Good morning, I am honored to be here today to talk about a subject that is near and dear to my heart, pathophysiology of septic cardiomyopathy, back to basics. I have no disclosures to declare for this talk. Today we will review the history of our understanding of myocardial depression and septic shock, describe the epidemiology and risk factors for septic cardiomyopathy, understand the pathophysiology of septic cardiomyopathy, and understand how septic cardiomyopathy differs from stress cardiomyopathy. Reversible myocardial depression in patients with septic shock was first recognized using radionuclide scanning in 1984. In that study, survivors had a decreased left ventricular ejection fraction which returned to normal 7-10 days later. This slide shows the left ventricle at end diastole in the left panel circled in red and end systole in the right panel circled in yellow in a patient acutely during septic shock in the upper two panels when the ejection fraction was 13% and then 10 days later when the patient had recovered at which time the ejection fraction was 67%. The patients in this study had a hyperdynamic hemodynamic profile despite a reduced ejection fraction. Early in septic shock, for example, the left ventricular end diastolic volume might be 200 mL with a left ventricular end systolic volume of 150 mL giving an ejection fraction of 25% and a stroke volume of 50 mL. For a patient with a heart rate of 100, the cardiac output would be 5 mL per minute. When the patient recovers, the left ventricular end diastolic volume might be 100 mL with an end systolic volume of 50 mL. At this point, the ejection fraction would be 50% with a stroke volume of 50 mL. If the patient had a heart rate of 70, the cardiac output would be 3.5 mL per minute. This demonstrates the hyperdynamic hemodynamic profile early in septic shock with resolution to normal as the ejection fraction recovers. Initially, septic cardiomyopathy was defined as reversible depression of left and usually right ventricular ejection fraction with left ventricular dilation. With increasing sophistication and the availability of echocardiography, our understanding of septic cardiomyopathy has grown, but still many questions remain. Ejection fraction is load dependent and not the most accurate measure of myocardial function. Global longitudinal strain is a more sensitive and accurate measure. There are other diagnostic tools and echocardiographic measures that provide different definitions for septic cardiomyopathy, leading to difficulty in comparing studies for frequency and prognosis of septic cardiomyopathy. Initially, depression of ejection fraction was associated with survival, with non-survivors having a normal ejection fraction. But there has been controversy in many subsequent studies as to the prognosis related to ejection fraction. Left ventricular ejection fraction was reported by Sevilla and Berrios in a meta-analysis in 2014 not to be a sensitive or specific predictor of mortality. Sanfilippo reported that longitudinal strain was a better predictor of mortality. Left ventricular ejection fraction may also be associated with mortality as reported by Brown et al. in 2012. Right ventricular ejection fraction may also be associated with mortality as reported by a number of investigators. More recently, Ciotaglia et al. reported that a hyperdynamic left ventricular ejection fraction in critically ill septic patients was associated with higher mortality, 58.9%, compared with a depressed left ventricular ejection fraction, which had a 34% mortality, or those with a normal left ventricular ejection fraction with a 24% mortality. A hyperdynamic left ventricular ejection fraction was also associated with a lower systemic vascular resistance, leading the authors to suggest that perhaps unmitigated vasoplegia contributed to the mortality in this patient group. Septic cardiomyopathy is a common phenomenon occurring in 10-70% of septic patients. The variation in occurrence is related to variation in definitions, severity of sepsis, and perhaps to management of the septic patient as well. A Japanese study reported a higher prevalence in younger patients, males, those with more severe disease, patients with a higher lactate, and those with pre-existing heart failure. A more recent study from Korea reported association with older age, diabetes, and pre-existing heart failure. It is likely that pre-existing heart failure is a significant risk factor for septic cardiomyopathy, but clearly those with normal hearts can also develop reversible myocardial depression and septic shock. The finding of reversible depression of ejection fraction led to questions as to how this phenomenon occurred. One of the potential theories was that there was global myocardial ischemia producing reversible depression of cardiac function. Early studies by Kanyon and by Deneau, however, demonstrated that septic cardiomyopathy was not associated with myocardial ischemia. Coronary sinus blood flow was measured in patients with septic shock and was not reduced, and in fact may even be increased in tachycardic patients with septic shock. So global myocardial ischemia does not explain septic cardiomyopathy. Another theory about the pathophysiology of septic cardiomyopathy is that there is one or more myocardial depressant substances causing depression of myocardial function. This has been suggested in many in vitro studies. Parillo et al. demonstrated that serum from septic patients depressed function in a spontaneously beating rat myocardial cell assay. Subsequent studies by many investigators using a variety of different models have identified a host of potential mediators for septic cardiomyopathy. A variety of processes have been identified as being involved in the pathophysiology of septic cardiomyopathy. Serum mediators including cytokines such as IL-2, IL-6, and others. The complement system, especially C5A, and high-mobility group BOX1 have been reported as being involved. Changes in mitochondrial morphology and function lead to generation of reactive oxygen species and oxidative stress. Coal-like receptor activation leads to expression of inflammatory mediators. Abnormal calcium movement within the cells decreases calcium-binding troponin and contractility. Nitric oxide is also involved in the pathophysiology of septic cardiomyopathy. Increased expression of inducible nitric oxide synthase produces NO, which can lead to autonomic dysregulation, decreased myocardial sensitivity to calcium, and damaged mitochondria. Autonomic dysregulation can also contribute to decreased myocardial function. Endothelial disruption can also occur producing myocardial edema. Structural abnormalities including inflammatory infiltrates, necrosis, and apoptosis have also been reported, mostly from animal models as there are very few studies of myocardial biopsy acutely in septic shock, and autopsy studies may be done very much later after the acute illness. Stress cardiomyopathy is another form of reversible myocardial depression, but is quite different from septic cardiomyopathy. It is believed to be a neurocardiogenic myocardial stunning and predominantly occurs in postmenopausal women. It is defined as a regional wall motion abnormality beyond a single epicardial coronary artery distribution and there is typically apical ballooning with basal hyperkinesis. Stress cardiomyopathy is related to or follows a stressful event, either emotional or physical. The stress of sepsis has been reported to trigger stress cardiomyopathy, confusing this distinction a bit, but is a very small percentage of the cases of stress cardiomyopathy. Stress cardiomyopathy is transient, typically resolving in 3-6 months, a much longer period of time than it takes for septic cardiomyopathy to resolve. To summarize, cardiac dysfunction in sepsis is common and a very complex process. Multiple abnormalities occur and likely interact to produce septic cardiomyopathy, including metabolic, microvascular, functional, and structural abnormalities, but not ischemic heart disease. The complexity of the pathophysiology and the variability of definitions has hindered the development of specific therapies as well as better understanding of the prognosis and clinical significance, and much work remains to be done. I thank you for your attention and I thank the program committee for inviting me to speak.

septic cardiomyopathy

pathophysiology

diagnostic tools

left ventricular dilation

research