Pathophysiology of right ventricular failure in acute pulmonary embolism and chronic thromboembolic pulmonary hypertension: a pictorial essay for the interventional radiologist
Pulmonary embolus (PE) is the third most common cause of cardiovascular death with more than 600,000 cases occurring in the USA per year. About 45% of patients with acute PE will have acute right ventricular failure, and up to 3.8% of patients will develop chronic thromboembolic pulmonary hypertension (CTEPH) with progressive, severe, chronic heart failure. The right ventricle (RV) is constructed to accommodate a low-resistance afterload. Increases in afterload from acute massive and submassive PE and CTEPH may markedly compromise the RV function leading to hemodynamic collapse and death. The purpose of this educational manuscript is to instruct on the pathophysiology of RV failure in massive and submassive PE and CTEPH. It is important to understand the pathophysiology of these diseases as it provides the rationale for therapeutic intervention by the Interventional Radiologist. We review here the pathophysiology of right ventricular (RV) failure in acute massive and submassive PE and CTEPH.
KeywordsRight ventricular failure Submassive pulmonary embolism Massive pulmonary embolism Chronic thromboembolic pulmonary hypertension
Beta natriuretic peptide
Balloon pulmonary angioplasty
Chronic thromboembolic pulmonary hypertension
Left bundle branch block
Left ventricle or left ventricular
Pulmonary artery pressure
Pulmonary artery systolic pressure
Pulmonary capillary wedge pressure
Pulmonary vascular resistance
Right heart catheterization
Right ventricle or right ventricular
Right ventricle/left ventricle
Single-photon emission computed tomography
The anatomic construct of the right heart is suitable for its task. The right ventricle (RV) as part of a low-pressure system with a low-resistance afterload (the pulmonary artery) is thin-walled, compliant, and crescent-shaped.
With increases in afterload, the right ventricle cannot unload sufficiently resulting in dilatation of the compliant right ventricle, impinging on the left ventricle resulting in decreased left ventricle output and supply to the coronary arteries.
Massive pulmonary embolus (PE) is defined as PE with sustained hypotension (systolic BP < 90 for at least 15 min), need for inotropic support, or persistent bradycardia (HR < 40 bpm with signs or symptoms of shock).
Patients with submassive PE are systemically normotensive with evidence of myocardial dysfunction and ischemia.
In chronic thromboembolic pulmonary hypertension (CTEPH), RV dilatation and wall hypertrophy increase oxygen demand to which the coronary artery blood flow cannot meet, resulting in ischemia, necrosis, and fibrosis of the RV wall.
PE is the third most common cause of cardiovascular death (after myocardial infarction and stroke), and more than 600,000 cases are believed to occur in the USA per year . About 45% of patients with PE will have right ventricular compromise, carrying a mortality of up to 25% when the patient is normotensive and up to 65% in the setting of hypotension . Moreover, up to 3.8% of patients with PE develop chronic thromboembolic pulmonary hypertension (CTEPH), a long-term progressive complication of acute PE leading to severe heart failure and death [3, 4]. Understanding the pathophysiology of RV heart failure in these diseases formulates the rationale for therapeutic intervention by the interventional radiologist.
Differences in the right and left heart
Acute pulmonary embolus and right ventricular compromise
RV afterload increases with pulmonary emboli. In patients without pre-existing cardiopulmonary disease, 25–30% of the pulmonary vasculature must be occluded before the pulmonary artery pressure rises, increasing the RV afterload . The RV compensates until greater than 50–75% of the pulmonary vasculature is obstructed by emboli with a pulmonary artery pressure increase above 40 mmHg . Afterload is further worsened when hypoxia, induced by the emboli, causes localized vasoconstriction by stimulating the release of vasoactive mediators, such as serotonin, thromboxane, and histamine . When afterload has reached the critical level, the RV dilates, the LV underfills, and decreases supply to the coronary arteries. Perfusion to the right ventricle drops because there is decreased output to the coronary arteries and increased intramuscular pressure impeding the coronary artery flow, leading to right ventricular ischemia .
Differences in massive and submassive PE
PE subtypes, % of patients, clinical definition, and mortality rate
% of PE patients
Sustained hypotension (systolic < 90 mmHg for at least 15 min), need for inotropic support, persistent profound bradycardia (HR < 40 bpm with signs or symptoms of shock)
Systemically normotensive (systolic BP > 90 mmHg), myocardial ischemia (elevated troponins, ECG changes), and/or RV dysfunction (dysmotility on Echo, Increased RV/LV ratio > 0.9, elevated BNP/pro BNP), ECG changes)
Systemically normotensive (systolic BP > 90 mmHg), no RV dysfunction, no myocardial ischemia
Up to 1%
Submassive PE, seen in about 40% of patients with PE, carries a 5–25% mortality rate (Table 1) . Patients with submassive PE are systemically normotensive with evidence of myocardial ischemia or dysfunction as demonstrated by elevated troponins and electrocardiogram (ECG) changes, and/or RV dysfunction demonstrated by decreased motility on echo, increased right ventricle/left ventricle (RV/LV) ratio greater than 0.9 on Echo or CT, elevation of beta natriuretic peptide (BNP) and pro-BNP which mark heart failure, and ECG changes .
The remaining 55% of patients with PE present with nonmassive or low-risk PE, also called uncomplicated PE, with a mortality rate of up to 1% (Table 1) . Patients with simple PE are systemically normotensive, without right ventricular dysfunction or myocardial ischemia.
Clinical considerations in acute PE and RV compromise
Chronic thromboembolic pulmonary hypertension
CTEPH is a chronic progressive pulmonary vascular complication of acute PE severely and progressively affecting the RV, that occurs in 1.5 to 3.8% of patients with one or more episodes of acute PE [3, 4]. It is a subtype of pulmonary hypertension characterized by a mean pulmonary artery pressure ≥ 25 mmHg due to obstructive fibrotic thromboembolic material in the pulmonary arteries from remodeled unresolved pulmonary embolus . Patients with infected ventriculoatrial shunts for the treatment of hydrocephalus, indwelling catheters and leads, thyroid replacement therapy, malignancy, and chronic inflammatory disorders, such as osteomyelitis and inflammatory bowel diseases, have a higher risk of developing CTEPH . Studies have demonstrated an association with inflammatory markers such as C-reactive protein (CRP), IL-10, monocyte chemotactic protein-1, macrophage inflammatory protein-1α, matrix metalloproteinase (MMP)-9, interferon-γ-induced protein (IP)-10, and tumor necrosis factor-α in these patients [23, 24, 25]. In addition, the bacterium Staphylococcus aureus has been harvested in the blood and thrombi of some of these patients [22, 26]. Therefore, it is believed that inflammation and infection play a part in the development of CTEPH . The process involves progressive remodeling of residual thrombi into a fibrotic material of collagen, elastin, inflammatory cells, re-canalized vessels, and rarely calcification, progressively obstructing the pulmonary vasculature in the form of bands, webs, stenoses, and occlusions resulting in a chronically increased afterload for an ill-equipped right ventricle .
CTEPH and right ventricular compromise
Clinical considerations in CTEPH
CTEPH may occur several months or years after the acute PE event, which may be silent. Patients must receive at least 3 months of effective anticoagulation treatment with an acute PE before diagnosis of CTEPH . Symptoms of CTEPH are indicative of RV failure and include new or ongoing worsening shortness of breath, dyspnea on exertion, inability to tolerate activity, and less often hemoptysis and should prompt further workup with imaging .
Imaging findings in CTEPH. (PAP = pulmonary artery pressure, PCWP = pulmonary capillary wedge pressure)
• PAP > 25 mmHg
• Right atrial and right ventricular dilatation
• Reduced right ventricular contractility
Nuclear medicine studies
• Segmental wedge-shaped mismatched defects on perfusion scan
Right heart catheterization
• PAP is ≥ 25 mmHg
• Pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg
• Pulmonary vascular resistance is > 240 dyn-sec-cm-5
Invasive and noninvasive pulmonary angiogram
• Stenoses and occlusions
• Bands, webs, stenoses, and occlusions
Dual energy CT
CTA portion of study:
• Bands, webs, stenoses, and occlusions
Perfusion blood volume of study
• Decreased perfusion in regions of involvement
Pulmonary embolus can be devastating leading to acute and chronic RV failure. Understanding the pathophysiology of RV failure in massive and submassive PE and CTEPH is the key factor in the justification for percutaneous interventions in selected patients. In addition, it aids communication with patients, their families, and the referring clinicians.
YB, as the first author, did the large portion of the research, created the majority of the illustrations, and wrote the drafts. RP provided the MRI illustrations and helped with revisions. EB reviewed the clinical aspects of the manuscript and helped with revisions. HB contributed data on Dual Energy CT. ESM, as the senior author, guided the idea and helped with revisions. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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