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Pathophysiology

The most common cause for cardiogenic shock is left ventricular 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, either alone or in combination, for the 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

The Pathophysiologic "Spiral" of Cardiogenic shock

The pathologic process begins with myocardial ischemia that leads 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, parameters like stroke volume and cardiac output will therefore decrease. The pressure gradient produced between the pressure within the coronary arteries and within the left ventricle, along with the duration of the diastole, will dictate myocardial perfusion. This will then be compromised by the hypotension and the tachycardia, worsening the myocardial ischemia. The pump failure will 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 increase, which will consequently propagate the ischemia.

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, which 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 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.

Inflammation and Hemodynamics

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

• The the range of elevated systemic vascular resistance 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 possibility that inflammation plays a part in the development and persistence of cardiogenic shock, contributing to myocardial dysfunction and vasodilation.

At the time of the cardiac injury, the myocardium releases into circulation cytokines, these will induce the enzyme nitric oxide synthase, thereby increasing the level on 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, there is 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. Besides the aforementioned changes in macrocirculation, in cardiogenic shock there are also microcirculatory abnormalities, caused in part by the inflammatory cascades, that play an important part in the pathogenesis of organ failure.

Pathology

Myocardium

• INFARCT EXTENSION AND EXPANSION
• REMOTE ISCHEMIA
• DIASTOLIC DYSFUNCTION
• VALVULAR ABNORMALITIES

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 — ↓	↓	↓