Pathophysiology of right ventricular failure in acute pulmonary embolism and chronic thromboembolic pulmonary hypertension: a pictorial essay for the interventional radiologist

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 [1]. 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 [2]. 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.

The anatomic construct of the right heart and the left heart are suitable for their task. The RV is part of a low-pressure system with a low-resistance afterload (the pulmonary artery), and is thin-walled, compliant, and crescent-shaped (Fig. 1), able to accommodate a large amount of blood, but without a lot of pressure generated (see Fig. 2) [5]. The left ventricle (LV), on the other hand, is thick-walled (Fig. 1) and non-compliant generating a large amount of pressure against a high-resistance afterload (the aorta) (Fig. 2) [5].

Because the right ventricle is thin-walled and compliant, it is ill-equipped for acute increases in afterload compared to the muscular thick-walled noncompliant left ventricle. When there are acute incremental increases in afterload, there are drastic decreases in stroke volume, or forward flow of blood (Fig. 3) [6, 7]. With acute increases in afterload, the compliant right ventricle cannot unload sufficiently and dilates which gives rise to three important outcomes: (1) the dilated RV pushes the interventricular septum toward the left ventricle, impinging on the left ventricle, resulting in underfilling of the left ventricle (Fig. 4), decreased left ventricle output, and therefore decreased supply to the coronary arteries; (2) right ventricular intramuscular pressure increases, straightening normal muscular folds, impeding coronary blood flow in the right heart wall (Fig. 5), further leading to ischemia; and (3) stretching of the annulus of the tricuspid valve results in tricuspid regurgitation (Fig. 6), further decreasing forward flow of blood from the right ventricle [5, 8‐10].

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 [11]. 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 [11]. 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 [9]. 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 [12].

As the right ventricle becomes ischemic, its contractility further suffers, further decreasing right ventricular output, increasing right ventricular dilatation, and decreasing left ventricular output, resulting in a downward hemodynamic spiral that augments itself and leads to cardiogenic shock (Fig. 7) [8, 13]. It should be noted that medications such as propofol used for the induction and maintenance of general anesthesia decrease venous return to the right heart, or the preload, due to peripheral venous dilatation, further compromising the RV’s output and ability to perform against an elevated afterload (Fig. 8) [14].

Massive or high-risk and submassive or intermediate-risk PE are divided by hemodynamic presentation (Table 1) [15]. Massive PE occurs in about 5% of patients with PE and carries a mortality rate of 18–65% [2]. It is defined as PE with sustained hypotension (systolic BP < 90 for at least 15 min), the need for inotropic support, or persistent bradycardia (HR < 40 bpm with signs or symptoms of shock) [15]. Persistent bradycardia may be a result of complete atrioventricular (AV) block due to injury to the right bundle branch that runs superficially in the right ventricular wall and in the intraventricular septum, and is sensitive to acute right ventricular dilatation, in a patient with pre-existing electrical conduction system disease like left bundle branch block (LBBB) [16]. Of note, the right bundle branch can also be disturbed during pulmonary catheterization, a technique that may be used by interventional radiologists in diagnosing and treating massive and submassive PE, causing a complete AV block in a patient with existing LBBB [17]. Therefore, a temporary pacemaker placement should be considered in patients with LBBB [17].

Submassive PE, seen in about 40% of patients with PE, carries a 5–25% mortality rate (Table 1) [2]. 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 [15].

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) [2]. Patients with simple PE are systemically normotensive, without right ventricular dysfunction or myocardial ischemia.

When evaluating a CT in a patient with PE to assess for RV compromise and significance of PE burden, one may note the RV/LV ratio which has been associated with clinical outcome [18‐20]. The RV/LV ratio is determined by measuring the maximal RV and LV diameters from inner wall to inner wall on the axial slice that best approximates the four-chamber view (Fig. 9) [21]. A value > 0.9 is considered abnormal. It is important to note that an axial RV/LV diameter ratio is no less accurate than a reformatted four-chamber RV/LV diameter ratio [21].

Treatment of massive PE is aimed at relieving the RV afterload to improve RV function. Treatment methods include pulmonary artery endarterectomy, systemic IV thrombolytics, and relatively more recent, percutaneous intervention such as catheter-directed thrombectomy and thrombolysis performed by interventional radiologists (Figs. 10 and 11) [15]. Historically, treatment of submassive PE has been only anticoagulation. However, given the compromise of the RV, other treatments such systemic low-dose IV thrombolytics and percutaneous interventions like catheter-directed thrombectomy and thrombolysis may be performed by interventional radiologists (Figs. 10 and 12) [15]. For patients with uncomplicated PE, treatment remains anticoagulation only (Fig. 10) [15]. Suboptimal or incomplete treatment of any PE can sometimes result in CTEPH [3]. Figure 10 provides a treatment algorithm for acute PE [15].

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 [3]. 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 [22]. 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 [23‐25]. 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 [27]. 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 [27].

In CTEPH, to accommodate the RV afterload and wall stress to the RV, adaptive remodeling occurs with RV wall hypertrophy (Fig. 13), through the addition of sarcomeres, the functional unit of striated muscle, in a process called adaptive hypertrophy [28, 29]. Adaptive right ventricular wall hypertrophy results in decreased wall stress and improved pumping capability, with RV function more closely mimicking that of the LV [30]. However, the ill-equipped RV is not capable of sustaining the long-term progressively increased afterload and remodeling becomes maladaptive [29]. RV dilatation and wall hypertrophy increase oxygen demand to a level which the coronary artery blood flow cannot meet, resulting in ischemia, necrosis, and fibrosis of the RV wall (Fig. 14), worsening contractility of the right ventricle, and right ventricular failure. Right ventricular failure leads to further RV dilatation impinging on the LV, worsening LV filling, decreased LV stroke volume, increased heart rate to compensate for the decrease in the LV stroke volume (SV), and decreased output to the coronary arteries [28, 29]. Decreased output to the coronary arteries therefore occurs by both (1) decrease in the LV SV and (2) increase in the heart rate to compensate for the decreased in the SV [28, 29]. The increase in heart rate shortens the time coronary artery blood can flow, which occurs during diastole [31]. The compromise of the coronary arteries is accentuated as the coronary arteries already cannot meet the demand of the hypertrophied dilated RV [31]. Moreover, in addition to RV systolic dysfunction, there is RV diastolic dysfunction, as the hypertrophied, noncompliant, stiff, fibrotic RV wall, requires more time to relax than normal and cannot fill as normal in its allotted time [32, 33]. As with acute RV dysfunction, the chronic RV dysfunction creates a progressive downward spiral leading to severe heart failure (Fig. 15).

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 [34]. 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 [34].

Imaging reflects the consequences of CTEPH on the pulmonary vasculature and/or the right ventricle. Imaging often begins with an echocardiogram in patients with suspected CTEPH, where the pulmonary artery systolic pressure (PASP), estimated by using the velocity of the tricuspid regurgitation jet (Fig. 16), may be elevated. Echocardiography may also demonstrate the deterioration of the right heart with the right ventricular size increased and motility compromised (Fig. 17) [35]. Additionally, patients with suspected CTEPH may undergo planar (Fig. 18) or single-photon emission computed tomography (SPECT) ventilation/perfusion (V/Q) scan (Fig. 19), which remains the screening imaging tool of choice where one notes mismatched segmental defects [36]. After echocardiogram and V/Q scan, pulmonary vasculature hemodynamics are confirmed with a right heart catheterization (RCH) where pulmonary artery pressure (PAP) is ≥ 25 mmHg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg, and pulmonary vascular resistance (PVR) > 240 dynes s⁻¹ cm⁻⁵ is noted in CTEPH [37]. RCH is very important pre-treatment, as patients with a preoperative PVR > 1000 dynes s⁻¹ cm⁻⁵ have a significantly higher mortality rate than those with a preoperative PVR < 1000 dynes s⁻¹ cm⁻⁵ [38]. Finally, in CTEPH, invasive pulmonary angiogram and CT pulmonary angiograms will demonstrate the bands, webs, stenoses, and occlusions obstructing the pulmonary vasculature (Fig. 20a–d) resulting in the progressive severe RV failure, and can be used to plan treatment [27]. Dual energy computed tomography can be utilized to combine the benefits of a V/Q scan demonstrating perfusion defects and a pulmonary angiogram demonstrating the abnormality of the pulmonary vasculature (Fig. 21) [39]. Table 2 provides a summary of imaging findings in CTEPH and Fig. 22 provides an imaging algorithm for suspected CTEPH [34].

Treatment for CTEPH is aimed at relieving the afterload for the deteriorating RV (Fig. 23). Pulmonary artery endarterectomy is utilized for patients with more central disease (central-type CTEPH) and patients who are surgical candidates [40]. For more distal disease in the segmental and subsegmental regions (distal-type CTEPH), medical therapy with Riociguat and more recently balloon pulmonary angioplasty (BPA) may be performed [40‐42]. BPA is a revolutionary procedure performed by an interventional radiologist that changes the face of inoperable and distal-type CTEPH by using angioplasty balloons to disrupt regions of obstruction in the pulmonary vasculature and decrease RV afterload (Fig. 24) [42]. Figure 23 provides a treatment algorithm for CTEPH [34].

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.