals that are more likely to die display decreased cardiac output [
80] due to cardiac contractile dysfunction (i.e., the “hypodynamic phase of sepsis”) [
81]. Conversely to the CLP model, endotoxin models (e.g., using bacterial lipopolysaccharide (LPS)) show very early cardiac contractile dysfunction, skipping the phase of hemodynamic disturbances with maintained cardiac performances [
83,
84]. Surviving animals experience total recovery of their cardiac performances within 10 days [
85‐
87]. Unlike endotoxin models, infected animals that mimic the different phases of human septic cardiomyopathy were very useful to analyze the early pathophysiological mechanisms of this syndrome. For example, CLP animals display an early increase in the adrenergic response of the cardiomyocytes, altering calcium sensitivity of cardiac myofibrillar proteins [
81,
88‐
90]. This early mechanism is at least in part responsible for the later attenuation of adrenergic response and septic cardiomyopathy [
81,
88‐
90]. Thus, these CLP-specific data helped researchers to hypothesize that preventing adrenergic stimulation in the early phase of sepsis might prevent cardiomyopathy to occur. Although CLP models are usually fluid-resuscitated, only a minority of the studies used antibiotic regimens [
80,
82], and none of them performed complete causal treatments (i.e., both antibiotics administration and surgical source control). Therefore, one might hypothesize that like CLP models with only partial basic resuscitation, CLP models with full causal treatment could bring new significant insights on the pathophysiological mechanisms of septic cardiomyopathy (i.e., still “wrong” but maybe more “useful” models [
2]).
Finally, preclinical trials on septic cardiomyopathy yielded conflicting results with poor extrapolation to critically ill patients. Several factors might explain the failure to detect new efficient drugs in this context. First, numerous preclinical experiments were performed on endotoxin models, known to poorly mimic human features of the septic cardiomyopathy [
91‐
100]. Second, like mechanistic studies, although preclinical trials using fecal peritonitis models were usually fluid-resuscitated, none of them combined a causal treatments to the tested drugs [
91,
101‐
108]. Third, only a few studies administered vasoconstrictors to maintain an appropriate systemic blood pressure when testing heart medications with vasodilator properties [
107,
108]. Fourth, tested drugs were sometimes administered very early (< H4) [
105,
106] after the induction of fecal peritonitis, or even before the insult [
91,
92,
109]. All these factors might have favored the beneficial effects of the tested drugs and led to false positive results. Therefore, although sophisticated treatments (e.g., mechanical ventilation) may improve the quality of animal studies in the context of septic cardiomyopathy [
110], implementation of the most basic causal treatments should be a prerequisite for future preclinical studies in this field.