Frontiers in Myocardia

Septic cardiomyopathy can be classified as a secondary form of cardiomyopathy, the heart being involved in the systemic disease “sepsis”. The pathophysiology of septic cardiomyopathy is much more complex than the pathophysiology of most of the textbook heart diseases. This complexity is the consequence of the impact of numerous toxins and sepsis mediators on the heart in the course of the disease.

Main trigger substances of septic pump failure are endotoxin, TNF-α, IL-1 and NO, which interfere with receptors, inotropic signal transduction pathways, Ca2+ transients and the contractile apparatus of the cardiomyocyte. These inflammatory mediators also impair mitochondrial function of cardiac cells, with the consequence of cytopathic hypoxia and energy depletion, but also increased production of reactive oxygen species and induction of apoptosis in the organ.

Cardiac dysfunction is characterized by systolic as well as diastolic dysfunction of the left and the right ventricle and – typically – by reversible dilation of the heart; diastolic dysfunction of the left ventricle seems to be the prognostically most relevant alteration. For compensation of the sepsis-induced vasoplegia resulting in a fall in blood pressure, the diseased heart has to pump even more, to furnish the demands of circulation, which further stresses the organ. Thus “afterload-related cardiac performance” (ACP) characterizes the cardiac pump failure in sepsis much better than isolated measures of systolic or diastolic dysfunction.

Septic cardiomyopathy is not a primary ischemic disease: Coronary macrocirculation seems not impaired, while coronary microcirculation probably is. Drastic alterations are seen in cardiac metabolism, with a strong reduction of free fatty acids fuelling, with cytopathic hypoxia and some form of myocardial hibernation.

Also chronotropic and bathmotropic dysregulation characterizes septic cardiomyopathy: resting heart rate is high and heart rate variability is reduced. This is the result of cardiac autonomic dysfunction with a strongly depressed vagal as well as sympathetic regulation in sepsis. Moreover, endotoxin interacts with the HCN channels of the pacemaker current in sinus node, thereby contributing to the intrinsic impairment of heart rate regulation.

The pathophysiology of septic cardiomyopathy is complex, the cardiac alterations can be reversible and the impairments of heart function contribute to the unfavorable prognosis of septic patients.

Cardiac dysfunction is a well-known complication of severe sepsis and septic shock. Septic cardiomyopathy is characterized by reduced cardiac output and left ventricular pressures and biventricular dilatation, resulting in systemic hypoperfusion and multi-organ failure. There is emerging evidence suggesting that mediators of septic cardiomyopathy include cardio-depressive cytokines, Toll-like receptor signaling, cardiomyocyte production of reactive oxygen species and nitric oxide, and dysregulated Ca²⁺ homeostasis. This chapter will review the current evidence describing the cellular and molecular mechanisms of septic cardiomyopathy.

Excitability and contractility of the heart rely on proper functioning of cardiac ion channels. Ion channels are transmembrane proteins enabling ions to cross the cell membrane and thereby changing membrane potential. Multiple studies have shown that remodelling of ion channel function occurs in various heart diseases (e.g. atrial fibrillation, heart failure) and there is growing evidence that alterations in ion channel activity play an important role in septic cardiomyopathy. The purpose of this chapter is to review sepsis-induced ion channel dysfunction. Particular emphasis is placed on the L-type calcium and the pacemaker channel. The L-type calcium channel is a key nexus linking cellular excitation and contraction and sepsis-induced channel impairment very likely contributes to the pathogenesis of myocardial depression. A reduction of heart rate variability is a further characteristic of cardiac dysfunction in sepsis probably attributable to autonomic dysfunction and/or a reduced responsiveness of the sinus node to autonomic stimuli. The pacemaker channel comprises an important final common pathway for autonomic heart rate regulation and is directly impaired by endotoxin. These facts strongly imply a major contribution of the pacemaker channel to the sepsis-induced reduction of heart rate variability.

Sepsis is the leading cause of death in critical ill patients in intensive care units around the world. Cardiac dysfunction is one of the major clinical manifestations in septic patients (about 60%), with mortality rate of approximately 80%, while septic patients without cardiovascular impairment present mortality rates around 20%. However, cardiac involvement as an important contributing factor to the multiple organ dysfunction in the sepsis syndrome, has been rejected. Principal mechanisms proposed to explain the cardiac dysfunction in sepsis originates from functional abnormalities, not from structural changes. In spite of the evolution of septic cardiomyopathy concept, the study of structural change as an important component in the development of myocardial dysfunction has been omitted in sepsis. In 2007, morphological analysis of human heart samples obtained by autopsy reported cases of severe sepsis/septic shock condition in patients submitted a longer periods of hospitalization. Septic patients showed structural myocardial alterations classified as "inflammatory cardiomyopathy" probably responsible for the myocardial depression induced by sepsis. Since then, structural changes on cardiac dysfunction in sepsis/septic shock has been object of several studies, experimental and clinical, aiming to improve the diagnosis and treatment of this syndrome. In this chapter, will be presented results of studies conducted in our laboratory analyzing cellular and molecular mechanisms underlying sepsis/septic shock, which may result in morphological alterations in the myocardium of mice subjected to CLP-sepsis model.

During the course of sepsis, myocardial dysfunction occurs in 20-30% of patients. Septic cardiomyopathy has a high mortality and the underlying molecular pathophysiology remains still largely unclear. Sepsis induced cardiac dysfunction (SICD) or septic cardiomyopathy (SC) gathered increasing denotation during the last years since mortality rates are high.

Septic shock is characterized by circulatory compromise, microcirculatory alterations and mitochondrial damage, which all reduce cellular energy production in the myocardium. As the specific underlying molecular causes of septic cardiomyopathy remain largely unclear, characteristic alterations in the organ proteome (“tissue proteomics”) and metabolome are of high interest to understand emerging dysfunction and to identify molecular details to establish new treatment approaches.

Thus, it is of outstanding importance to diagnose septic cardiomyopathy effectively being able to treat specifically this entity of a disease.

Cardiomyopathy of sepsis has been described over three decades ago while sporadic description of the phenotype has permeated the literature for two decades prior to the emergence of a coherent description. Although its prevalence is high in severe sepsis and septic shock, its impact on the overall prognosis of patients with sepsis is less clear. The clinical manifestations are varied and the syndrome presents several phenotypes, depending on when observations are made and how severe the underlying sepsis is. The most important concepts underlying the current understanding of the cellular pathophysiology, namely inflammation-driven elevations on various forms of intracellular nitric oxide synthases, their interaction with calcium fluxes, cellular respiration and oxidative stress are reviewed. The links between current concepts of pathophysiology, clinical manifestations and therapeutic options are discussed.

Sepsis-induced myocardial dysfunction (SIMD) is a common and reversible complication in severe sepsis and septic shock patients. Its pathogenesis is complex and probably mediated by cytokines. Echocardiography is the gold standard to make the diagnosis of SIMD. Cardiac biomarkers have a high negative predictive value for SIMD. Norepinephrine is the first line vasopressor. Inotropic drugs should be used in the case of left ventricular systolic dysfunction associated with persisting tissular hypoperfusion.

Septic shock is one of the most complex hemodynamic failure syndromes, and its mode of expression is highly variable and may include each one to a variable degree: absolute or relative reduction of volemia, severe peripheral vasodilatation, right and left ventricular (RV and LV) myocardial failure and global myocardial dysfunction. Because of this variability and to optimize the treatment, it seems necessary to perform echocardiography at admission in intensive care unit (ICU) for septic shock and repeat it at least once a day or more in case of hemodynamic instability.

Echocardiographic findings should be integrated with clinical data and other monitoring information, especially with those related to peripheral tissue perfusion. Transesophageal echography (TEE) enables for a complete assessment, also detailing heart-lung interactions and fine volume responsiveness evaluation but TEE is not necessarily required if the transthoracic echography (TTE) provided answers to questions.

Echocardiography allows help intensivists to establish therapeutic such as inotropes, vasopressors or to optimize volemia after volume expansion. Thus, echocardiography is now an unavoidable tool in assessing hemodynamic instability in septic shock patients. A1ccordingly, echocardiography training is crucial to help its widespread use in all ICUs.

Alteration of myocardial performance, characterized by left ventricular systolic and diastolic dysfunction, is a common and early complication of septic shock and has a significant impact on patient's prognosis. Cardio-vascular biomarkers are commonly used for diagnosis and risk stratification in cardiac patients. In particular, troponins are included in the definition of acute coronary syndrome and natriuretic peptides are the gold standard biomarkers for the diagnosis and the risk stratification of acute heart failure. Interest has recently focused on the use of these biomarkers as tools to identified cardiac sepsis-induced dysfunction and prognosis. Although echocardiography would be needed to confirm the diagnosis of cardiac dysfunction, biomarkers can alert physician and lead to perform a cardiac ultrasound. Whereas many evidences suggest that cardiac troponins are useful in severe sepsis or septic shock to identify those patients requiring early and aggressive therapy more studies are needed before considering natriuretic peptides in this indication. Among the most recently described biomarker, few data suggest that mid-regional pro-adrenomedullin (MRproADM) could be useful for risk stratification of septic patients.

Septic cardiomyopathy is frequently observed in patients with severe sepsis however it often does not require specific therapy. In patients presenting signs of tissue perfusion and inadequate cardiac output, manipulation of cardiac output should be considered. The first line therapies consist in optimization of preload by fluid administration and of afterload by decreasing the doses of vasopressor agents whenever possible. Inotropic agents should then be considered. Among these dobutamine remains the most commonly used, even though there is a huge individual variability in the response to it. The lowest dose associated with a satisfactory hemodynamic state should be used, as high doses for a prolonged period of time can be associated with impaired outcome. Phosphodiesterase inhibitors are often limited by their peripheral dilatory properties. Levosimendan is a promising inotropic agent, but its superiority to classical adrenergic inotropic agents remains to be determined.

Tachycardia is an independent risk factor for mortality and morbidity in different clinical conditions such as coronary artery disease, myocardial infarction, as well as congestive heart failure. Evidence suggests that an elevated heart rate is associated to increased mortality even in septic shock. It has been recently demonstrated that tachycardia persisting at 24 hours, after volume resuscitation and commencement of vasopressors, early identifies a particularly severe subset of septic shock patients. These high-risk patients would likely benefit most from HR control. A reduction in HR should be therefore considered as one of the therapeutic targets to improve patient outcome. Nevertheless, reducing HR in septic shock is difficult, because the right time for treatment and the optimal HR range are not currently defined. Based on the underlying mechanisms of elevated heart rate in septic shock, both beta blocker esmolol and hyperpolarization-activated cyclic nucleotide gated channel inhibitor ivabradine appear to be the most appropriate drugs for treating elevated HR. Nevertheless, the effectiveness and safety of these agents, the degree of HR reduction, as well as the appropriate target population, should be better defined before widely adopting this therapeutic strategy in the common clinical practice. The aim of this chapter is therefore to provide an overview of the underlying mechanisms of sepsis-induced tachycardia and their implications in the clinical management of affected patients.

Sepsis remains the most common admission diagnosis to ICU and approximately half of these patients develop some form of cardiac dysfunction. Genetic factors, large vessel and microcirculatory changes, depressant factors, metabolic changes, autonomic dysregulation and a myriad of cellular regulators have all been implicated in the myocardial dysfunction. The cardiomyopathy is reversible may include elements of LV and RV systolic and diastolic dysfunction. Current approaches to treatment include guideline based septic shock therapy often along with inotropic support, however a new approach may include heart rate control.