Characterization of cardiac dysfunction in sepsis: an ongoing challenge.

SHOCK, Vol. 41, No. 1, pp. 12Y24, 2014

Review Article CHARACTERIZATION OF CARDIAC DYSFUNCTION IN SEPSIS: AN ONGOING CHALLENGE Ahmed Zaky,* Steven Deem,* Karim Bendjelid,† and Miriam M. Treggiari* *Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington; and † Department of Anaesthesiology, Pharmacology and Intensive Care, Geneva University Hospitals, Geneva, Switzerland Received 14 May 2013; first review completed 29 May 2013; accepted in final form 25 Sep 2013 ABSTRACT—Sepsis-induced cardiomyopathy (SIC), which is a common morbid condition, occurs in patients with severe sepsis and septic shock. The clinical characterization of SIC has been largely concept-driven. Heart function has traditionally been evaluated according to two basic conceptual models: a hydraulic pump system, whereby the output from the heart is entirely dependent on its input, or a hemodynamic pump, whereby the cardiac output is a function of preload, global ventricular performance, and afterload. Minimal attention has been given to the intrinsic contractile function of the heart or to the interaction between the peripheral circulation and the intrinsic myocardial function in sepsis. Currently, SIC is assumed to be the result of the interaction of microorganisms that activate the physiopathological pathways and cellular signaling mechanisms that lead to intrinsic myocardial dysfunction. However, the animal models used to study SIC exhibit multiple limitations. This review addresses the conceptual background, historical perspectives, physiologic mechanisms, current evidence, and limitations of SIC characterization. It also highlights potential future directions for the hemodynamic assessment of the intrinsic contractile function of the heart to overcome current methodological limitations. Finally, the present review recommends the exploration of additional potential mechanisms underlying SIC. KEYWORDS—Septic shock, cardiomyopathy, toll-like receptors, mechanisms, myocardial dysfunction, echocardiography

INTRODUCTION

model. Using this theory, the pump function may be best assessed by the cardiac index. Driven by echocardiography, the other model conceptualizes the heart as a Bhemodynamic[ pump in which the heart globally contracts to peripherally propel blood. Using this global hemodynamic pump concept, the cellular and architectural determinants of contractility are not appraised. This school of thought relies on the left ventricular (LV) ejection fraction (EF) as the most sensitive measure of myocardial performance. Both schools of thought conceptualize LV contractility and relaxation as global and mutually exclusive events that occur during systole and diastole. Both schools of thoughts also visualize the heart and the peripheral arterial circulation as discrete structures and do not take into account that ventriculoarterial Bcoupling[ is an intrinsic property of ventricular performance. As a result of these conceptual limitations, the majority of hemodynamic studies in sepsis have focused on cardiac performance to characterize SIC without considering the impact of the systemic arterial circulation and effective arterial elastance on cardiac function (6). Equally interesting (and likely consequential) is the fact that, despite the key contributory role of the cardiovascular system to the diagnosis and prognosis of sepsis, no societal classification exists for SIC from the perspectives of critical care and cardiology. In the present review, we discuss the current clinical characterization of SIC and its commonly described mechanisms. We emphasize the fact that the major hemodynamic studies have focused on cardiac performance to predict prognosis without assessing the interactions of the heart and vessels (heart efficiency) and the systemic arterial circulation. Finally, we highlight several current limitations in the evaluation of SIC and

Sepsis, the systemic inflammatory response to infection, is characterized by a cascade of events that can evolve from multiorgan dysfunction to failure and death (1). There is a high mortality rate associated with sepsis (2), which may be attributed to the lack of specific treatment beyond infection source control, antimicrobial therapy, and supportive management. The heart is one of the most frequently affected organs in sepsis. Approximately 50% of the patients who are diagnosed with sepsis exhibit signs of myocardial dysfunction (3). Several reports have suggested that patients with sepsis who develop myocardial dysfunction are more likely to die compared with those without evidence of myocardial dysfunction (4). The clinical characterization of sepsis-induced cardiomyopathy (SIC) appears to be concept-driven. Conceptually, the myocardium in sepsis represents a pump that functions in two ways (5). Influenced by the technological limitations of hemodynamic monitoring, the heart in the first model is conceived as a passive Bhydraulic[ input-output system in which cardiac output is a function of preload and afterload with no appraisal of ventricular contractility. The Frank-Starling law applies to this conceptual

Address reprint requests to Ahmed Zaky, MD, MPH, Department of Anesthesiology and Pain Medicine, 1660 S Columbian Way, Seattle, WA 98108. E-mail: [email protected]. No funding was received for this study. The authors have no conflicts of interest to declare. DOI: 10.1097/SHK.0000000000000065 Copyright Ó 2013 by the Shock Society

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Copyright © 2013 by the Shock Society. Unauthorized reproduction of this article is prohibited.

SHOCK JANUARY 2014 propose avenues for further investigation to bring together heart dysfunction and distributive shock. HISTORICAL PERSPECTIVE Cardiac dysfunction in sepsis: the heart as a hydraulic pump

Role and utility of central venous pressure measurement— Technological limitations have contributed to the early concepts of cardiac dysfunction in sepsis. The inability to assess cardiac contractility at the bedside led investigators to use loaddetermined indices as proportionate surrogates of cardiac contractility. MacLean et al. (7) interpreted a low cardiac index in response to a low or high central venous pressure as a surrogate of a late and irreversible Bcold[ phase of sepsis-induced cardiac depression, which is characterized by lactic acidemia and low flow state. Although these endeavors were considered to be pioneering at that time, they are physiologically limited; cardiac index is a load-determined marker of cardiac function. For example, a patient with poor myocardial contractility may demonstrate a normal cardiac index in the presence of abnormally low afterload, whereas a patient with normal contractile function may manifest a low cardiac index in the setting of a pathologically low preload. Technologically, the use of the dye dilution in measuring cardiac output and the lack of central venous catheter position confirmation are all limitations in these early reports (8). Over time, these early reports were undermined by the accumulating evidence of a poor correlation between the central venous pressures, which were used in these studies to assess LV preload and LV end-diastolic pressure in septic shock (9). Role and utility of pulmonary artery catheters—With the advent of the pulmonary artery catheter, which allowed simultaneous evaluation of individual ventricular cardiac output and filling pressures at the bedside, the concept of sepsis-induced myocardial dysfunction was further challenged. Unchanged in the use of the surrogate marker, yet specifically addressing the LV load-output relationship, studies that used pulmonary artery catheter to assess SIC regarded septic shock as a hyperdynamic state that was characterized by high cardiac output and low systemic vascular resistance, which was persistent in nonsurvivors of septic shock (10). The concept of a terminal hypodynamic phase in septic shock, proposed in earlier studies, was thus attributed to inadequate volume resuscitation, rather than a primary myocardial dysfunction (11). As one might conceive from these studies, using an inputoutput concept of cardiac function in the absence of diagnostic modalities capable of measuring the intrinsic receptive and contractile function of the heart was a major impediment in the understanding of SIC. That static indices of cardiac filling, such as central venous pressures (12) and pulmonary capillary pressures (13), were reliable indices of cardiac preload was an incorrect assumption that has been recently challenged. Interestingly, growing evidence (14) emerged, which suggested that a substantial portion of the hypotension observed in septic patients is due to primary alterations in systolic cardiac function, rather than the consequence of dysfunction originating from the peripheral circulation and absolute or relative intravas-

CARDIAC DYSFUNCTION IN SEPSIS

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cular volume depletion. The advent of these reports signaled the beginning of a new chapter in the story of SIC. Cardiac dysfunction in sepsis: the heart as a global hemodynamic pump

Linking the load to the pump: ventriculography and pulmonary artery catheter Left ventricular systolic function. Pioneering attempts were made to characterize and prognosticate intrinsic contractile dysfunction in sepsis. Conceptually, these theories proposed EF, a global surrogate of myocardial contractility, as a proportionate indicator of myocardial function. Although these reports discovered Bnew[ findings, severe technical, conceptual, and methodological limitations tempered the reproducibility of these reports. The initial concept of sepsis-induced myocardial depression, despite a high cardiac output, came from a seminal study conducted by Parker et al. (15), using serial radionucleotide ventriculograms in 20 patients with septic shock. A striking yet paradoxical finding was demonstrated in this study: sepsis survivors manifested a reversible reduction in EF coupled with a severe increase in LV end-systolic and -diastolic volumes compared with nonsurvivors, who maintained a normal EF and LV volumes throughout the observation period. Parker et al. (15) attributed this paradoxical EF/survivorship observation (in the presence of elevated cardiac index in both groups) to a greater reduction in systemic vascular resistance in nonsurvivors. Of note, cardiac output was calculated using thermodilution techniques, LV volume indices were calculated indirectly from cardiac output, and EF was measured using thermodilution and ventriculograms. The study population was heterogeneous with four patients who presented with underlying cardiac disease and nonsurvivors who received significantly higher doses of levarterenol, a weak inotropic agent yet a potent vasopressor. Based on the findings of this study, Parrillo (16) introduced the concept of preload adaptation in sepsis survivors, whereby the left ventricle acutely dilates as a compensatory response to the decline in systolic function to maintain a normal cardiac output before full functional and structural recovery. These novel findings on LV performance in sepsis triggered attempts to characterize right ventricular performance. Right ventricular systolic function. Using the same methodology, Parker et al. (17) attempted to characterize right ventricular function (in conjunction with LV function) in sepsis. Although several findings were replicated, others were slightly different. Whereas the survivors of septic shock maintained a reversible reduction in biventricular EF, coupled with elevated end-diastolic and -systolic volumes, the same pattern was maintained in nonsurvivors throughout the study period; i.e., survivors and nonsurvivors varied only in the reversibility of an initially abnormal picture. More interestingly, this study demonstrated an elevation of biventricular filling pressures, defeating the concept of preload adaption proposed by the same authors in their previous study in which LV dilatation was accompanied by normal filling pressures (17). The work performed by Parker and colleagues (15, 17) is an example of a technically limited conceptual derivation. Indeed,


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SHOCK VOL. 41, NO. 1

radionucleotide ventriculography, albeit a sensitive tool for measuring EF, is a low-resolution tool for measuring LV enddiastolic volumes, which likely explains why the magnitude of LV dilatation in the study performed by Parker et al. was not reproduced in studies in which LV volumes were measured directly with echocardiography. Based on the findings of these studies, we observed a need for a facile tool that would be capable of directly measuring ventricular volumes and pump function. This need signaled the recruitment of echocardiography to explore SIC. Role, utility, and performance of echocardiography in sepsis Systolic versus diastolic dysfunction during sepsis. Recent human studies using echocardiography have replicated a similar Bsurvivorship[ hemodynamic profile, which consisted of an initial and transient decline in EF followed by recovery of a physiologic Frank-Starling relationship (15). Neither the initial increase in LV end-diastolic volume nor the resultant preservation of stroke volume initially observed by Parker et al. (15) was consistently replicated using echocardiography-based studies. These studies, which were single-centered and observational in nature, lacked control groups and were inconsistent regarding their resuscitation goals, timing of echocardiographic examination, thereby potentially confounding the external validation of their results. Vieillard-Baron and colleagues (18) questioned the concept of preload-adaptation observed by Parker et al. (15) in a transesophageal echocardiographic (TEE) study. After adequate preload optimization, the authors directly measured ventricular volumes and calculated cardiac and stroke volume indices. Interestingly, the authors observed no correlation between the LV end-diastolic volumes and the stroke volume index. A strong correlation existed between ventricular systolic indices (EF) and stroke volume index. Importantly, the authors reported normal ventricular end-diastolic volumes in all patients. The authors interpreted the discrepancy using the concept of preload adaptation by the constraining role of the pericardium on volume-resuscitated ventricles. Intriguingly, there is no discrepancy between the two studies (15) when LV volume index is indexed to afterload, i.e., the systemic vascular resistance index (SVRI). Calculating SVRI for the patients studied by Vieillard-Baron et al. (on the basis of the hemodynamic data provided) permits us to ascertain that LV volume index is related to SVRI in both studies (19). The findings in the study by Vieillard-Baron et al. (18) were confirmed in another longitudinal TEE study in which survivors of septic shock showed a reversible decline in EF compared with nonsurvivors who maintained an irreversible pattern of systolic dysfunction. As measured by TEE, there was no evidence of an increase in LV end-diastolic volumes. In addition, a reversible diastolic dysfunction (as measured by lateral mitral annulus tissue velocity using Doppler tissue imaging) was observed in survivors compared with nonsurvivors (20). In contrast, other echocardiographic studies, although revealing a similar pattern of transient and reversible decline in LV systolic function, demonstrated a reversible increase in LV enddiastolic area (21). Adding serum troponins to the imaging equation, Bouhemad and colleagues (22) identified a subgroup of patients in whom acute LV dilatation occurred in the presence of elevated serum troponins and decline in EF and stroke

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volume. The authors adopted the phenomenon of preloadadaptation (21) to explain their findings. Given the limitations and controversy surrounding the relationship between ventricular EF and dimensions on one side and survival on the other, a recent meta-analysis (23) was conducted to answer this question by pooling the evidence from relevant studies. In this meta-analysis that included more than 700 patients from 14 studies, there were no significant differences between sepsis survivors and nonsurvivors in terms of biventricular EF and indexed biventricular dimensions. Only unindexed LV dimensions were significantly larger in survivors (23). The findings of this meta-analysis provided the most recent evidence that preload adaptation (if it, in fact, exists) is not related to survival. Whether more sensitive indices of preclinical ventricular systolic dysfunction are associated with mortality remains to be proven. The results reported by Bouhemad et al. (22) should be interpreted with caution because of limitations that include, but are not limited to, the heterogeneity of the study population with regard to several clinical characteristics, the arbitrary group classification based on serum troponins and LV function, the lack of electrocardiographic data, and the lack of specification of physiologic goals of fluid resuscitation. Most importantly, the study lacked a correlation between the fractional area of change (a surrogate of ventricular systolic function) and the LV diastolic area (a surrogate of ventricular end-diastolic volume). Furthermore, the correlation between an increase in the enddiastolic area and a reduction in stroke volume was reported only on day 1 of the study. In the absence of such data and with a lack of proof that an increase in the LV end-diastolic area leads to a change in stroke volume or cardiac output, it is uncertain whether preload adaptation is an antecedent or a consequence of LV systolic dysfunction. The study by Bouhemad and colleagues (22) has fueled a surge of subsequent studies that explored the diastolic function in sepsis. Diastolic dysfunction during sepsis. Until recently, the role of diastolic dysfunction in SIC was unexplored. Diastolic function in sepsis has previously been echocardiographically assessed individually and in conjunction with serum biomarkers, in small prospective studies in critically ill patients with severe sepsis and septic shock. In a replication of their study, Bouhemad et al. (22) observed an isolated and reduced reversible LV relaxation in 20% of 54 patients with septic shock coupled with an increase in serum troponin I and tumor necrosis factor ! (TNF-!), interleukin 8 (IL-8), and IL-10. The authors used tissue Doppler mitral annular imaging (E¶) and mitral flow propagation velocity (Vp) as echocardiographic indices of diastolic dysfunction. Doppler tissue echocardiography uses high-amplitude and low-velocity Doppler signals derived from the myocardial tissue, in contrast to mitral inflow, which uses low-amplitude and high-velocity Doppler signals derived from blood cells. By assessing myocardial tissue motion, tissue Doppler imaging is thought to be less load-dependent compared with transmitral Doppler (24). Mitral flow propagation velocity assesses the basal apical diastolic propagation of blood within the left ventricle. It provides a spatial-temporal information of blood flow velocities across a vertical line and is thought to be


SHOCK JANUARY 2014 less load-dependent than transmitral flow velocities (25). Additional limitations of this study included nonconformation to consensus guidelines (26) of diagnosing diastolic dysfunction, such as the ratio of early mitral inflow velocity (E) to (E)¶, E/E¶, and their use of fractional area or change, rather than EF, and indexed LV end-diastolic volume as measures of systolic dysfunction. Importantly, the authors provided no information on comorbidities known to influence indices of LV dysfunction. No statistical adjustments were performed for age, sex, and use of vasopressors, which are known factors that influence diastolic cardiac function (26). In a subsequent study, Ikonomidis et al. (27) observed a statistically significant association between the aminoterminal proYbrain natriuretic peptide (NT-pro-BNP) and E/E¶ in a group of 58 mechanically ventilated patients with septic shock with preserved LV EF. Both T-BNP and E/E¶ were prognostically related to in-hospital mortality. The patients’ baseline comorbidities were not provided, echocardiographic measurements were not consistent among patients, and the calculations were not performed serially. In the largest and most recent study to date that assessed diastolic dysfunction in sepsis, Landesberg et al. (28) prospectively evaluated the diastolic function of 262 ICU patients. Both lateral and septal E¶ and E/E¶ were independent predictors of mortality, after adjusting for age, hypertension, and diabetes. Interestingly, Vp originally described by Bouhemad et al. (22) was not found to be significantly associated with mortality. Of note, patients with diastolic dysfunction had significantly higher serum troponin T and NTpro-BNP. Interestingly, LV EF, which was not previously found to be associated with mortality, was shown to be a predictor of mortality. The authors did not perform serial echocardiograms to monitor the effect of sepsis resolution on indices of diastolic dysfunction. In summary, diastolic dysfunction is a recognized phenomenon in critically ill patients with septic shock. Multiple inconsistencies exist in the timing and the use of echocardiographic indices of diastolic function. Whether serum biomarkers are modifiable risk factors or simply markers of diastolic dysfunction remains to be elucidated. At this stage, the effects of peripheral circulation on sepsis-induced diastolic dysfunction have not been established. Limitations of currently used indices of ventricular function—The current assessment of SIC is liable to limitations of both indices sought and imaging modalities used to assess these indices. We discuss these limitations by index and modality. Cardiac index is a load-determined index of ventricular function. It is not an intrinsic measure of ventricular contraction or relaxation. In addition, cardiac index does not provide information about the function of other chambers of the heart, such as the atria and pericardium. It does not provide information about myocardial tissue motion or size, the latter being relevant functional and prognostic indices of ventricular function. Using this flow index as a marker of ventricular contractility (7, 8) conforms to the conceptual modeling of the heart as a Bhydraulic pump[ (Table 1). Ejection fraction, another global index of ventricular ejection, reflects the circumferential shortening of the left ventricle; in this regard, it does not take into account the longitudinally arranged subendocardial fibers that are more prone to ischemia


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and fibrosis earlier than the circumferentially arranged fibers (29). Furthermore, EF is a load-dependent index that does not reflect the intrinsic myocardial contractile function (30, 31), which shares this limitation with cardiac index. It is therefore possible that EF varies across studies, depending on the amount of resuscitation patients have received (preload) and their stage of sepsis (afterload), rather than on a true contractile deficiency. Ejection fraction being a global index of ventricular function could be insensitive to regional myocardial abnormalities. Hyperkinetic segments bordering hypokinetic segments may thus erroneously produce a normal EF. In this respect, the use of EF as a surrogate of ventricular contractility (15, 17, 18, 20, 21) conforms conceptually to regarding the heart as a Bhemodynamic pump,[ not taking into account the intrinsic mechanical function of the heart (Table 1). Indeed, ventricular volumes are dimensional indices of ventricular function that are unable to provide insight into the underlying ventricular function. In addition, the size of cardiac chambers, elastance, and valvular competency are all confounding factors that can potentially affect the consistency of ventricular volumetric measurements across different studies (Table 1). Isotopic ventriculography is one of the oldest and most costeffective modalities used to assess ventricular function. Although it is a sensitive modality for measuring EF, it is less sensitive for measuring ventricular volumes. It relies on accurate border detection, which is not always achievable. Moreover, ventriculography-derived measurements may be invalidated in the presence of pericardial disease, such as effusion and constriction. In addition, there are hazards of contrast and radiation exposure (32). Echocardiography has emerged as a recent modality that is capable of assessing the intrinsic function of the heart. Its use in the assessment of SIC has focused primarily on measurements of EF, ventricular volumes, and diastolic function using twodimensional and spectral Doppler transmitral and mitral annular tissue velocities. Two-dimensional echocardiography is less accurate than three-dimensional echocardiography for measuring ventricular volumes and EF; however, the latter suffers from a wide interobserver variability (33). Moreover, TEE underestimates ventricular volumes in 10% of the cases (34). In addition, EF measurement using echocardiography depends on an accurate identification of the endocardial borders, which could be inaccurate in approximately 30% of the cases when the images assessed are of low resolution (35). Transthoracic echocardiography may be less optimally performed in critically ill patients, who receive mechanical ventilation, have chest tubes, or have increased body habitus (31). Notably, TEE may underestimate ventricular volume compared with TTE and transpulmonary thermodilution (34). Doppler tissue imaging, which is used to assess mitral annular tissue velocity as a surrogate of diastolic function, is not without limitations. As mentioned above, Doppler tissue imaging measures the diastolic displacement of the mitral annulus, in contradistinction from the transmitral spectral Doppler that measures blood velocity. Compared with transmitral flow Doppler, tissue Doppler is less load dependent and hence may be a more reliable surrogate of intrinsic ventricular diastolic function (24). Doppler imaging requires that the plane of tissue motion of interest is


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TABLE 1. Summary of human studies of SIC References

Study design No. patients Conceptual model

Diagnostic criteria

Findings

MacLean et al. (7)

Case series

56

Hydraulic pump

CVP/CI

‘‘Warm’’ initial high CI in survivors; ‘‘cold’’ late low cardiac index in nonsurvivors

Clowes et al. (8)

Case series

25

Hydraulic pump

CVP/CI

High CI in survivors; ‘‘heart failure’’ (low CI) in nonsurvivors

Parker et al. (10)

Cohort

48

Hydraulic pump

CI/HR/SVRI

j CI both in survivors and nonsurvivors (initially), with normalization in survivors only; reversible jj EDV in survivors

Parker et al. (17)

Cohort

39

Hemodynamic pump EF/EDV-RV/LV

Survivors: initial decline in RV/LV EF and elevation in EDV

Vieillard-Baron et al. (18)

Cohort

40

Hemodynamic pump EF/EDV/SI

SI correlated with EF; no j LVEDV

Etchecopar-Chevreuil (20)

Cohort

35

Hemodynamic pump EF/EDV LV Survivors: initial decline in EF, LV relaxation, diastolic function and increase in LVEDV (with no LV dilatation)

Bouhemad et al. (21)

Cohort

45

Hemodynamic pump FAC/EDA/AV VTI

AV VTI , with LVEDA j

Bouhemad et al. (22)

Cohort

54

Hemodynamic pump FAC/E¶/Vp

Parallel reversible isolated diastolic dysfunction and inflammatory biomarkers

Ikonomidis et al. (27)

Cohort

58

Hemodynamic pump E/E¶, E, S¶ by TDI NT-pro-BNP correlated with j E/E¶, and , E¶, and all correlated with j in-hospital mortality

Landesberg et al. (28)

Cohort

262

Hemodynamic pump E¶/EF

, E¶, , EF alone or together associated with in-hospital mortality and with j NT-pro-BNP and j troponin T

, Indicates decrease; jj, highly increased; j, increase; AV; aortic valve; CI, cardiac index; CVP, central venous pressure; E¶, early diastolic velocity of mitral annulus; EDA, end-diastolic area; EDP, end-diastolic pressure; EDV, end-diastolic volume; E/E¶, ratio of early diastolic mitral inflow to early diastolic velocity of mitral annulus; FAC, fractional area of change; HR, heart rate; LV, left ventricle; Vp, early diastolic propagation velocity of mitral inflow; RV, right ventricle; S¶, early systolic velocity of mitral annulus; SI, stroke index; TDI, tissue Doppler imaging; VTI, velocity time integral.

parallel to the ultrasound beam. Therefore, only motions that occur away and toward a parallel plane of motion can be detected by Doppler tissue imaging. Motions that are sideways to this plane cannot be captured. Moreover, Doppler tissue imaging is more prone to noise and aliasing originating from neighboring blood flow velocities (36). Taken together, global indices (Table 1), both in principle and in practicality, are insensitive markers of cardiac performance in sepsis. Relying on insensitive parameters of LV contractility might be the reason for misclassifying nonsurvivors as patients with preserved EF. Whether more accurate imaging technology could reproduce these findings and reveal early manifestations of cardiac dysfunction is a relevant question. Peripheral Circulation in Sepsis and the ‘‘Overlooked’’ Concept of Ventriculoarterial Decoupling

There is considerable confusion about the evaluation of the myocardium in situ without reflecting on the state of the peripheral circulation. The major hemodynamic studies have focused on cardiac performance without assessing the role of arterial vessels and systemic circulation. The present misconception is related to our nearly complete inability to assess the ventriculoarterial coupling in patients with septic shock, making it difficult to assess cardiovascular efficiency in these patients. When the heart pumps blood into the vascular tree at a rate and volume that the arterial system is incapable of receiving it, both the cardiovascular performance and its associated cardiac energetics are worsened (6). Interestingly, the hemodynamic profile of septic patients is characterized by both a significant decrease in effective arterial elastance and a decrease in ventricular elastance that is secondary to depressed myocardial contractility

(6). In this setting, because effective arterial elastance is generally corrected by pharmacological vasoconstriction (norepinephrine) and the consequent increase in arterial tone, a decrease in ventricular elastance creates a ventriculoarterial decoupling with unfavorable cardiac energetics that are sacrificed to maintain tissue perfusion. Up to this point, we have considered the heart and the vessels as different parts; it is therefore tempting to blame the heart without considering the impact of the arterial vessels on the blood distribution. Moreover, both changes in the venous capacitance and the arterial resistance play a central role in the present ventriculoarterial decoupling as vasoplegia on the venous side increases splanchnic blood pooling and edema formation, thereby leading ultimately to the loss of stressed blood volume and cardiac preload (16, 37) (Table 1). Based on the findings of studies that merely evaluated the global heart-vessels interactions, a need arose for clinical mechanistic investigations that consider basic cellular research and mediators linked to the pathophysiology of SIC. PROPOSED MECHANISMS UNDERLYING SIC Coronary microcirculatory changes and myocardial injury

Decreased coronary blood flow is unlikely to represent a major underlying contributor to the development of SIC. To the contrary, coronary blood flow was shown to be either normal or increased in patients with septic shock and myocardial depression (38). Despite reports of elevated troponins, there has been no evidence of myocardial structural necrosis or cell death in the heart of humans with sepsis-induced cardiac dysfunction (39) or animal models of septic shock (40). Elevated cardiac troponins have been associated with LV systolic dysfunction in severe sepsis and septic shock (41). Troponin levels also


SHOCK JANUARY 2014 correlate with the duration of hypotension and the intensity of vasopressor therapy and have been associated with a higher mortality rate (42). It is speculated that the elevation of cardiac troponins may be attributed to an increase in myocardial membrane permeability in response to inflammatory mediators, rather than myocardial ischemic necrosis (43). It is unknown whether normalization of serum cardiac troponins correlates to the recovery of LV function in sepsis (Fig. 1). Rather than a quantitative decrease in coronary blood flow, a qualitative defect has been suggested as a mechanism of SIC. Generalized microvascular dysfunction is a prominent feature of sepsis that does not spare the cardiac microvasculature. Specifically, the observations of coronary blood flow maldistribution, the increased coronary microvascular resistance with impaired reactivity to vasodilators (44), and the transendothelial migration of neutrophils into the interstitial space (45) were demonstrated in animal models of septic shock (Table 2). The latter may


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augment myocyte inflammation, vascular leakage, and edema formation, thereby resulting in decreased cardiac compliance. In summary, current evidence does not support myocardial death as an underlying mechanism of elevated serum troponins, and the underlying mechanisms of their elevations are speculative at best. Autonomic dysregulation

It is now recognized that in physiologic conditions rhythms exhibit a certain degree of variability and that in disease states rhythms are frequently marked by increased regularity (or loss of variability). The loss of variability represents the loss of organ-to-organ communication (46). In sepsis, the loss of heart rate variability has heralded the onset of clinical sepsis and the progression to multiorgan failure with poor outcomes (47). Both central and peripheral mechanisms have been linked to the loss of heart rate variability. Centrally, septic shock is

FIG. 1. Schematic representation of the different mechanisms of SIC. Invasion of microorganisms activates both cellular and extracellular mechanisms. Activated TLRs provoke the transcription of cytokines (IL-1", TNF) from the nucleus. Interleukin 1" and TNF stimulate the coronary endothelial cells to release adhesion molecules (VCAM) that lead to the recruitment of neutrophils (polymorphonuclear neutrophils). Neuronal and glial apoptosis of the autonomic nervous system might explain the lack of responsiveness to elevated levels of catecholamines. The accumulation of intracellular calcium occurs because of the lack of sequestration of calcium to the SR mediated by the sarcoplasmic endoplasmic reticulum calciumYadenosine triphosphatase. Matrix metalloproteinases are incriminated in the degradation of the contractile pump of the cardiomyocyte. Nitric oxide released by iNOS inhibits mitochondrial cytochromes and leads to decreased adenine triphosphate (ATP) production. It also inhibits actin/myosin function. Peroxynitrate (PNO3) derived from nitrous oxide (NO) is theorized to mediate and add to the inhibitory effects of NO. MDF indicates myocardial depressant factors; mRNA, messenger radionucleic acid; mit, mitochondrial; PB, phospholamban; j, increase; ,, decrease.


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TABLE 2. Summary of experimental studies of sepsis-induced cardiomyopathy References Zhong et al. (66) Lalu et al. (70)

Species

Sepsis model

Guinea pig LPS (4 mg/kg) Rat

LPS (4 mg/kg)

Biological mechanism

Tissue examined

Inflammatory mediator(s)

Calcium

Ventricle ex vivo

NA

MMP

Ventricle ex vivo

NA

Measurement of cardiac depression

Pathway , L-Ca2+

, Cell length using motion detector

, MMP-2 activity in LV

, Cardiac work (CO PSPP)

j MMP-9 in plasma Isolated cardiomyocyte

NA

j NO, j cGMP

, Maximum myocyte shortening

Intact heart in vivo

NOS2

C3H/HeJ ,

, LV ejection phase (FS%, Vcf)

(C3H/HeJ)

NOS2

(C3H/HeN)

‘‘cardiac’’

, Isometric systolic/diastolic LV indices (dP/dt)

Kumar et al. (76)

Rat

IL1-", TNF-!, IL-1" + TNF-!, HSS

Baumgarten et al. (90)

Mice

LPS (25 mg/kg)

Zhu et al. (92)

PAL (50 Hg)

Mice

NO TLR-4

TLR-2

Intact heart

TNF-!, CGSF, interferon %

In vivo; isolated cardiomyocyte

, TNF-!, CGSF, IFN-% in TLR-2j/j, MyD-88j/j

j LVEDV , FAC , PWT , Sarcomere shortening

Rolli et al. (94)

Mice

Flagellin (40Y200 ng/kg)

TLR-5

Intact heart in vivo; cardiac myoblasts; isolated cardiomyocytes

NF-.B

, TLR-5, NF-.B

, EF

MAP kinases

, MAP kinases

j LVEDP/V

IL-1", IL-6, MIP-2, MCP-1

, IL-1", IL-6

, ESE

Fas, NF-.B

TLR-3j/j , NF-.B

VCAM-1, ICAM

VCAM-1, ICAM

, MIP-2, MCP-1 , EF, , FAC

Gao et al. (93)

Mice

Cecal ligation

TLR-3

In vivo intact heart

Knuefermann et al. (93)

Mice

DNA (CPG-ODN) (1 nm/g)

TLR-9

Isolated cardiomyocytes

Piel et al. (83)

Mice

Cecal ligation

Mitochondria LV pressure in vivo

NA

Exogenous cytochrome C LVP, dP/dt max-min to restore cytochrome oxidase activity

Raeburn et al. (55)

Mice

IP LPS (0.5 mg/kg)

Endothelium LV pressure in vivo

NA

VACM-1 antibodies to decrease neutrophil accumulation

j LVDP after adding VCAM-1 antibodies

NA

Mitochondria Heart in vivo

NA

Apoptosis, autophagy

Low levels of apoptotic cardiomyocytes, connnexin 43 redistributed to lateral membranes, j autophagosomes

Takasu et al. (39) Human autopsied heart

TNF-!, IL-1", IL-6, , TLR-9 iNOS, and NF-.B , TNF-!, IL-1", IL-6, iNOS, NF-.B

Loss of sarcomere shortening

, Indicates decreased; j, elevated; C3H/HeJ, mice deficient in TLR-4; C3H/HeN, wild-type mice not deficient in TLR-4; cGMP, cyclic guanylate monophosphate; CGSF, colony granulocyte stimulating factor; CO, cardiac output; CPG-ODN, bacterial sequenced DNA; dP/dt, pressure with respect to time; ESE, end-systolic elastance; FAC, fractional area of change; FS%, fractional shortening; HSS, human septic shock serum; IFN, interferon; IP, intraperitoneal; LPS, lipopolysaccharide; LV, left ventricle; LVP; LV pressure; MyD-88j, myeloid differentiation gene; MAP, mitogen-activated protein; max-min; maximum-minimum; MIP, macrophage inflammatory protein; MCP, monocyte chemotactic protein; NA, not applicable; NF, nuclear factor; NO, nitrous oxide; NOS2, NO synthase 2; PSPP, peak systolic pressure product; TLR-2j, TLR-2 deficient; Vcf, ventricular circumferential shortening.

associated with glial and neuronal apoptosis within the cardiovascular modulator centers (48). These changes are thought to represent an inflammatory response, which is primarily mediated by inducible nitric oxide (NO) synthase expression (48). Peripheral mechanisms are mediated by an increase in IL-6 levels (49), elevation of plasma free fatty acids (50), direct current blockade of the sinoatrial node (51), and sepsis-induced uncoupling of the sinoatrial node from cholinergic neural control (52). The latter is of particular interest because it has been theorized that stimulation of the vagal nerve induces an antiinflammatory response (53). Whereas the loss of heart rate variability as a negative prognostic sign in sepsis is an agreed-upon concept, there is no current consensus on the tools that quantitatively assess this variability (54). Moreover, the variability of other physiologic

parameters that are controlled by the autonomic nervous system, such as blood pressure, must be addressed in future studies. Endothelial dysfunction

Sepsis induces a host of endothelial abnormalities that are incriminated in organ dysfunction. Sepsis-induced endothelial activation describes an increased expression of adhesion molecules on endothelial cells in response to inflammatory cytokines, such as IL-1" and TNF-!, thereby resulting in a vicious cascade of injurious neutrophilic infiltration to cardiomyocytes. The expression of vascular cell adhesion molecule 1 (VCAM-1) has been demonstrated in the coronary endothelium and cardiomyocytes of murine models of septic shock. The blockade of VCAM-1 by monoclonal antibodies prevented myocardial depression and neutrophil accumulation in mice (55). Sepsis also


SHOCK JANUARY 2014 induced the physical disruption of endothelial cells, allowing inflammatory fluid and cells to seep into the interstitial space, simultaneously inducing a procoagulant state that may result in tissue microthrombi and ischemia. The markers of endothelial cell injury, such as intercellular adhesion molecule (ICAM), E-selectin, von Willebrand factor and its propeptide, and thrombomodulin, were all found to be elevated in sepsis (56). Sepsis-induced endothelial dysfunction may also reflect on the vascular tone, inasmuch as a decrease in the expression and the activity of endothelial-constitutive NO synthase, which leads to the failure of vascular relaxation (56). Given these abnormalities, it is not surprising that the markers of endothelial dysfunction are prognostically related to sepsis mortality (57) and to cardiac systolic and diastolic dysfunction (58). More studies are needed to explore specific markers of cardiac endothelial dysfunction and to investigate the relationship between these markers and the phenotypical abnormalities of cardiac performance. Circulating cardiodepressants

There are conflicting animal data on the role of circulating inflammatory mediators acting as myocardial depressants. Activated complement 3, IL-6, and TNF-! have been shown to inhibit myocardial shortening (59). In a canine model of septic shock, TNF-! produced a dose-dependent depression of LV EF (60). The administration of antibody against TNF-! to patients in septic shock was associated with an improvement in LV function (61). In contrast, in a rat model of sepsis, myocardial shortening appeared to be decreased in the absence of septic plasma (62), which suggests that circulating factors may not be exclusively responsible for myocardial depression. Despite their potential role in animal models of sepsis, the role of circulating cardiodepressants in humans remains speculative. Disorders of intracellular calcium regulation

Under physiologic conditions, calcium enters the cardiomyocytes via L-type channels during phase 2 of the cardiac action potential and releases intracellular calcium from the sarcoplasmic reticulum (SR). Intracellular calcium binds to troponin to relieve its inhibitory effect on actin/myosin bonding, leading to their cross linkage. At the end of phase 2, calcium is actively sequestered in the SR via sarcoplasmic endoplasmic reticulum calciumYadenosine triphosphatase regulated by the enzyme phospholamban (63). In this regard, disorders of calcium homeostasis, which have been described in sepsis, are related to calcium kinetics, i.e., calcium flux, intracellular handling, and disorders of sensitivity to intracellular calcium. Scattered foci of disrupted actin-myosin contractile apparatus were described in septic human hearts (64). Sepsis-induced cardiomyopathy has been reported to be associated with a decrease in the calcium current across cardiomyocytes (65), a decrease in the density of calcium L-type channels (66), and disordered calcium sequestration due to alterations in the phosphorylation of phospholamban. Similarly, myofilament calcium sensitivity and responsiveness of the ryanodine receptor to calcium are reduced (67). Collectively, SIC is characterized by disordered calcium homeostasis that is associated with impaired cardiac contractility.


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The current mechanisms, as well as the time course of these abnormalities, must be further elucidated. Matrix metalloproteinases

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that degrade components of extracellular matrix and modulate inflammatory proteins. They can be classified broadly by substrate specificity into collagenases (MMP-1, -8, and -13), gelatinases (MMP-2 and -9), stroma-lysins (MMP-3, -10, -11), elastases (MMP-7 and -12), and membrane-type (MT-MMPs-14 and -17). The regulation of MMPs is modulated by tissue-specific MMPs inhibitors (68). In sepsis, inflammatory cytokines (such as IL-1, TNF-!) and peroxynitrates activate the release of MMPs, which leads to matrix degradation, coagulopathy, and organ damage (69). The role of different MMPs has been investigated in both animal and human models of sepsis with conflicting results. In a rat model of sepsis (70), lipopolysaccharide-induced myocardial depression was associated with decreased activity of MMP-2 and increased circulating levels of MMP-9, which suggests that MMP-9 may contribute to endotoxin-induced myocardial depression. In another rat model of early sepsis, MMP-9 was found to correlate with the severity of sepsis and histologic tissue damage (lungs, kidneys, liver) (71). Consistent with these observations, MMP inhibitors were found to be protective against SIC in a rat model of sepsis (72). In contrast to animal models of sepsis, several human studies reported a correlation between MMP-9 and sepsis severity and mortality (73), whereas others reported an inverse correlation with sepsis severity and mortality (74). Based on these findings, a definitive and exclusive role of MMPs is unclear in human sepsis. These contrasting findings might be the result of the variability in the site, timing, assay, and end points in the investigations of MMPs. More importantly, multiple (and potentially conflicting) factors modulate the release of MMPs and their inhibitors at different time points and severity stages of sepsis. Nitric oxide

Nitric oxide role in SIC is not fully elucidated, in part because of the existence of multiple isoforms of inducible NO synthase (iNOS), each with a different mechanism of action on the heart (75). Additional uncertainty centers around whether NO per se or its metabolites, peroxynitrites, are the primary offenders in myocardial depression. Nitric oxide plays a role in cytokinemediated inhibition of cardiac contractility, and these effects are reversed by the inhibition of iNOS (76). Evidence indicates that NO produces myocardial depression by affecting the excitation coupling mechanism and that this effect is iNOS triggered (67). Furthermore, peroxynitrites generated from the reaction between NO and superoxide radicals exert a cardiodepressant action (77) and cause dysfunction of the mitochondrial respiratory chain (78). The intracoronary injection of the NO donor nitroprusside has been shown to suppress myocardial function, despite improving LV relaxation properties. Recently, a mitochondrial NOS has been identified and incriminated in SIC via NO overproduction and mitochondrial permeability transition pore


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opening (79). Additional studies are needed to better define the role of NO in human sepsis. Mitochondrial dysfunction and apoptosis

Impaired mitochondrial function is one of the postulated mechanisms that explains the lack of peripheral oxygen utilization by the cardiomyocyte, also termed cytopathic hypoxia. Mitochondrial dysfunction is considered to be a key mechanism for the development of multiorgan failure in sepsis (80). Mitochondrial abnormalities implicated in SIC include the following: ultrastructural damage, mitochondrial DNA damage (81), increased mitochondrial permeability transition pores (82), and decreased cytochrome oxidase activity (83). The increase in mitochondrial NO production coupled with a decreased concentration of glutathione has been associated with reduced adenosine triphosphate (ATP) production in patients with septic shock (84). Animal models suggest that the reversal of mitochondrial dysfunction is associated with the recovery of cardiac function and a decrease in mortality (85). A novel theory to explain myocardial dysfunction in sepsis is a hibernationrelated phenomenon, whereby cardiomyocytes attempt to decrease their cellular oxygen expenditure under conditions of limited mitochondrial ATP production (86). Myocardial mitochondrial dysfunction in sepsis is thought to be mediated via the activation of apoptosis. The data from animal models (87) have shown that endotoxin-induced activation of caspase 3 and mitochondrial cytochrome C lead to sarcomere degradation and cleavage of contractile proteins. These cardiodepressant effects have been shown to be blocked by caspase 3 inhibitors (88). In a recent study, Takasu and colleagues (39) demonstrated ultrastructural changes in the human septic heart in the form of mitochondrial swelling and lateralization of connexin 43, without significant evidence of apoptotic cell death. The authors postulated that this picture might contribute to the commonly accepted theory of cell Bhibernation[ in sepsis, which can serve to promote cell repair and protect against additional ultrastructural damage (89). In this setting, we may postulate that the present cell Bhibernation[ could be protective during sepsis and that strategies designed to normalize heart function, such as inotropic agents, may be counterproductive (89). The recent study by Takasu and colleagues (39) adds additional insights on the reversibility of mitochondrial dysfunction in sepsis. Based on the reversible nature of cardiomyopathy and the recent findings of Takasu and colleagues (39), and in contrast to the elevated caspase 3 levels observed in animal models of sepsis, apoptotic cell death is an unlikely mechanism of human SIC. It remains to be proven whether there are nonapoptotic mechanisms of elevation of serum caspase 3. Toll-like receptors

Toll-like receptors (TLRs) are transmembrane glycoproteins with extracellular domains that recognize specific molecular patterns of microbial pathogens. Toll-like receptors play an important role in the innate immune inflammatory response to those pathogens. Toll-like receptorYmediated signaling predominantly activates nuclear factor .B, an important transcription factor that controls the expression of inflammatory cytokine genes.

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Among the TLRs discovered to date, TLR-4 is the most studied in the heart. The lack of a functional TLR-4 gene has been associated with protection from decreased myocardial shortening, a surrogate of decreased cardiac contractility in mice (90). Whether myeloid or parenchymal cells are responsible for TLR-4Ymediated myocardial dysfunction in sepsis is debatable. The mechanism of cardiac depression is thought to be through NO released by the cardiomyocytes (91). Recently, other TLRrelated genes (TLR-2, -5, and -9) have been shown to mediate sepsis-induced cardiac dysfunction (92Y94). A recent study showed that TLR-3 knockout mice were well protected from sepsis-induced cardiac dysfunction (95). These studies are undermined by a recent report of the failure of an antiYTLR-4, eritoran, in reducing the 28-day mortality in patients with severe sepsis (96). More studies are needed to explore the role of antiTLR in improving specific and well-agreed-upon surrogates of cardiac performance in sepsis and the effects of this improvement on sepsis outcomes. Heat shock proteins

Heat shock proteins (HSP), which are a group of highly selective proteins produced by cells in reaction to stress, protect the cells by a mechanism known as thermotolerance (97). Studies have shown that these proteins may protect cardiomyocytes from the damage of endotoxins and oxidative stress (98). Heat shock proteins are categorized into subfamilies according to their molecular weight. HSP70 is the most studied, and members of this subfamily can locate themselves in the cytoplasm (HSP72) or in the mitochondria (GRP75) (97). In the cytoplasm, HSP72 functions as molecular chaperones that assist in the transport of newly synthesized proteins to the mitochondria to maintain its integrity in sepsis. Mitochondrial GRP75 may participate in protein folding, refolding, protein complex formation, and protection from proteolytic damage (99). The downregulation of GRP75 in sepsis is associated with a decline in expression and function of mitochondrial respiratory chain enzymes (98). The in vitro induction of HSP70 inhibits TNF-! production from macrophages during simulated sepsis (100). Of importance is the current paradigm shift in sepsis. Growing evidence has suggested that immune Bparalysis,[ which results from a hyperactive and efficient immune system at the initial stages of sepsis, is likely responsible for delayed reactivation of opportunistic infections and adverse outcomes (101). This revolutionary evidence may gear research toward activation, rather than suppression, of the immune function by anti-inflammatory therapy. The primary focus of studying the different cellular mediators of sepsis may be more of a promotive, rather than a suppressive, strategy. It is thus important to study the Bstage[ of sepsis. It remains to be determined the influence of this paradigm shift on cardiac function in sepsis. LIMITATIONS IN THE CURRENT UNDERSTANDING OF SIC Despite the relentless efforts to uncover the cellular mechanisms of SIC, the big picture of SIC remains elusive. Disappointingly, this elusion is likely to continue if physicians continue to explore mechanisms before an adequate and realistic characterization of SIC is established. It is therefore conceivable that


SHOCK JANUARY 2014 understanding SIC should proceed along two consecutive steps: first, adequate and physiologically plausible characterization of SIC and, second, exploration of mechanisms that explain this characterization. The current concept of SIC as a Breversible[ condition is not conclusive because it is based on technically and methodologically limited studies that were not uniformly reproducible. More importantly, the Breversible[ nature of this syndrome was concept driven by focusing on a single global aspect of the heart that is not representative of a Btrue[ mechanical, electrical, or metabolic cardiac function. In this venture, to challenge the reversibility of this concept, no studies have explored or demonstrated a reversibility of the electrical or the metabolic function of the heart or the mechanical function of other components of the heart. Surprisingly, the Breversibility[ of SIC has been neither tested nor explored in large outcome studies to prove its existence. Collectively, it is hard to find a mechanism for a condition that has an inadequate characterization and unknown magnitude. Sepsis-induced myocardial depression is part of a widespread inflammatory response that is mediated mostly by inflammatory cytokines and NO. The same mediators might have conflicting effects (directly and or indirectly) on the heart and vessels. For example, whereas excessive NO production may produce severe hypotension and catecholamine-resistant shock that may worsen coronary perfusion and cytokine-mediated myocardial depression, it may improve ventricular diastolic filling and hence augment coronary perfusion. The hierarchical and multifaceted cardiac actions of inflammatory mediators may make it difficult to characterize and mechanistically treat SIC. The magnitude and severity of sepsis vary over time. It is therefore conceivable that the effects of inflammatory mediators may vary according to the stage of sepsis, which may explain why, for example, MMP-9 may be elevated early versus late in sepsis, being controlled by the anti-inflammatory IL-10. It may thus be difficult to consistently capture a single mechanism that explains a constantly changing clinical picture. Finally, much of our current knowledge is derived from animal models of experimental sepsis, which suffer from limitations, such as the following: the use of substantially high doses of microbial inoculates to induce sepsis and the inconsistencies in measurements, timing, and cardiac tissue preparations used to measure cardiac performance (Table 2). The species difference will always hinder the extrapolation of firm conclusions on the mechanisms and the characterization of SIC to humans. Taken together, the inadequate characterization, the diversity of inflammatory response, and the methodological and interspecies-based differences all explain the challenges in characterizing and studying SIC. CONSIDERATIONS TO APPROACH SIC The heart is an embryologically heterogeneous organ that is inherently and intrinsically load-interactive (102). Models of cardiac structure (103, 104) have agreed on a multilayered heterogeneous arrangement of myocardial fibers. Consequently, the cardiac motion is reciprocal during both systole and diastole. Meanwhile, this reciprocal heterogeneity is interactive with both preload and afterload. This fact argues against the assump-


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tion of clear-cut phases of the cardiac cycle, where the heart only and uniformly contracts or relaxes. It also suggests that load interaction should be considered an intrinsic function of the heart. Accordingly, Bload-independent[ indices of cardiac performance may not be a physiologically appropriate term to describe cardiac performance. Studying SIC, both in animals and humans, should first take into account the intrinsic interaction between myocardial architecture and load (Fig. 2). Additional physiologic mechanisms should be sought to improve our understanding of SIC. The identification of monitoring modalities and the validation of appropriate surrogate end points to reliably measure myocardial dysfunction would be an initial step to achieve a better understanding of SIC in human studies. One potential modality to detect subtle myocardial dysfunction in sepsis is to study the regional deformation of the left ventricle along different planes of motion. In this regard, the present assessment could be achieved by measuring strain and strain rate using advanced echocardiographic techniques, such as Doppler tissue imaging and speckle-tracking echocardiography. Strain measures segmental myocardial deformation, and strain rate measures the rate at which this deformation occurs (105). Measuring strain across the longitudinal plane of motion has been shown to be a more sensitive measure of ischemia, fibrosis, and hypertrophy compared with more global indicators of LV systolic function, such as EF (105). This is, in part, due to the arrangement of the more vulnerable subendocardial fibers of the left ventricle across this plane of motion. Doppler tissue imaging used to measure myocardial velocities is angle dependent and cannot be performed in retrospect. Speckle-tracking imaging creates reflections and interferences between the ultrasound beam and the myocardial tissue Bspeckles[ that can be tracked retrospectively throughout the cardiac cycle and is angleindependent (106). In a recent study in a pediatric population with septic shock, speckle-tracking imaging modality was able to detect impaired myocardial performance that was not revealed by EF measurement (107). Future studies should focus on other anatomical components of the heart, which might lead to more insights and early detection of subtle cardiac changes in sepsis. The left atrial volume and mechanics, the pericardium, and the right ventricular function are all potential targets for future investigation. These new approaches for studying SIC remedy several shortcomings in the current understanding of SIC. Rather than being regarded as a discrete mechanical global pump, the heart is approached as an intrinsically load-interactive organ with architectural heterogeneity. This heterogeneity is further assessed and respected electrically, mechanically, and metabolically (symmorphosis concept). This approach conceptually challenges the existing competing concept of load dependency and intrinsic cardiac function. By equally appraising all of the anatomical components of the heterogeneous heart and all aspects of function, this approach provides the entirety of a picture and the focality of appraisal. As such, this approach appraises each segment of the heart and coupled vessels in the most informative manner. Using this approach, we can achieve a better diagnostic and prognostic appraisal of the heart. In addition, we can revisit the


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FIG. 2. Proposed approach for the characterization of SIC. The proposed approach assumes preload and afterload interaction to be an intrinsic cardiac function. This approach ‘‘dissects’’ the heart into segments. It assesses each segment in terms of metabolic, mechanical, and electric abnormalities. The mechanical properties of the heart are clearly specified and are not confused with intervals, such as ‘‘systole’’ and ‘‘diastole.’’ Note the characterization of metabolic abnormalities that are believed to occur at the cellular level and to precede mechanical and electrical abnormalities. The proposed approach details potential diagnostic tools for each abnormality. This approach precisely determines the site and characterizes the abnormality in relation to loading conditions. MRS indicates magnetic resonance spectroscopy; EKG, electrocardiography; Echo, echocardiography; CMR, cardiac magnetic resonance; DTI, Doppler tissue imaging; 3-D, three-dimensional echocardiography; STE, speckle-tracking echocardiography; V-V, ventriculovenous; V-A, ventriculoarterial.

effects of generic therapies used in the treatment of sepsis in terms of its effects on the cardiac effects versus only its systemic effects. CONCLUSIONS Sepsis-induced cardiomyopathy remains a serious condition that accompanies sepsis; however, our understanding of its mechanisms and our characterization of its patterns are incomplete. From a pragmatic standpoint, Koch’s postulates (108), linking a given microorganism to a specific SIC profile, cannot be fulfilled by the current mechanistic understanding of SIC because of the lack of controlled mechanistic studies and of tissuesequencing analyses. From a hemodynamic point of view, the persistent inability to appraise ventriculoarterial decoupling clinically remains a major impediment in the assessment and in the quest of an intrinsic marker of LV contractility. Based on the current evidence and until preclinical echocardiographic markers of ventricular dysfunction become available, the routine use of

echocardiography, particularly Doppler tissue imaging, for all patients with a diagnosis of sepsis, is highly desirable to guide therapy. REFERENCES 1. Annane D, Bellissant E, Cavaillon JM: Septic shock. Lancet 365(9453): 63Y78, 2005. 2. Martin GS, Mannino DM, Eaton S, Moss M: The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 348(16):1546Y1554, 2003. 3. Charpentier J, Luyt CE, Fulla Y, Vinsonneau C, Cariou A, Grabar S, Dhainaut JF, Mira JP, Chiche J: Brain natriuretic peptide: a marker of myocardial dysfunction and prognosis during severe sepsis. Crit Care Med 32(3):660Y665, 2004. 4. Blanco J: Incidence, organ dysfunction and mortality in severe sepsis: a Spanish multicentre study. Crit Care 12(6):R158, 2008. 5. Brutsaert DL: Cardiac dysfunction in heart failure: the cardiologist’s love affair with time. Prog Cardiovasc Dis 49(3):157Y181, 2006. 6. Guarracino F, Baldassarri R, Pinsky MR: Ventriculo-arterial decoupling in acutely altered hemodynamic states. Crit Care 17(2), 2013. 7. MacLean LD, Mulligan WG, McLean AP, Duff JH: Patterns of septic shock in manVa detailed study of 56 patients. Ann Surg 166(4):543Y562, 1967. 8. Clowes GH Jr, Vucinic M, Weidner MG: Circulatory and metabolic alterations associated with survival or death in peritonitis: clinical analysis of 25 cases. Ann Surg 163(6):866Y885, 1966.


SHOCK JANUARY 2014 9. Packman MI, Rackow EC: Optimum left heart filling pressure during fluid resuscitation of patients with hypovolemic and septic shock. Crit Care Med 11(3):165Y169, 1983. 10. Parker MM, Shelhamer JH, Natanson C, Alling DW, Parrillo JE: Serial cardiovascular variables in survivors and nonsurvivors of human septic shock: heart rate as an early predictor of prognosis. Crit Care Med 15(10):923Y929, 1987. 11. Wilson RF, Chiscano AD, Quadros E, Tarver M: Some observations on 132 patients with septic shock. Anesth Analg 46(6):751Y763, 1967. 12. Michard F, Teboul JL: Predicting fluid responsiveness in ICU patients: a critical analysis of the evidence. Chest 121(6):2000Y2008, 2002. 13. Jardin F, Valtier B, Beauchet A, Dubourg O, Bourdarias JP: Invasive monitoring combined with two-dimensional echocardiographic study in septic shock. Intensive Care Med 20(8):550Y554, 1994. 14. Weisel RD, Vito L, Dennis RC, Valeri CR, Hechtman HB: Myocardial depression during sepsis. Am J Surg 133(4):512Y521, 1977. 15. Parker MM, Shelhamer JH, Bacharach SL, Green MV, Natanson C, Frederick TM, Damske BA, Parrillo JE: Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med 100(4):483Y490, 1984. 16. Parrillo JE: Pathogenetic mechanisms of septic shock. N Engl J Med 328(20): 1471Y1477, 1993. 17. Parker MM, McCarthy KE, Ognibene FP, Parrillo JE: Right ventricular dysfunction and dilatation, similar to left ventricular changes, characterize the cardiac depression of septic shock in humans. Chest 97(1):126Y131, 1990. 18. Vieillard Baron A, Schmitt JM, Beauchet A, Augarde R, Prin S, Page B, Jardin F: Early preload adaptation in septic shock? A transesophageal echocardiographic study. Anesthesiology 94(3):400Y406, 2001. 19. Bendjelid K, Suter PM: Does early preload adaptation exist in patients with septic shock? Anesthesiology 95(6):1535, 2001. 20. Etchecopar-Chevreuil C, Franc¸ois B, Clavel M, Pichon N, Gastinne H, Vignon P: Cardiac morphological and functional changes during early septic shock: a transesophageal echocardiographic study. Intensive Care Med 34(2):250Y256, 2008. 21. Bouhemad B, Nicolas-Robin A, Arbelot C, Arthaud M, Fe´ger F, Rouby JJ: Acute left ventricular dilatation and shock-induced myocardial dysfunction. Crit Care Med 37(2):441Y447, 2009. 22. Bouhemad B, Nicolas-Robin A, Arbelot C, Arthaud M, Fe´ger F, Rouby JJ: Isolated and reversible impairment of ventricular relaxation in patients with septic shock. Crit Care Med 36(3):766Y774, 2008. 23. Huang SJ, Nalos M, McLean AS: Is early ventricular dysfunction or dilatation associated with lower mortality rate in adult severe sepsis and septic shock? A meta-analysis. Crit Care 17(3):R96, 2013. 24. Bryg RJ, Pearson AC, Williams GA, Labovitz AJ: Left ventricular systolic and diastolic flow abnormalities determined by Doppler echocardiography in obstructive hypertrophic cardiomyopathy. Am J Cardiol 59(9):925Y931, 1987. 25. Garcia MJ, Thomas JD, Klein AL: New Doppler echocardiographic applications for the study of diastolic function. J Am Coll Cardiol 32(4):865Y875, 1998. 26. Paulus WJ: How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 28(20):2539Y2550, 2007. 27. Ikonomidis I: Association of left ventricular diastolic dysfunction with elevated NT-pro-BNP in general intensive care unit patients with preserved ejection fraction: a complementary role of tissue Doppler imaging parameters and NTpro-BNP levels for adverse outcome. Shock 33(2):141Y148, 2010. 28. Landesberg G: Diastolic dysfunction and mortality in severe sepsis and septic shock. Eur Heart J 33(7):895Y903, 2012. 29. Bruch C, Gradaus R, Gunia S, Breithardt G, Wichter T: Doppler tissue analysis of mitral annular velocities: evidence for systolic abnormalities in patients with diastolic heart failure. J Am Soc Echocardiogr 16(10):1031Y1036, 2003. 30. De Keulenaer GW, Brutsaert DL: Systolic and diastolic heart failure: different phenotypes of the same disease? Eur J Heart Fail 9(2):136Y143, 2007. 31. Robotham JL, Takata M, Berman M, Harasawa Y: Ejection fraction revisited. Anesthesiology 74(1):172Y183, 1991. 32. Celebi AS, Yalcin H, Yalcin F: Current cardiac imaging techniques for detection of left ventricular mass. Cardiovasc Ultrasound 8:19, 2010. 33. Dorosz JL, Lezotte DC, Weitzenkamp DA, Allen LA, Salcedo EE: Performance of 3-dimensional echocardiography in measuring left ventricular volumes and ejection fraction: a systematic review and meta-analysis. J Am Coll Cardiol 59(20):1799Y1808, 2012. 34. Stoddard MF, Liddell NE, Vogel RL, Longaker RA, Dawkins PR: Comparison of cardiac dimensions by transesophageal and transthoracic echocardiography. Am Heart J 124(3):675Y678, 1992. 35. Leong DP, De Pasquale CG, Selvanayagam JB: Heart failure with normal ejection fraction: the complementary roles of echocardiography and CMR imaging. JACC Cardiovasc Imaging 3(4):409Y420, 2010. 36. Biswas M, Sudhakar S, Nanda NC, Buckberg G, Pradhan M, Roomi AU, Gorissen W, Houle H: Two- and three-dimensional speckle tracking echocardi-


37. 38. 39. 40.

41.

42. 43.

44.

45.

46. 47.

48.

49.

50.

51.

52.

53. 54.

55.

56. 57.

58.

59. 60.

61.

62. 63.

23

ography: clinical applications and future directions. Echocardiography 30(1): 88Y105, 2013. Peters J, Mack GW, Lister G: The importance of the peripheral circulation in critical illnesses. Intensive Care Med 27(9):1446Y1458, 2001. Cunnion RE, Schaer GL, Parker MM, Natanson C, Parrillo JE: The coronary circulation in human septic shock. Circulation 73(4):637Y644, 1986. Takasu O: Mechanisms of cardiac and renal dysfunction in patients dying of sepsis. Am J Respir Crit Care Med 187(5):509Y517, 2013. Zhou M, Wang P, Chaudry IH: Cardiac contractility and structure are not significantly compromised even during the late, hypodynamic stage of sepsis. Shock 9(5):352Y358, 1998. ver Elst KM, Spapen HD, Nguyen DN, Garbar C, Huyghens LP, Gorus FK: Cardiac troponins I and T are biological markers of left ventricular dysfunction in septic shock. Clin Chem 46(5):650Y657, 2000. Mehta NJ: Cardiac troponin I predicts myocardial dysfunction and adverse outcome in septic shock. Int J Cardiol 95(1):13Y17, 2004. Wu AH: Increased troponin in patients with sepsis and septic shock: myocardial necrosis or reversible myocardial depression? Intensive Care Med 27(6):959Y961, 2001. Bogle RG, McLean PG, Ahluwalia A, Vallance P: Impaired vascular sensitivity to nitric oxide in the coronary microvasculature after endotoxaemia. Br J Pharmacol 130(1):118Y124, 2000. Madorin WS, Rui T, Sugimoto N, Handa O, Cepinskas G, Kvietys PR: Cardiac myocytes activated by septic plasma promote neutrophil transendothelial migration: role of platelet-activating factor and the chemokines LIX and KC. Circ Res 94(7):944Y951, 2004. Tjardes T, Neugebauer E: Sepsis research in the next millennium: concentrate on the software rather than the hardware. Shock 17(1):1Y8, 2002. Hoyer D, Friedrich H, Zwiener U, Pompe B, Baranowski R, Werdan K, Mu¨ller-Werdan U, Schmidt H: Prognostic impact of autonomic information flow in multiple organ dysfunction syndrome patients. Int J Cardiol 108(3): 359Y369, 2006. Sharshar T, Gray F, Lorin de la Grandmaison G, Hopkinson NS, Ross E, Dorandeu A, Orlikowski D, Raphael JC, Gajdos P, Annane D: Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock. Lancet 362(9398):1799Y1805, 2003. Tateishi Y, Oda S, Nakamura M, Watanabe K, Kuwaki T, Moriguchi T, Hirasawa H: Depressed heart rate variability is associated with high IL-6 blood level and decline in the blood pressure in septic patients. Shock 28(5):549Y553, 2007. Nogueira AC: Changes in plasma free fatty acid levels in septic patients are associated with cardiac damage and reduction in heart rate variability. Shock 29(3):342Y348, 2008. Zorn-Pauly K, Pelzmann B, Lang P, Ma¨chler H, Schmidt H, Ebelt H, Werdan K, Koidl B, Mu¨ller-Werdan U: Endotoxin impairs the human pacemaker current If. Shock 28(6):655Y661, 2007. Gholami M, Mazaheri P, Mohamadi A, Dehpour T, Safari F, Hajizadeh S, Moore KP, Mani AR: Endotoxemia is associated with partial uncoupling of cardiac pacemaker from cholinergic neural control in rats. Shock 37(2):219Y227, 2012. Tracey KJ: The inflammatory reflex. Nature 420(6917):853Y859, 2002. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Eur Heart J 17(3): 354Y381, 1996. Raeburn CD: Vascular cell adhesion moleculeY1 expression is obligatory for endotoxin-induced myocardial neutrophil accumulation and contractile dysfunction. Surgery 130(2):319Y325, 2001. Vallet B: Bench-to-bedside review: endothelial cell dysfunction in severe sepsis: a role in organ dysfunction? Crit Care 7(2):130Y138, 2003. Skibsted S, Jones AE, Puskarich MA, Arnold R, Sherwin R, Trzeciak S, Schuetz P, Aird WC, Shapiro NI: Biomarkers of endothelial cell activation in early sepsis. Shock 39(5):427Y432, 2013. Furian T, Aguiar C, Prado K, Ribeiro RV, Becker L, Martinelli N, Clausell N, Rohde LE, Biolo A: Ventricular dysfunction and dilation in severe sepsis and septic shock: relation to endothelial function and mortality. J Crit Care 27(3):319e9Y319e15, 2012. Hartemink KJ, Groeneveld AB: The hemodynamics of human septic shock relate to circulating innate immunity factors. Immunol Invest 39(8):849Y862, 2010. Eichenholz PW, Eichacker PQ, Hoffman WD, Banks SM, Parrillo JE, Danner RL, Natanson C: Tumor necrosis factor challenges in canines: patterns of cardiovascular dysfunction. Am J Physiol 263(3 Pt 2):H668YH675, 1992. Vincent JL, Bakker J, Mare´caux G, Schandene L, Kahn RJ, Dupont E: Administration of anti-TNF antibody improves left ventricular function in septic shock patients. Results of a pilot study. Chest 101(3):810Y815, 1992. Niederbichler AD: An essential role for complement C5a in the pathogenesis of septic cardiac dysfunction. J Exp Med 203(1):53Y61, 2006. Flynn A, Chokkalingam Mani B, Mather PJ: Sepsis-induced cardiomyopathy: a review of pathophysiologic mechanisms. Heart Fail Rev 15(6):605Y611, 2010.


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64. Rossi MA, Celes MR, Prado CM, Saggioro FP: Myocardial structural changes in long-term human severe sepsis/septic shock may be responsible for cardiac dysfunction. Shock 27(1):10Y18, 2007. 65. Liu S, Schreur KD: G proteinYmediated suppression of L-type Ca2+ current by interleukin-1 beta in cultured rat ventricular myocytes. Am J Physiol 268(2 Pt 1): C339YC349, 1995. 66. Zhong J: Reduced L-type calcium current in ventricular myocytes from endotoxemic guinea pigs. Am J Physiol 273(5 Pt 2):H2312YH2324, 1997. 67. Dong LW: Impairment of the ryanodine-sensitive calcium release channels in the cardiac sarcoplasmic reticulum and its underlying mechanism during the hypodynamic phase of sepsis. Shock 16(1):33Y39, 2001. 68. Brinckerhoff CE, Matrisian LM: Matrix metalloproteinases: a tail of a frog that became a prince. Nat Rev Mol Cell Biol 3(3):207Y214, 2002. 69. Khadour FH: Enhanced NO and superoxide generation in dysfunctional hearts from endotoxemic rats. Am J Physiol Heart Circ Physiol 283(3):H1108Y H1115, 2002. 70. Lalu MM, Csont T, Schulz R: Matrix metalloproteinase activities are altered in the heart and plasma during endotoxemia. Crit Care Med 32(6):1332Y1337, 2004. 71. Teng L: Matrix metalloproteinase-9 as new biomarkers of severity in multiple organ dysfunction syndrome caused by trauma and infection. Mol Cell Biochem 360(1-2):271Y277, 2012. 72. Lalu MM, Gao CQ, Schulz R: Matrix metalloproteinase inhibitors attenuate endotoxemia induced cardiac dysfunction: a potential role for MMP-9. Mol Cell Biochem 251(1Y2):61Y66, 2003. 73. Hoffmann U: Matrix-metalloproteinases and their inhibitors are elevated in severe sepsis: prognostic value of TIMP-1 in severe sepsis. Scand J Infect Dis 38(10):867Y872, 2006. 74. Lorente L: Matrix metalloproteinase-9, -10, and tissue inhibitor of matrix metalloproteinases-1 blood levels as biomarkers of severity and mortality in sepsis. Crit Care 13(5):R158, 2009. 75. Khan SA: Nitric oxide regulation of myocardial contractility and calcium cycling: independent impact of neuronal and endothelial nitric oxide synthases. Circ Res 92(12):1322Y1329, 2003. 76. Kumar A: Role of nitric oxide and cGMP in human septic serum-induced depression of cardiac myocyte contractility. Am J Physiol 276(1 Pt 2):R265Y R276, 1999. 77. Ishida H: Peroxynitrite-induced cardiac myocyte injury. Free Radic Biol Med 20(3):343Y350, 1996. 78. Xie YW, Kaminski PM, Wolin MS: Inhibition of rat cardiac muscle contraction and mitochondrial respiration by endogenous peroxynitrite formation during posthypoxic reoxygenation. Circ Res 82(8):891Y897, 1998. 79. Xu C: Mitochondrial nitric oxide synthase participates in septic shock myocardial depression by nitric oxide overproduction and mitochondrial permeability transition pore opening. Shock 37(1):110Y115, 2012. 80. Exline MC, Crouser ED: Mitochondrial mechanisms of sepsis-induced organ failure. Front Biosci 13:5030Y5041, 2008. 81. Suliman HB, Carraway MS, Piantadosi CA: Postlipopolysaccharide oxidative damage of mitochondrial DNA. Am J Respir Crit Care Med 167(4):570Y579, 2003. 82. Larche J: Inhibition of mitochondrial permeability transition prevents sepsisinduced myocardial dysfunction and mortality. J Am Coll Cardiol 48(2): 377Y385, 2006. 83. Piel DA: Mitochondrial resuscitation with exogenous cytochrome c in the septic heart. Crit Care Med 35(9):2120Y2127, 2007. 84. Brealey D: Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 360(9328):219Y223, 2002. 85. Piel DA, Deutschman CS, Levy RJ: Exogenous cytochrome C restores myocardial cytochrome oxidase activity into the late phase of sepsis. Shock 29(5): 612Y616, 2008.

ZAKY ET

AL.

86. Rudiger A, Singer M: Mechanisms of sepsis-induced cardiac dysfunction. Crit Care Med 35(6):1599Y1608, 2007. 87. Lancel S: Ventricular myocyte caspases are directly responsible for endotoxininduced cardiac dysfunction. Circulation 111(20):2596Y2604, 2005. 88. Neviere R: Caspase inhibition prevents cardiac dysfunction and heart apoptosis in a rat model of sepsis. Am J Respir Crit Care Med 163(1):218Y225, 2001. 89. Crouser E: A rare glimpse behind the mask of sepsis-induced organ failures provides hope for an eventual cure. Am J Respir Crit Care Med 187(5):460Y462, 2013. 90. Baumgarten G: Toll-like receptor 4, nitric oxide, and myocardial depression in endotoxemia. Shock 43Y49, 2006. 91. Panaro MA: Toll-like receptor 4 mediates LPS-induced release of nitric oxide and tumor necrosis factor-alpha by embryonal cardiomyocytes: biological significance and clinical implications in human pathology. Curr Pharm Des 16(7):766Y774, 2010. 92. Zhu X: Toll-like receptor 2 activation by bacterial peptidoglycan-associated lipoprotein activates cardiomyocyte inflammation and contractile dysfunction. Crit Care Med 35(3):886Y892, 2007. 93. Knuefermann P: Bacterial DNA induces myocardial inflammation and reduces cardiomyocyte contractility: role of Toll-like receptor 9. Cardiovasc Res 78(1):26Y35, 2008. 94. Rolli J: Bacterial flagellin triggers cardiac innate immune responses and acute contractile dysfunction. PLoS One 5(9):e12687, 2010. 95. Gao M: Toll-like receptor 3 plays a central role in cardiac dysfunction during polymicrobial sepsis. Crit Care Med 40(8):2390Y2399, 2012. 96. Opal SM: Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA 309(11): 1154Y1162. 97. Kregel KC: Heat shock proteins: modifying factors in physiological stress responses and acquired thermotolerance. J Appl Physiol 92(5):2177Y2186, 2002. 98. Chen HW: Heat shock pretreatment prevents cardiac mitochondrial dysfunction during sepsis. Shock 20(3):274Y279, 2003. 99. Stuart RA, Cyr DM, Neupert W: HSP70 in mitochondrial biogenesis: from chaperoning nascent polypeptide chains to facilitation of protein degradation. Experientia 50(11Y12):1002Y1011, 1994. 100. Meng X, Harken AH: The interaction between HSP70 and TNF-alpha expression: a novel mechanism for protection of the myocardium against post-injury depression. Shock 17(5):345Y353, 2002. 101. Leentjens J: Immunotherapy for the adjunctive treatment of sepsis: from immunosuppression to immunostimulation. Time for a paradigm change? Am J Respir Crit Care Med 187(12):1287Y1293, 2013. 102. Borlaug BA, Kass DA: Ventricular-vascular interaction in heart failure. Heart Fail Clin 4(1):23Y36, 2008. 103. Torrent-Guasp F: The structure and function of the helical heart and its buttress wrapping. I. The normal macroscopic structure of the heart. Semin Thorac Cardiovasc Surg 13(4):301Y319, 2001. 104. Buckberg G: Ventricular torsion and untwisting: further insights into mechanics and timing interdependence: a viewpoint. Echocardiography 28(7):782Y804. 105. Sanderson JE, Fraser AG: Systolic dysfunction in heart failure with a normal ejection fraction: echo-Doppler measurements. Prog Cardiovasc Dis 49(3): 196Y206, 2006. 106. Helle-Valle T: New noninvasive method for assessment of left ventricular rotation: speckle tracking echocardiography. Circulation 112(20):3149Y3156, 2005. 107. Basu S: Two-dimensional speckle tracking imaging detects impaired myocardial performance in children with septic shock, not recognized by conventional echocardiography. Pediatr Crit Care Med 2011. 108. Croce P: The four postulates of Robert Koch. Riv Biol 89(2):275Y278, 1996.


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