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Pathophysiology

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 nevertheless, a smaller infarct may also originate this condition in a patient with a previously compromised ventricle function. However, 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:

• 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, 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

Luckily many of these abnormalities are fully or partially reversible. This justifies the fact that most of the survivors have good chances of having a good outcome and living with considerable quality of life, assuming that they follow their physician's advice.

The Pathophysiologic "Spiral" of Cardiogenic shock

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. When ischemia reaches a point that the left ventricle 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 pump 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.

Other important reference to make in the setting of cardiac pump failure and hypoperfusion of the peripheral tissues is that this last one leads to the release of catecholamines. Catecholamines will increase the heart's contractility and peripheral blood flow, by causing constriction of arterioles to maintain perfusion, however, this will also increase the heart's oxygen demand and have proarrhythmic and myocardiotoxic consequences.

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 in 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:

• Tachycardia and increased contractility through sympathetic stimulation
• Activation of the renin/angiotensin/aldosterone system, leading to fluid retention and consequently increased preload

However, these compensatory mechanisms eventually become maladaptive seeing that:

• 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, 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 it 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.

Right Ventricle Myocardial Infarction

Accounts for about 5% of the cases but represents as high mortality rate as left ventricle 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. 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.

Right ventricle failure may affect left ventricular performance by several means:

• Decrease in right ventricle output leading to a decrease in left ventricle filling thereby affecting cardiac output;
• Increased right ventricle telediastolic pressure, leading to shifting of the interventricular septum into the left ventricle therefore jeopardizing left ventricle filling and systolic function.

Ventricular Septal and Free Wall Rupture

In the case of ventricular septal rupture, in the SHOCK registry, it accounted for 4.6% of the cases of cardiogenic shock. 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:

• most common in the setting of transmural myocardial infarction, generally associated with anterior or anterolateral infarction, with about 60% of cases being related to left anterior descending coronary artery occlusion;
• 20 to 40% of cases are associated with inferior ventricular septal rupture and are related to dominant right coronary artery, or less frequently, dominant left circumflex coronary artery occlusion;
• can be classified as:

• simple
• complex

In the case of free wall rupture...

Inflammation and Hemodynamics

Studies like the SHOCK trial show that not all patients follow this classic paradigm, since:

• The the range of elevation of systemic vascular resistance in this trial was wide, suggesting that the compensatory vasoconstriction wan'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 a 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.

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. NO may also form a toxic radical, called peroxynitrite, by combining with superoxide, affecting myocardial contractility. Among these released cytokines during cardiogenic shock, are interleukin-6 and tumor necrosis factor. In the case of IL-6, this specific cytokine is correlated with the degree of organ failure and therefore mortality. 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. 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. 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.

Iatrogenic Cardiogenic Shock

An important number of patients in cardiogenic shock complicating myocardial infarction (around 3/4), develop it after hospital admission. 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:

• 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 lead or contribute to the development of shock.

Pathology

Myocardium

• INFARCT EXTENSION AND EXPANSION
• REMOTE ISCHEMIA
• DIASTOLIC DYSFUNCTION
• VALVULAR ABNORMALITIES - (page 155 article #2)

Cellular

• ENERGY METABOLISM
• ION PUMPS
• NECROSIS
• APOPTOSIS

Myocardial dysfunction

• STUNNING
• HIBERNATING

Reperfusion Injury

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The Impact of Cardiogenic shock on the Pressure-Volume Loop

Cardiogenic shock shifts the pressure volume loop to the right: that is to say at a given pressure, the heart is able to eject less blood per heart beat, and stroke volume is reduced. Diastolic compliance is reduced, and left ventricular volumes are increased. This leads to the classic observation that an increased left ventricular end diastolic pressure is required to maintain adequate cardiac output. The rise in end diastolic pressure increases the wall stress and oxygen demands of the myocardium. These hemodynamic abnormalities contributes to the pathophysiologic spiral described below.

Cardiogenic shock and Inflammatory Mediators

Myocardial infarction or ischemia lead to production of superoxide radicals which combine with nitrous oxide to form perioxinitrite which in turn causes myocardial depression and hypotension.

The Pathophysiologic "Spiral" of Cardiogenic shock

Among patients with acute MI, there is often a downward spiral of hypoperfusion leading to further ischemia which leads to a further reduction in cardiac output and further hypoperfusion. The lactic acidosis that develops as a result of poor systemic perfusion can further reduce cardiac contractility. Reduced cardiac output leads to activation of the sympathetic nervous system, and the ensuing tachycardia that develops further exacerbates the myocardial ischemia. The increased left ventricular end diastolic pressures is associated with a rise in wall stress which results in further myocardial ischemia. Hypotension reduces epicardial perfusion pressure which in turn further increases myocardial ischemia.

Patients with cardiogenic shock in the setting of STEMI more often have multivessel disease, and myocardial ischemia may be present in multiple territories. It is for this reason that multivessel angioplasty may be of benefit in the patient with cardiogenic shock. Non-culprit or remote territories may also exhibit myocardial stunning in response to an ischemic insult which further reduces myocardial function. The pathophysiology of myocardial stunning is multifactorial and involves calcium overload in the sarcolemma and "stone heart" or diastolic dysfunction as well as the release of myocardial depressant substances. Areas of stunned myocardium may remain stunned after revascularization, but these regions do respond to inotropic stimulation. In contrast to stunned myocardium, hibernating myocardium does respond earlier to revascularization.

The multifactorial nature of cardiogenic shock can also be operative in the patient with critical aortic stenosis who has "spiraled": There is impairment of left ventricular outflow, with a drop in cardiac output there is greater subendocardial ischemia and poorer flow in the coronary arteries, this leads to further left ventricular systolic dysfunction, given the subendocardial ischemia, the left ventricle develops diastolic dysfunction and becomes harder to fill. Inadvertent administration of vasodilators and venodilators may further reduce cardiac output and accelerate or trigger such a spiral.

Pathophysiologic Mechanisms to Compensate for Cardiogenic shock

Cardiac output is the product of stroke volume and heart rate. In order to compensate for a reduction in stroke volume, there is a rise in the heart rate in patients with cardiogenic shock. As a result of the reduction in cardiac output, peripheral tissues extract more oxygen from the limited blood that does flow to them, and this leaves the blood deoxygenated when it returns to the right heart resulting in a fall in the mixed venous oxygen saturation.

Pathophysiology of Multiorgan Failure

The poor perfusion of organs results in hypoxia and metabolic acidosis. Inadequate perfusion to meet the metabolic demands of the brain, kidneys and heart leads to multiorgan failure.

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Differential Diagnosis

Classification of shock based on hemodynamic parameters. (CO, cardiac output; CVP; central venous pressure; PAD, pulmonary artery diastolic pressure; PAS, pulmonary artery systolic pressure; RVD, right ventricular diastolic pressure; RVS, right ventricular systolic pressure; SVO2, systemic venous oxygen saturation; SVR, systemic vascular resistance.)

Type of Shock	Etiology	CO	SVR	PCWP	CVP	SVO2	RVS	RVD	PAS	PAD
Cardiogenic	Acute Ventricular Septal Defect	↓↓	↑	N — ↑	↑↑	↑ — ↑↑	N — ↑	↑	N — ↑	N — ↑
	Acute Mitral Regurgitation	↓↓	↑	↑↑	↑ — ↑↑	↓	↑	N — ↑	↑	↑
	Myocardial Dysfunction	↓↓	↑	↑↑	↑↑	↓	N — ↑	N — ↑	N — ↑	↑
	Right Ventricular Infarction	↓↓	↑	N — ↓	↑↑	↓	↓ — ↑	↑	↓ — ↑	↓ — ↑
Obstructive	Pulmonary Embolism	↓↓	↑	N — ↓	↑↑	↓	↓ — ↑	↑	↓ — ↑	↓ — ↑
	Cardiac Tamponade	↓ — ↓↓	↑	↑↑	↑↑	↓	N — ↑	↑	N — ↑	N — ↑
Distributive	Septic Shock	N — ↑↑	↓ — ↓↓	N — ↓	N — ↓	↑ — ↑↑	N — ↓	N — ↓	↓	↓
	Anaphylactic Shock	N — ↑↑	↓ — ↓↓	N — ↓	N — ↓	↑ — ↑↑	N — ↓	N — ↓	↓	↓
Hypovolemic	Volume Depletion	↓↓	↑	↓↓	↓↓	↓	N — ↓	N — ↓	↓	↓