**7. Burn-induced cardiomyopathy**

### **7.1 Research achievements from relevant research institutions**

Severe burns can lead to severe hemodynamic and cardiodynamic disturbances, which can lead to sepsis, multiple organ failure, and death. Cardiac stress is a hallmark of acute-phase response to burns, and poorer burn recovery outcomes are associated with severe cardiac insufficiency [134–136]. Severe burn injury has a profound and widespread effect on an individual's cardiovascular system. Early features include myocardial contractile dysfunction and increased vascular permeability.

Plasma levels of catecholamines, vasopressin, angiotensin-II [137] and neuropeptide-Y [138] are significantly elevated after severe burns, which may be responsible

for the deleterious effects on cardiovascular function. Nearly 7% of children with 70% burn area develop dilated cardiomyopathy (DCM) [139, 140]. Burn-induced cardiomyopathy usually develops several weeks to several months after injury [139, 141]. The initial cardiac response to severe burns is characterized by reduced cardiac output and metabolic rate (**Figure 1**). Other hemodynamic features of burn shock include stroke volume, venous return, coronary blood flow, peak systolic blood pressure, mean arterial pressure, estimated myocardial work, stroke work, myocardial oxygen consumption, myocardial oxygenation, myocardial contractility, decreased force and myocardial compliance [142]. This initial response will result in left-right heart failure and decreased cardiac contractility and is thought to be mediated by circulating vasoconstrictors (**Figure 1**).

Physiologically, burn-induced myocardial dysfunction is characterized by decreased isovolumic relaxation, impaired contractility, and decreased left ventricular diastolic compliance [143, 144] resulting in decreased cardiac output and metabolic rate [138, 145], leading to myocardial oxygen demand, leading ultimately to right and left heart deficits (**Figure 1**) [143, 146]. Following burn injury, the volume of circulating plasma is markedly reduced due to increased capillary permeability [147] and a concomitant decrease in cardiac output. Depending on the extent of the burn injury, this defect may directly lead to a severe hypermetabolic response [148] and is positively correlated with the size of the original injury [148]. Poor functional recovery from severe burns is associated with high mortality, high infection rates, and cardiac insufficiency [136, 149, 150].

Cardiac stress-induced increases in plasma catecholamines mediate postburn hypermetabolic responses [136, 151, 152]. Upregulation of catecholamines and other catabolic agents such as glucagon and cortisol may induce hyperdynamic cardiovascular responses [134]. Elevated catecholamines and other catabolic agents are further exacerbated by the substantial loss of plasma volume following burns. Hypovolemic shock, typified by severe burns and major tissue trauma, results in marked tachycardia, increased myocardial oxygen demand, and decreased contractility (**Figure 1**) [134]. This eventually leads to increased mortality during acute hospitalization [153]. Severe burns suffer from a profound hypermetabolic response mediated by a surge in plasma catecholamines. Sustained release of large circulating catecholamines may be detrimental to the myocardium, increasing myocardial oxygen delivery and leading to focal degeneration and hypertrophy of the myocardium [134]. Elevated plasma catecholamine levels persist for months to years resulting in cardiac stress and cardiac physiologic disturbance for at least 2 years [154]. This in turn leads to cardiac insufficiency, regional myocardial hypoxia, and cardiac death [155]. Therefore, clinical concern about catecholamine levels is related to burninduced cardiomyopathy, myocarditis, pathological myocardial injury and necrosis [156, 157].

#### **7.2 Research achievements from our laboratory**

We applied mature animal burn models including rat and mouse, established by UTMB Health's Blocker Burn Center, to identify the heart tissue-specific up−/ down-regulated genes/proteins/metabolisms via transcriptomics/proteomics/metabolomics, and have many hypothesizes based on the differences. Briefly, the SIRT1- PGC1α-NFE2L2-ARE pathway [158], and PDE5A-cGMP-PKG pathway [159] were involved in the burn-induced cardiomyopathy. To confirm our above observations, we treated burn injury animals with PDE5A inhibitor [159, 160] (Sildenafil), and APMK inhibitor (Domorsorphin)/APMK activator (A769662)/PGC1α activator (ZLN005) [158] to partially/completely recoveries of burn-induced cardiomyopathy. Another important contribution for burn-induced cardiomyopathy was that burn injury disrupts the heart mitochondria (mt) with evidence of cardiomyocyte mtDNA damage [159, 161], mt electron transport chain (ETC) dysfunction, mt membrane potential damage, disrupted mt integrity and significant increase of mt ROS production [159, 161]. Treatment with mitochondrial-target drug (Mito-TEMPO) can be beneficial for burn injury–induced cardiomyopathy (**Figure 1**) [161].
