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Pathophysiology of cardiovascular dysfunction in sepsis

2015; Elsevier BV; Volume: 15; Issue: 6 Linguagem: Inglês

10.1093/bjaceaccp/mkv003

2058-5357

JR Greer,

Cardiac Arrest and Resuscitation

Key points•Cardiovascular dysfunction is a common complication of sepsis and severe sepsis.•Left ventricular performance is compromised by poor contractility and this is worsened by the imposed challenge of systemic vasodilatation.•Right ventricular performance can be compromised by pulmonary hypertension.•Nitric oxide is an inflammatory mediator which disrupts intracellular calcium flux leading to myocyte dysfunction, peripheral vasodilatation, and disruption of compensatory reflexes.•Arrhythmogenesis is a feature of cardiovascular dysfunction in sepsis. •Cardiovascular dysfunction is a common complication of sepsis and severe sepsis.•Left ventricular performance is compromised by poor contractility and this is worsened by the imposed challenge of systemic vasodilatation.•Right ventricular performance can be compromised by pulmonary hypertension.•Nitric oxide is an inflammatory mediator which disrupts intracellular calcium flux leading to myocyte dysfunction, peripheral vasodilatation, and disruption of compensatory reflexes.•Arrhythmogenesis is a feature of cardiovascular dysfunction in sepsis. Sepsis is a common condition with a high mortality, which can also lead to severe sepsis and shock. This review will look at the physiological disruption of the cardiovascular system and the reflexes which occur during sepsis. The host response to sepsis is controlled by inflammatory mediators, which transmit, amplify, and maintain the generation of the host response. A specific myocardial-depressant factor has been suggested for some time, but the concept of a single agent underestimates the complexity of the immune system in sepsis.1Nduka OO Parillo JE The pathophysiology of septic shock.Crit Care Clin. 2009; 25: 677-702Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar These are intermediate signalling molecules, which respond to the inflammatory stimulus and lead to the release of tumour necrosis factor α (TNF-α). These receptors impair myocyte function in vitro. The major pro-inflammatory mediators in sepsis are TNF-α, interleukin (IL) 1β, IL-6, and IL-8. They are secreted from macrophages and monocytes and are responsible for amplification of the septic cascade and have been demonstrated to cause fever, hypotension, and myocardial suppression. Nitric oxide (NO) is secreted from the endothelium and is central to cardiovascular control in health. During sepsis, NO production is increased after activation of the endothelium by pro-inflammatory mediators, resulting in up-regulation of the enzyme inducible NO synthetase (iNOS). This inducible (pathological) NO is responsible for vasodilatation. It is also responsible for dysfunction of enzyme messenger systems associated with normal intracellular calcium homeostasis and the maintenance of reflexes. Oxidative stress is a term applied to cellular damage by oxygen and nitrogen free radicals, which are produced in excess in sepsis. Oxygen free radicals include peroxide and hydroxyl groups, while nitrogen free radicals include peroxynitrite. These affect cellular and subcellular function, including damaging DNA, structural proteins, and mitochondrial enzyme systems. They are also responsible for the cytopathic hypoxia associated with damage to the electron transport chain. In vitro evidence for myocardial dysfunction is summarized in Table 1Table 1Molecular mechanisms of myocyte dysfunction—in vitro evidenceImmune modulatorActionPathophysiologyLipopolysaccharideIndirectRelease of TNF-αToll-like receptorsIndirectRelease of TNF-α and IL-1βTNF-αDirectDefective cellular Ca trafficIL-1βDirectDefective cellular Ca trafficNitric oxideDirectDefective cellular Ca trafficDirectDefective β-adrenergic responseDirectArrhythmogenesisPeroxynitriteIndirectEnhanced cytokine toxicityMacrophage migration inhibitory factor (MIF)IndirectEnhanced cytokine toxicityDirectCellular apoptosis Open table in a new tab The left ventricle (LV) is a muscular contractile chamber which pumps blood into the systemic circulation to perfuse and oxygenate the vital organs. It contracts in a circumferential manner and it creates a mean arterial pressure of 90 mm Hg. The systemic circulation has a high resistance and a low capacitance. The stroke volume of the ventricle in systole is determined by preload, afterload, and contractility. During diastole, ventricular filling and coronary artery perfusion takes place. Determinants of diastolic function include myocardial relaxation and passive properties of the ventricle such as stiffness and geometry. Excitation–contraction (E–C) coupling is the process by which an action potential is converted to muscle contraction. When a cardiac muscle action potential occurs, calcium enters the cell and this leads to the further release of calcium from the sarcoplasmic reticulum. This calcium-induced calcium release is mediated by the cardiac ryanodine receptor (RyR2). The calcium binds to troponin-C which then leads to conformational change and allows the binding of actin to myosin causing shortening of the myocyte and the onset of systole. Then, during diastole, calcium reuptake into the sarcoplasmic reticulum occurs by an ATP-dependent pump (SERCA—sarco-endoplasmic reticulum ATP-ase). A decrease in intracellular calcium concentration then occurs and prepares the myocardium for the next systolic event.2Ferreira-Martins J Leite-Moreira AF Physiologic basis and pathophysiological implications of the diastolic properties of the cardiac muscle.J Biomed Biotechnol. 2010; 2010: 807084Crossref PubMed Scopus (11) Google Scholar The clinical picture of early sepsis is a patient with a low systemic vascular resistance (SVR) and a normal or increased cardiac output, although the heart is compromised by poor contractility. Although the stroke volume may be maintained, there is an increase in left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV) and very often a decrease in the ejection fraction (EF), with cardiac output maintained by an increase in heart rate. There is also diastolic dysfunction with decreased left ventricular compliance and a subsequent increase in left ventricular end-diastolic pressure (LVEDP) (Fig 1, Fig 2, Fig 3).Fig 2Pressure–volume curve for the LV during sepsis. During sepsis, LVESV and LVEDV are both increased. Stroke volume (SV) is maintained. The end-systolic pressure–volume relationship demonstrates decreased contractility.View Large Image Figure ViewerDownload (PPT)Fig 3Pressure–volume curve for the LV during severe sepsis. During severe sepsis, there is a decrease in LVEDV and LVESP. There is hypotension.View Large Image Figure ViewerDownload (PPT) During sepsis, excessive NO is produced by iNOS.3Boisramme Helms J Kremer H Schini-Kerth V Meziani F Endothelial dysfunction in sepsis.Curr Vasc Pharm. 2013; 11: 150-160PubMed Google Scholar4Massion PB Feron O Dessy C Ballingand J-L Nitric oxide and cardiac function—ten years after, and continuing.Circ Res. 2003; 93: 388-398Crossref PubMed Scopus (492) Google Scholar The excess NO causes ventricular dysfunction by three methods; it decreases both calcium trafficking during systole (leading to decreased contractility) and calcium flux during diastole (which leads to abnormal cardiac filling). In these circumstances, cardiac force is compromised by the resulting abnormalities of fibre length. This diastolic dysfunction can be seen globally as increased LVEDP. Finally, NO decreases the sensitivity of the myocardium to endogenous adrenergic ligands by altering the response of second messenger systems. The protein kinase and cyclic GMP messenger systems are affected in this manner. Vasodilatation is the principal physiological abnormality in the cardiovascular response to sepsis. This leads to a low SVR and hypotension. One of the physiological functions of NO is to provide an intrinsic response to alterations in peripheral blood flow (myogenic control). When NO is formed in the endothelium, it diffuses into the vascular smooth muscle cells where it activates the enzyme guanylyl cyclase. This increases concentrations of cyclic GMP levels which lead to a reduction in intracellular calcium levels and activation of potassium channels. This leads to vascular smooth muscle relaxation. Peripheral vascular dysfunction during sepsis is mediated by excessive production of NO by the enzyme iNOS. Increased NO concentration leads to hyperpolarization of potassium channels and persistent relaxation of smooth muscle. In addition to vasodilatation, there is a failure of the cardiovascular reflexes, which normally control arterial pressure. The sympathetic and neuroendocrine responses to shock cause vasoconstriction, which is mediated by G-proteins and second messenger systems, in turn activating intracellular pathways. These responses to sympathetic activity and angiotensin II are decreased due to the increased production of NO, which decreases the cellular activity of signal transduction mechanisms. The right ventricle (RV) differs embryologically, structurally, and functionally from the LV. The principle function of the RV is to facilitate efficient gas exchange. It has a thin wall with a low muscle mass, ejecting into the pulmonary circulation, which has a low resistance and a high compliance. The pressures generated on the right side are low; mean pulmonary artery pressure is 15 mm Hg. The RV depolarizes and then contracts in a longitudinal manner from the inflow tract to the outflow tract and produces a wave which is peristaltic in manner. This contrasts with the circumferential pressure generating contraction of the left side of the heart. Like the LV, the cardiac output of the RV is determined by changes in preload, afterload, and contractility. The changes in ventricular function in sepsis are similar to those on the left side. The function is compromised by changes in contractility and afterload. The free wall of the RV has a low muscle mass and can respond to increases in preload by dilating, but it responds poorly to afterload because of its relative inefficiency as a muscle pump. The onset of sepsis leads to a change in contractility due to effects of circulating inflammatory mediators which are the same as those outlined above. There is an increase in RVEDV and RVESV (stroke volume is maintained). There is a decrease in RVEF similar to that in the systemic circulation. The stresses imposed by sepsis on the RV muscle mass and the changes in afterload can ultimately lead to right ventricular failure.5Chan CE Klinger JR The right ventricle in sepsis.Clin Chest Med. 2008; 29: 661-676Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar The pulmonary circulation is a low-pressure system, which can respond to an increased cardiac output during exercise or after a physiological stress. The ability of the pulmonary circulation to respond to a large cardiac output without a major change in pressure ensures that effective gas exchange can take place. It is important to consider the concept of blood flow in addition to generated pressure when considering the physiology of the pulmonary circulation. The right-sided circulation responds to changes in cardiac output by recruitment of pulmonary vessels which have low perfusion during stable conditions. In addition to recruitment, distension of these vessels allows an increase in blood flow which will support the need for improved gas exchange. These processes occur without vasomotor control. The major stress imposed on the RV during sepsis is an increase in the afterload due to pulmonary hypertension. Hypoxic pulmonary vasoconstriction (HPV) is a response of the small arterioles of the pulmonary circulation to a decrease in alveolar or mixed venous oxygen content. The greater influence is from alveolar hypoxia. The function of this response is to divert blood from the hypoxic areas of the lungs to those which are ventilated, thus attempting to maintain optimum ventilation and perfusion ratios and ensure efficient gas exchange. It is a rapid response and occurs within seconds of induced hypoxia. The reflex occurs in the isolated lung and is independent of neural connections. The precise mechanism has not been proven, but NO is implicated. During sepsis, unregulated NO production in the systemic circulation leads to vasodilatation. In the presence of hypoxia, NO production decreases in the pulmonary circulation and local vasoconstriction occurs. It is also thought that local release of the potent vasoconstrictor endothelin occurs due to hypoxia. There is evidence that the active control of the pulmonary circulation is influenced by ligands of systemic origin which lead to receptor activation. There are both cholinergic and adrenergic receptors in the pulmonary vascular tree, which allow changes in pulmonary vascular tone and resistance. Sympathetic stimulation can cause pulmonary vasoconstriction by α-1 receptor activity while they can cause vasodilatation by β-adrenergic stimulation. The predominant response is vasoconstriction. Cholinergic parasympathetic nerves cause vasodilatation by stimulation of muscarinic (M3) receptors, with NO acting as a mediator for cholinergic transmission. Other circulating humoral factors can induce a local vasoconstrictor response, including endothelin, angiotensin, and histamine.6Lumb AB The pulmonary circulation.in: Lumb AB Nunn's Applied Respiratory Physiology. 6th Edn. Butterworth Heinemann, Oxford2005: 92-109Google Scholar Pulmonary hypertension is thus a multifactorial consequence of sepsis and is probably due to inhibition of NO production due to hypoxia and also an enhanced vasoconstriction due to acidosis, increased adrenergic stimulation, and local mediators such as endothelin (Table 2).Table 2The mediators involved in the active control of the pulmonary circulation6Lumb AB The pulmonary circulation.in: Lumb AB Nunn's Applied Respiratory Physiology. 6th Edn. Butterworth Heinemann, Oxford2005: 92-109Google ScholarPhysiological changeMediator agonistPulmonary vascular responseReceptorNeural controlSympathetic stimulationNorepinephrineVasoconstrictionα1 adrenoceptorSympathetic stimulationNorepinephrineVasodilatationβ2 adrenoceptorParasympatheticAcetyl-cholineVasodilatationM3 muscarinicNANCUnknownVasodilatationNO-mediatedReceptor-mediatedAdrenergic responseEpinephrineVasoconstrictionα1 adrenoceptorAdrenergic responseEpinephrineVasodilatationβ2 adrenoceptorHistamine releaseHistamineVariableH1Histamine releaseHistamineVasodilatationH2Angiotensin releaseAngiotensinVasoconstrictionATEndothelin releaseEndothelinVasoconstrictionET-AEndothelin releaseEndothelinVasodilatationET-BPain and stressSubstance PVasoconstrictionNeurokinin-1Pain and inflammationNeurokinin AVasoconstrictionNeurokinin-2 Open table in a new tab Ventricular interdependence is defined as the forces that are transmitted from one ventricle to the other ventricle through the myocardium and pericardium, independent of neural, humoral, or circulatory effects. Ventricular interdependence is a result of the close anatomical correlation of the ventricular cavities within the pericardium.7Santamore WP Dell'Italia LJ Ventricular interdependence: significant left ventricular contributions to right ventricular systolic function.Prog Cardiovasc Dis. 1998; 40: 289-308Abstract Full Text PDF PubMed Scopus (408) Google Scholar8Magder S The left heart can only be as good as the right heart: determinants of function and dysfunction of the right ventricle.Crit Care Resusc. 2007; 9: 344-351PubMed Google Scholar The round cavity of the LV approximates the interventricular septum during systole, while the less muscular RV contracts along its long axis to expel blood through the pulmonary valve. The ventricles can be considered in series. Stroke volume of systolic contraction of one cavity creates the preload of the next (Fig. 4). The RV becomes impaired by increased afterload due to HPV. LVEDP increases in sepsis and this can impair RV function by increasing RV afterload further. This can lead to increased RVEDP and subsequently RVEDV increases as the ventricle dilates. The failing RV can impede left-sided performance by decreasing LV preload. The failing RV has an increased RVEDV. Normally, LVEDP exceeds RVEDP and concentric contraction will maintain normal chamber shape during systole and diastole. However, in the presence of severe RV overload, the septum can shift towards the LV in end-diastole if the pressure gradient is reversed and RVEDP exceeds LVEDP. This severe RV diastolic dysfunction can be seen in sepsis (Fig. 5). The pericardium normally allows free movement of the ventricular cavities even in the presence of a dilated heart; however, this may itself be compromised by pericardial disease during sepsis or high intrathoracic pressures caused by mechanical ventilation. Supraventricular tachyarrhythmias are commonly found in patients with sepsis, especially atrial fibrillation. It has been demonstrated that 32% of patients in intensive care who developed supraventricular tachyarrhythmias had sepsis and that septic shock was an independent predictor of their occurrence. The voltage-dependent L-channels which are responsible for calcium flux in phase 2 of the cardiac action potential have a specific heteromeric structure. This calcium channel has five subunits (α1, α2, β, γ, and δ). The α1 subunit spans the cell membrane and forms the conduction pore, the voltage sensor, and the gating apparatus. It is a known site of channel regulation by second messenger systems. Animal studies have demonstrated that during sepsis, NO decreases the influx of calcium by alteration of the activity of this channel during phase 2 of repolarization. The potassium channel is also affected during sepsis and an increased influx of potassium occurs in myocytes during repolarization. These two mechanisms are responsible for the timing of repolarization. Action potential duration (APD) is decreased during sepsis in atrial myocytes. There is no change in resting membrane potential. A decrease in influx of calcium during phase 2 of repolarization is one of the electrophysiological changes associated with the genesis of tachyarrhythmias in sepsis (Fig. 6).10Aoki Y Hatakeyama N Yamamoto S et al.Role of ion channels in sepsis-induced tachyarrhythmias in guinea pigs.Br J Pharmacol. 2012; 166: 390-400Crossref PubMed Scopus (27) Google Scholar There is no evidence that global ischaemia leads to myocardial dysfunction in sepsis, with no alteration in coronary artery perfusion. There is a change in the metabolic activity of the heart during sepsis, as it develops an increased capacity to metabolize lactate as a substrate in preference to glucose and free fatty acids. High energy phosphate levels are maintained in the presence of normal arterial oxygen tension.11Merx MW Weber C Sepsis and the heart.Circulation. 2007; 116: 793-802Crossref PubMed Scopus (427) Google Scholar If a patient has pre-existing coronary artery disease then the increased work of the heart can lead to myocardial ischaemia. The oxygen demand is increased by the tachycardia and the supply may be limited by decreased subendocardial perfusion due to increased end-diastolic pressure. It is important to consider sepsis as a risk factor in patients with diagnosed coronary atheroma. The increased work of the RV in the presence of pulmonary hypertension and systemic hypotension can alter the supply–demand ratio of the RV. This may worsen RV failure due to increased oxygen demand in the presence of impaired coronary artery perfusion. The reflex response to shock is the activation of the sympathetic system. Hypotension stimulates high-pressure receptors in the aortic arch and the carotid bodies to transmit impulses to the medulla oblongata, which also co-ordinates the efferent responses. Norepinephrine is secreted locally and activates cellular activity via G-protein-coupled adrenergic receptors. This leads to increased heart rate, increased cardiac contractility, and peripheral vasoconstriction. In sepsis, the action of NO at the second messenger systems obtunds these reflex responses both at the heart and in the peripheral vascular system. These abnormal reflexes compromise the cardiovascular system in the presence of worsening disease. The parasympathetic system is also affected in sepsis. Respiratory sinus arrhythmia is a primitive reflex which is present in mammals. It is seen as an increase in heart rate during inspiration and this is commonly measured as a decrease in the R–R interval witnessed on an ECG (heart rate variation). The function of this reflex is to maximize gas exchange at rest by matching alveolar ventilation and capillary perfusion during respiration. Heart rate variation (HRV) is widely used as an index of vagal function and easily becomes impaired during physiological stress or disease. The loss of HRV is an early indicator of sepsis.12Hayano J Yasuma F Hypothesis: respiratory sinus arrhythmia is an intrinsic resting function of cardiopulmonary system.Cardiovasc Res. 2003; 58: 1-9Crossref PubMed Scopus (101) Google Scholar The parasympathetic nervous system interacts closely with the inflammatory system during sepsis. There is evidence to suggest that inflammatory products released during sepsis activate afferent signals to the nucleus tractus solitarius. This leads to inhibition of cytokine synthesis through the cholinergic anti-inflammatory pathway. This is termed 'The inflammatory reflex' and is mediated by the vagus nerve.13Tracey KJ The inflammatory reflex.Nature. 2002; 420: 853-859Crossref PubMed Scopus (2581) Google Scholar The neuroendocrine response to shock comprises secretion of hormones from the hypophyseal–pituitary–adrenal axis and the activation of the renin–angiotensin aldosterone pathway. Vasopressin and angiotensin are normally potent vasoconstrictors. The pro-inflammatory mediators decrease the secretion of vasopressin from the posterior pituitary gland and nitric oxide obtunds the effects of angiotensin at peripheral receptors. Cytokines decrease the secretion of glucocorticoids and the sensitivity of receptors to glucocorticoids. Glucocorticoids have an important role in the maintenance and sensitivity of the adrenergic receptor population. Relative adrenocortical insufficiency has been implicated in refractory shock and steroid replacement is associated with improved haemodynamic stability and earlier resolution of shock. In the early stages of sepsis, the sympathetic responses maintain cardiac output but as the disease evolves, the compensatory neuroendocrine responses become overwhelmed. This is due to progressive insensitivity of the peripheral circulation to circulating vasoconstrictors such as vasopressin and angiotensin II. This leads from sepsis to severe sepsis and septic shock when the hypotension becomes refractory to treatment. Improved technology has given us access to direct cardiac visualization by echocardiography. The current definition of myocardial dysfunction in sepsis is based upon an LVEF of <50% in the absence of cardiac disease that demonstrates reversibility on remission. A recent transthoracic echocardiographic study has applied contemporary technology to a series of septic patients. This study was done during standardized fluid resuscitation in sepsis and demonstrated the frequency of myocardial dysfunction in patients with severe sepsis or septic shock to be 64%. The incidence of LV diastolic dysfunction was 37%, LV systolic dysfunction 31%, and RV dysfunction also 31%. There was significant overlap between all groups. There was no difference in 30 day or 1 yr mortality rates between septic patients who had cardiac dysfunction and those who did not. Moreover, not all patients with cardiac dysfunction due to sepsis demonstrated complete reversibility of function.14Pulido JN Afessa B Masaki M et al.Clinical spectrum, frequency, and significance of myocardial dysfunction in severe sepsis and septic shock.Mayo Clin Proc. 2012; 87: 620-628Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar This study demonstrates that cardiac dysfunction during sepsis cannot be defined by a measurement based solely on LVE, but rather as a spectrum of functional changes throughout the cardiac cycle. Moreover, it is impossible to allow for differing host responses and individual differences in cardiorespiratory interaction and it is difficult to argue that a snapshot of activity in a complex and dynamic disease state is representative of the differing phases of sepsis, treatment, or resolution. It also suggests that echocardiographic techniques may be useful in sepsis. Improved knowledge of cellular dysfunction has led to the development of new therapeutic agents which are designed to improve calcium trafficking during sepsis. Levosimendan increases calcium sensitization within the cardiac myocyte and in higher doses, it acts as a vasodilator and a phosphodiesterase inhibitor. Clinical trials in heart failure have demonstrated that it can improve cardiac output and stroke volume. Trials of this drug in sepsis are ongoing. A number of other novel agents increase the activation of SERCA and may improve the cellular reuptake of calcium which is abnormal during sepsis. These include istaroxime, nitroxyl donor, and CXL-1020. SERCA activation is also considered to be treatable by gene transfer. Actin myosin cross-bridge activation is improved by omecamtiv mecarbil. These therapeutic strategies are currently undergoing trials.15Hasenfluss G Teerlink JR Cardiac inotropes: current agents and future directions.Eur Heart J. 2011; 32: 1838-1845Crossref PubMed Scopus (137) Google Scholar Cardiovascular dysfunction is a common sequel of sepsis. It is caused by the mediators of sepsis causing abnormalities of the normal cardiac physiology and additional disruption to the normal homeostatic and reflex responses. This review demonstrates that this process is widespread throughout all parts of the cardiovascular system. None declared. The associated MCQs (to support CME/CPD activity) can be accessed at www.access.oxfordjournals.org by subscribers to BJA Education. I would like to acknowledge Dr D. Atkinson for help with the echocardiographic image and Professor P.L.T. Willan with the anatomical image.