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mellitus4447—are shared with arterial disease, notably atherosclerosis.4851 However, this may be an indirect association mediated, at least in part, by the complications of coronary artery disease and, in the case of smoking, cancer.52,53 Myocardial infarction and heart failure increase the risk of PE.54,55 Conversely, patients with VTE have an increased risk of subsequent myocardial infarction and stroke, or peripheral arterial embolization.56 3.3 Pathophysiology and determinants of

outcome Acute PE interferes with both circulation and gas exchange. Right ventricular (RV) failure due to acute pressure overload is considered the primary cause of death in severe PE. Pulmonary artery pressure (PAP) increases if >3050% of the total cross-sectional area of the pulmonary arterial bed is occluded by thromboemboli.57 PE-induced vasoconstriction, mediated by the release of thromboxane A2 and serotonin, contributes to the initial increase in pulmonary vascular resistance (PVR) after PE.58 Anatomical obstruction and hypoxic vasoconstriction in the affected lung area lead to an increase in PVR, and a proportional decrease in arterial compliance.59 The abrupt increase in PVR results in RV dilation, which alters the contractile properties of the RV myocardium via the FrankStarling mechanism. The increase in RV pressure and volume leads to an increase in wall tension and myocyte stretch. The contraction time of the RV is prolonged, while neurohumoral activation leads to inotropic and chronotropic stimulation. Together with systemic vasoconstriction, these compensatory mechanisms increase PAP, improving flow through the obstructed pulmonary vascular bed and thus temporarily stabilizing systemic blood pressure (BP). However, the extent of immediate adaptation is limited, as a nonpreconditioned, thin-walled RV is unable to generate a mean PAP >40 mmHg. Prolongation of RV contraction time into early diastole in the left ventricle (LV) leads to leftward bowing of the interventricular septum.60 The desynchronization of the ventricles may be exacerbated by the development of right bundle branch block. As a result, LV filling is impeded in early diastole, and this may lead to a reduction in the cardiac output (CO), and contribute to systemic hypotension and haemodynamic instability.61 As described above, excessive neurohumoral activation in PE can be the result of both abnormal RV wall tension and circulatory shock. The finding of massive infiltrates of inflammatory cells in the RV myocardia of patients who died within 48 h of acute PE may be explained by high levels of epinephrine released as a result of the PE-induced ‘myocarditis’.62 This inflammatory response might explain the secondary haemodynamic destabilization that sometimes occurs 2448 h after acute PE, although early recurrence of PE may be an alternative explanation in some of these cases. Finally, the association between elevated circulating levels of biomarkers of myocardial injury and an adverse early outcome indicates that RV ischaemia is of pathophysiological significance in the acute phase of PE.63,64 Although RV infarction is uncommon after PE, it is likely that the imbalance between oxygen supply and demand can result in damage to cardiomyocytes, and further reduce contractile forces. Systemic hypotension is a critical element in this process, leading to impairment of the coronary driving pressure to the overloaded RV. The detrimental effects of acute PE on the RV myocardium and the circulation are summarized in Figure 2. Respiratory failure in PE is predominantly a consequence of haemodynamic disturbances.66 Low CO results in desaturation of the mixed venous blood. Zones of reduced flow in obstructed

Table 3 Predisposing factors for venous thromboembolism (data modified from Rogers et al.23 and Anderson and Spencer24)

Strong risk factors (OR > 10) Fracture of lower limb Hospitalization for heart failure or atrial fibrillation/flutter (within previous 3 months) Hip or knee replacement Major trauma Myocardial infarction (within previous 3 months) Previous VTE Spinal cord injury Moderate risk factors (OR 29) Arthroscopic knee surgery Autoimmune diseases Blood transfusion Central venous lines Intravenous catheters and leads Chemotherapy Congestive heart failure or respiratory failure Erythropoiesis-stimulating agents Hormone replacement therapy (depends on formulation) In vitro fertilization Oral contraceptive therapy Post-partum period Infection (specifically pneumonia, urinary tract infection, and HIV) Inflammatory bowel disease Cancer (highest risk in metastatic disease) Paralytic stroke Superficial vein thrombosis Thrombophilia Weak risk factors (OR < 2) Bed rest >3 days Diabetes mellitus Arterial hypertension Immobility due to sitting (e.g. prolonged car or air travel) Increasing age Laparoscopic surgery (e.g. cholecystectomy) Obesity Pregnancy Varicose veins HIV = human immunodeficiency virus; OR = odds ratio; VTE = venous thromboembolism. Downloaded from academic.oup.com/eurheartj/article/41/4/543/5556136 by guest on 07 October 2026