The pathophysiology of cardiogenic shock is complex and not fully understood. Ischemia to the myocardium causes derangement to both systolic and diastolic left ventricular function, resulting in a profound depression of myocardial contractility. This, in turn, leads to a potentially catastrophic and vicious spiral of reduced cardiac output and low blood pressure, perpetuating further coronary ischemia and impairment of contractility. Several physiologic compensatory processes ensue. These include:The activation of the sympathetic system leading to peripheral vasoconstriction which may improve coronary perfusion at the cost of increased afterload, and Tachycardia which increases myocardial oxygen demand and subsequently worsens myocardial ischemia.These compensatory mechanisms are subsequently counteracted by pathologic vasodilation that occurs from the release of potent systemic inflammatory markers such as interleukin-1, tumor necrosis factor a, and interleukin-6. Additionally, higher levels of nitric oxide and peroxynitrite are released, which also contribute to pathologic vasodilation and are known to be cardiotoxic. Unless interrupted by adequate treatment measures, this self-perpetuating cycle leads to global hypoperfusion and the inability to effectively meet the metabolic demands of the tissues, progressing to multiorgan failure and eventually death.

• The most common insult for cardiogenic shock is left ventricular pump failure in the setting of acute myocardial infarction.
• It usually takes a considerable area of infarcted myocardium (around 40%) to lead to cardiogenic shock.
• A smaller infarct may also originate this condition in a patient with a previously compromised ventricle function.
• There may also be other etiologies, other parts of the circulatory system may contribute, either alone or in combination, with inadequate compensation, or additional defects for this shock of cardiac origin, such as:^[1]
• Systolic Left Ventricular Dysfunction – acute myocardial infarction, CHF, Cardiomyopathy, Coronary artery bypass grafting, Myocarditis, Myocardial contusion and Hypophosphatemia
• Diastolic Left Ventricular Dysfunction – Ischemia
• Obstruction of Left Ventricular Outflow, with Increased Afterload – Aortic stenosis, Hypertrophic Cardiomyopathy, Coarctation of the Aorta and Malignant Hypertension
• Reversal of flow into the left ventricle – Acute aortic insufficiency and endocarditis
• Inadequate left ventricular filling due to mechanical causes – Tamponade and pulmonary embolism
• Inadequate left ventricular filling due to inadequate filling time – Tachycardia and tachycardia-mediated cardiomyopathy
• Conduction abnormalities – Atrioventricular block and sinus bradycardia
• Mechanical defect – VSD and left ventricle free wall rupture
• Right ventricular failure – Pulmonary embolism and hypoxic pulmonary vasoconstriction^[1]

• Cardiac dysfunction in patients with cardiogenic shock is usually initiated by myocardial infarction or ischemia.
• The myocardial dysfunction resulting from ischemia worsens that ischemia, creating a downward spiral.
• When a critical mass of left ventricular myocardium is ischemic or necrotic and fails to pump, stroke volume and cardiac output decrease.
• Myocardial perfusion, which depends on the pressure gradient between the coronary arterial system and the left ventricle.
• The duration of diastole, is compromised by hypotension and tachycardia. Which in turn, exacerbates ischemia.
• The increased ventricular diastolic pressures caused by pump failure further reduce coronary perfusion pressure, and the additional wall stress elevates myocardial oxygen requirements, further worsening ischemia.
• Decreased cardiac output also compromises systemic perfusion, which can lead to lactic acidosis and further compromise of systolic performance.
• The pathologic process begins with myocardial ischemia leading to an abnormal function of the cardiac muscle.
• This abnormality worsens the initial ischemia, which then deteriorates even further the ventricular function, creating the so called “downward spiral”.^[2]
• When ischemia reaches a point that the left ventricular myocardium fails to pump properly, parameters like stroke volume and cardiac output will therefore decrease.
• The pressure gradient produced between the pressure within the coronary arteries and the left ventricle, along with the duration of the diastole, dictate myocardial perfusion.
• This will be compromised by the hypotension and the tachycardia, worsening the myocardial ischemia and the perfusion of other vital organs.
• The fact that the heart is the only organ that benefits from a low blood pressure, as afterload decreases, makes these hemodynamical changes both beneficial and detrimental.
• The pump failure will then decrease the ability to push the blood out of the ventricle, thereby increasing the ventricular diastolic pressures.
• This will not only reduce the coronary perfusion pressure, as it will also increase the ventricle wall stress, so that the myocardial oxygen requirements will also raise, consequently propagating the ischemia.^[2][1][3]
• cardiac pump failure and hypoperfusion of the peripheral tissues is that this last one, leads to the release of catecholamines.
• Catecholamines such as norepinephrine, will increase the heart‘s contractility and peripheral blood flow, by causing constriction of arterioles, together with angiotensin II, to maintain perfusion, however, this will also increase the heart‘s oxygen demand and have proarrhythmic and myocardiotoxic consequences.
• The increased SVR coupled with the low cardiac output will lead to an even more pronounced reduction of tissue perfusion.^[1]
• The ischemia generated by all these processes increases the diastolic stiffness of the ventricle wall and this, along with the left ventricular dysfunction, will increase the left atrial pressure. The increased left atrial pressure will propagate through the pulmonary veins, generating pulmonary congestion, which by decreasing oxygen exchanges, leads to hypoxia.
• The hypoxia will further worsen the ischemia of the myocardium and the pulmonary congestion will propagate its effect through the pulmonary arteries to the right ventricle, hence jeopardizing its performance.
• Once myocardial function is affected, the body will put in motion compensatory mechanisms to try to increase the cardiac output. These include:^[4]
• Tachycardia and increased contractility through sympathetic stimulation
• Activation of the renin/angiotensin/aldosterone system, leading to fluid retention and consequently increased preload
• These compensatory mechanisms eventually become maladaptive seeing that:^[1][5]
• Tachycardia and increased contractility will increase cardiac muscle oxygen demand, thereby exacerbating the initial ischemia;
• Vasoconstriction, as a response to impaired cardiac output, in order to try to maintain coronary artery perfusion and systemic blood pressure (SVR) increases myocardial afterload, leading to an impairment in myocardial performance and an increase in its oxygen demand, worsening ischemia;
• The activation of the neurohormonal cascade will promote retention of water and sodium, in order to compensate for the hypotension and improve perfusion, yet this will also exacerbate pulmonary edema.
• The prolonged systemic hypoperfusion and hypoxia will cause a shift in cellular metabolism, prioritizing glycolysis, leading to a state of lactic acidosis, which jeopardizes contractility and systolic performance, thereby affecting the previously described system.
• All these factors affecting oxygen demand and cardiac performance create a vicious cycle that if not interrupted, may eventually lead to death.
• The therapeutic approach to cardiogenic shock focuses in disrupting this cycle.^[6]
• The area of original infarct, remote territories may also exhibit some kind of myocardial damage, called myocardial stunning.
• Myocardial stunning is the name given the myocardium which remains dysfunctional even though the restoration to normal perfusion.
• The pathophysiology of myocardial stunning is multifactorial and involves calcium overload in the sarcolemma and diastolic dysfunction, as well as the release of myocardial depressant substances.
• This calcium overload is responsible for the activation of proteases called calpains. These and other proteases will be responsible for the degradation of myofilaments, which will decrease the response to calcium, thereby explaining the temporary myocardial dysfunction after reperfusion.
• Areas of stunned myocardium may remain stunned after revascularization due to the need to resynthetize new myofilaments.^[7]
• These regions retain contractile reserve and usually respond to inotropic stimulation.
• Stunned myocardium, hibernating myocardium does respond earlier to revascularization since myocardial cells remain viable and when reperfused, calcium levels normalize.^[8][9][10]

• 5% of the cases but represents as high mortality rate as left ventricular shock.
• The right ventricular regions more commonly affected by infarction are the inferior and inferior-posterior walls.
• The coronary arteries frequently occluded in this setting are the right coronary artery, or the left circumflex coronary artery, in a left dominant system.^[11][12] Patients with right coronary artery occlusion, in a right dominant system, are at higher risk of developing papillary muscle rupture and therefore undergoing valvular heart disease, such as mitral regurgitation.^[12][13][14]
• Right ventricle failure may affect left ventricular performance by several means:^[15][16]
• Decrease in right ventricular output leading to a decrease in left ventricular filling thereby affecting overall cardiac output;
• Increased right ventricular telediastolic pressure, leading to a shifting of the interventricular septum into the left ventricle, therefore jeopardizing left ventricular filling and systolic function.

• Ventricular septal rupture and free wall rupture, which constitute two entities of cardiac rupture, represent the second most common cause of death in patients with acute myocardial infarction, during hospital stay.^[17][18][19]
• Ventricular septal rupture in the SHOCK registry, it accounted for 4.6% of the cases of cardiogenic shock.^[20]
• The most recent registries show that ventricular septal rupture generally develops within the first 16 to 24 hours post-MI and has the following characteristics:^{[21][22][23][24][25][12][26][12][27][28]}
• According to the SHOCK trial data, this type of rupture had 55% of mortality rate within the first 30 days.^[28] Free wall rupture may also be classified as simple or complex. It may occur either on the anterior or the lateral and posterior left ventricular walls.^[28][17] These last two are thought to rupture easier, however, because of the higher proportion of anterior MIs, they are seen less frequently.^[12]
• The rupture may present with different types of courses:
  • Acute – the patient generally feels acute onset of chest pain, developing cardiac tamponade, hemodynamical collapse and sudden death. Because of the rapid course of this type, it is usually not controlled with current therapies.^[29][30]
  • Subacute – this type generally results in smaller and contained ruptures. These may be stabilized by the formation of a clot or fibrinous pericardial adhesions for a short period of time. Therapeutical measures must be applied urgently.^[31][24]
  • Chronic – less frequently associated with cardiogenic shock.

• Studies like the SHOCK trial show that not all patients follow this classic paradigm, since:^[32][33][34]
• The range of elevation of systemic vascular resistance in this trial was wide, suggesting that the compensatory vasoconstriction wasn’t a rule in every patient;
• The mean ejection fraction was also moderately decreased in this trial, showing that other mechanisms besides cardiac failure were present;
• Some of the patients had leukocytosis and fever, which along with the decreased systemic vascular resistance suggested SIRS.
• These facts have introduced the concept that myocardial infarction may cause SIRS and that inflammation plays an important part in the development and persistence of cardiogenic shock, contributing to myocardial dysfunction and vasodilation.
• The possibility of developing SIRS raises with the increasing permanence in cardiogenic shock.^[1][35][36]
• At the time of the cardiac injury, the myocardium releases into circulation cytokines, particularly during the first 24 to 72 hours after the MI. *These will induce the enzyme nitric oxide synthase, thereby increasing the level of nitric oxide, which will be responsible for vasodilation and worsening of hypotension, further jeopardizing left ventricle performance.^{[37][38][39][40][41][42]} NO may also form a toxic radical, called peroxynitrite, when combined with superoxide, affecting myocardial contractility.^[43]
• Among these released cytokines during cardiogenic shock, are interleukin-6 and tumor necrosis factor.
• IL-6,is specific cytokine is correlated with the degree of organ failure and therefore mortality.^[44]
• These inflammatory mediators, among other actions, are responsible for the release of BNP, which makes the levels of BNP good markers, not only for the level of inflammation, but also to evaluate hemodynamic decompensation.^[45]
• Other circulatory factors, such as procalcitonin, complement and CRP, have been reported in some studies to contribute to the development of SIRS in cardiogenic shock.^[46][47]
• Besides the aforementioned macrocirculatory changes in cardiogenic shock, which may also be seen in septic shock, it is important to mention that microcirculatory abnormalities, caused in part by the inflammatory cascades, play an important part in the pathogenesis of organ failure as well.^[48][49][50]

• An important number of patients in cardiogenic shock complicating myocardial infarction (around 3/4), develop it after hospital admission.^[51][52]
• In some of these patients, it is reported that the development of shock, particularly in high risk patients, is related to the use of certain classes of medications, used to treat the MI. These include:^{[53][54][55][56]}
• Beta-blockers
• ACE inhibitors
• Morphine
• Diuretics (As a cause or aggravating factor. This is due to the fact that pulmonary edema is a common complication of cardiogenic shock, leading to a decrease of circulating plasma volume, particularly in patients with prior heart failure.
• After the administration of high-dose diuretics, the plasma volume will further decline)
• Excess fluid administration (In the case of right ventricular myocardial infarction, the excess volume loading in these patients may also contribute to the development of shock)

http://www.peir.net Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology]

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