Septic cardiomyopathy - A not yet discovered cardiomyopathy?

Abstract

Myocardial depression in human sepsis was only unequivocally proven in the 1980s by the group of Parrillo, who used nuclear imaging techniques to measure heart volumes and function in intensive care patients. Heart failure in sepsis is frequently masked by a seemingly normal cardiac output. However, relative to the lowered systemic vascular resistance - resulting in a reduced afterload - cardiac outputs and ventricular ejection fractions are often not adequately enhanced. This septic cardiomyopathy (impairment of the heart within the scope of systemic sepsis) involves both the right and the left ventricles, and is potentially reversible. In response to volume substitution, the heart can be considerably enlarged. The cardiomyopathy is not primarily hypoxic in nature, but may be aggravated by ischemia. Autonomic dysfunction, documented by a reduced heart rate variability and impaired baroreflex and chemoreflex sensitivities, forms part of the disease entity. The severity of myocardial depression correlates with a poor prognosis. Noninfectious systemic inflammatory response syndrome can give rise to an analogous disease entity, namely, systemic inflammatory response syndrome cardiomyopathy.The etiology of septic cardiomyopathy is multifactorial. Several candidates with a potential pathogenetic impact on the heart were identified: bacterial toxins; cytokines and mediators including tumour necrosis factor-alpha, interleukin-1 and nitric oxide; cardiodepressant factors; oxygen reactive species; and catecholamines. Symptomatic treatment consists of volume substitution and catecholamine support; causal therapeutic approaches aiming at an interruption of the proinflammatory mediator cascades are being tested.

Keywords: Autonomic dysfunction; Cardiomyopathy (septic); Heart failure (septic); Sepsis; Shock (septic).

Figures

Figure 1)

Pathophysiology of sepsis and escalating systemic inflammatory response syndrome (SIRS). For further explanation, see text. Gr Granulocytes; Ma Macrophages; MODS Multiple organ dysfunction syndrome; NS Nervous system

Figure 2)

Case report: cardiovascular changes in Pseudomonas sepsis. The patient suffered from an aspiration pneumonia on day 1. After initial stabilization, cardiovascular deterioration occurred, resulting in septic shock around day 7. Thereafter, the patient uneventfully recovered. This patient did not suffer from septic cardiomyopathy; notice the high cardiac output (CO) values of this patient even in the shock state. SVR Systemic vascular resistance. Reproduced from reference

Figure 3)

Correlation between cardiac output (CO) and systemic vascular resistance (SVR) in 31 patients with septic multiple organ dysfunction syndrome. In patients with septic multiple organ dysfunction syndrome, CO has been repeatedly measured during the course of the disease and plotted against the respective SVR. With decreasing after-load (fall in SVR), CO values increase, with considerable variation for each specific SVR value. The upper line of the graph represents the maximal achievable CO values for the respective SVR, while the values below indicate reduced CO values of different degrees

Figure 4)

Myocardial depression in patients with Gram-negative, Gram-positive and fungal septic shock. Left ventricular stroke work index (LVSWI) as a clinical marker of inotropy has been calculated in patients with septic shock of different etiologies. For further discussion, see text. E coli Escherichia coli; P species Pseudomonas species; Gram–Gram-negative pathogenic agents; Gram+ Gram-positive pathogenic agents; Fungi Fungal pathogenic agents. Modified from reference

Figure 5)

Cardiodepressive factors (CDFs) in sepsis – experimentally proven concepts. Besides unspecific damages to cardiomyocytes (eg, by staphylococcal alpha-toxin [4], Pseudomonas exotoxin A [4,11] and lipoteichoic acid [12]), specific alterations to inotropic signal transduction pathways are induced by toxins and mediators; alterations occur in the positive inotropic pathways, namely, the beta-adrenoceptor-G-protein-adenylyl cyclase cascade, the alpha-adrenoceptor-phosphoinositol cascade and the Ca2+ transient, as well as in the negative inotropic pathways, namely, the nitric oxide (NO)-guanylyl cyclase cascade – a counterpart to the beta-adrenoceptor-G-protein-adenylyl cyclase cascade – and the sphingomyelin-ceramide cascade. As a consequence, there is a complex alteration of basal contractility as well as of stimulated contractility (by beta- and alpha-adrenoceptors, by digitalis and by Ca2+) in cardiomyocytes. Further deterioration of contractile function of the cardiomyocyte comes from the impairment of energy metabolism with disturbed oxygen utilization at the cellular level (cytopathic hypoxia [67]), the induction of inflammatory signal transduction pathways (nuclear factor kappa B and cytokines) in cardiomyocytes, the damage triggered by reactive oxygen species and peroxynitrite, as well as by the induction of apoptosis. For further information, see references and , and for information on specific components, see the following references: CDFs (34,35,37); endotoxin (10); energy metabolism (44,56,65,66,108,109); complement (110); tumour necrosis factor-alpha (TNF-α) and interleukin (IL)-1-beta (,,,,–53); NO (,,,,–70,74,103,104); ceramide (42); phosphoinositol metabolism (43); apoptosis (–47); reactive oxygen species and peroxynitrite (–57); nuclear factor kappa B (58); NO-guanylyl cyclase pathway (64); and beta-adrenoceptor-G-protein-adenylyl cyclase pathway (70,72,74,111). cGMP Cyclic GMP; Complement Representative term referring to the activation of the complement pathway in cardiomyocytes; IP3 Inositol triphosphate

Figure 6)

Induction of inducible nitric oxide synthase (iNOS) in beating neonatal rat cardiomyocytes in culture by endotoxin, tumour necrosis factor-alpha (TNF-α) and interleukin-1-beta (IL-1β) in cardiodepressive concentrations. Spontaneously beating neonatal rat cardiomyocytes in culture were incubated for 24 h with either TNF-α, IL-1β or endotoxin in cardiodepressive (see Figure 7) concentrations as indicated, in the absence or presence of dexamethasone (Dex) to suppress iNOS induction. Thereafter, semiquantitative reverse transcription polymerase chain reaction (RT-PCR) for iNOS was carried out to document the induction of messenger RNA, with the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) used for reference. For further information, see text and references and . M Marker

Figure 7)

Preincubation of beating neonatal rat cardiomyocytes in culture with tumour necrosis factor-alpha (TNF-α) blocks beta-adrenoceptor-mediated increases in pulsation amplitude. Spontaneously beating neonatal rat cardiomyocytes were incubated for 24 h with 10 U/mL TNF-α (see Figure 6). Thereafter, cells were electrically driven and superfused with the beta-adrenergic agonist isoproterenol. In control cells, isoproterenol induced a reversible increase in pulsation amplitude, indicative of a positive inotropic effect of this catecholamine. In TNF-α-pretreated cells, however, no increase in pulsation amplitude could be seen, showing a block of the beta-adrenoceptor-mediated increase in pulsation amplitude by TNF-α. For further information, see text and references and

Figure 8)

Inhibition of mitochondrial oxygen consumption in beating neonatal rat cardiomyocytes by tumour necrosis factor-alpha (TNF-α). Spontaneously beating neonatal rat cardiomyocytes in culture were incubated for 24 h with the indicated concentrations of TNF-α. Thereafter, mitochondria were isolated from the cells and oxygen consumption of complexes I and II were measured. A concentration-dependent inhibition of complexes I and II activity by TNF-α can be seen. For a further explanation, see text and reference . Modified from reference

Figure 9)

Twenty-four hour heart rate monitoring in a patient with, as well as in a patient without, sepsis and multiple organ dysfunction syndrome (MODS). A higher heart rate (ordinate) is clearly evident, as well as heart rate rigidity in the registration of the patient with sepsis and MODS. From these data, heart rate variability (HRV) parameters can be calculated (see Table 3), demonstrating a strong reduction of HRV (HRV rigidity) in a patient with sepsis and MODS. For a further explanation, see text and reference . Modified from reference

Figure 10)

Predictive value of heart rate variability (HRV) in patients with multiple organ dysfunction syndrome. The Kaplan-Meier curve for 28-day survival uses the optimal cutoff point of the HRV parameter lnVLF (defined as the natural logarithm of HRV in the very low frequency range) (see Table 3) (3.9 lnms2) for the entire cohort of patients with multiple organ dysfunction syndrome (n=85). The dashed line indicates values above, and the solid line indicates values below, the cutoff point. The hazard ratio for 28-day mortality was 2.9 (95% CI 1.3 to 6.6). For a further explanation, see text and reference . Modified from reference