**2. Etiology**

Traditionally, CP had been described months to years after acute bacterial pericarditis, whereas in the last decades, chronic inflammation associated with previous thoracic surgery or radiotherapy has become the most frequent cause of CP. A recent meta-analysis of patients submitted to pericardiectomy for symptomatic CP [2] has collected data about 2114 patients admitted between 1991 and 2019. Idiopathic etiology was present in approximately half of patients (50.2%) followed by postcardiac surgery (26.2%) and mediastinal radiotherapy (8.9%). Interestingly, studies published after 2000 have reported a dramatic decrease of cases secondary to cardiac surgery with respect to previous reports (15% vs. 33%, p < .001). This could reflect the evolution of cardiac surgery techniques with progressively reduced operative times and close echocardiographic evaluation after surgery.

Moreover, end-stage renal disease, connective tissue disorders (i.e., lupus erythematosus, rheumatoid arthritis, systemic sclerosis, etc.), and pulmonary diseases, including pulmonary asbestosis and mesothelioma infiltrating the pericardium, are less frequent but important causes of CP. More exceptional is CP secondary to transmural myocardial infarction (Dressler's syndrome), given the spread of primary angioplasty and, consequently, the reduction of infarct size, in developed countries. Finally, CP secondary to tuberculosis infection in developed countries has been reported to be a rare condition (3%) with an increasing trend in the last decades due to imported cases and the spread of HIV infections. Nonetheless, taking into account socioeconomic background, tuberculosis infections and, along with them, late complications like CP are significantly increasing in developing countries. Consequently, tuberculosis has become the first cause of CP in countries of sub-Saharan Africa and few countries of Asia, including India where tuberculosis was associated with more than half of cases of CP (51.6%) in a retrospective single-center analysis, including patients submitted to pericardiectomy between 2009 and 2020 [3].

### **3. Pathophysiology**

Chronic pericardial inflammation usually drives a structural change of pericardial layers, resulting in progressive fibrosis and calcifications and leading to partial adhesions between the layers. Consequently, difficulties in diastolic ventricle filling can be observed. As a matter of fact, during diastole, ventricles experience an active (ATPconsuming) relaxation with a rapid decrease of chamber pressures leading to mitral valve opening and early inflow with a velocity as higher as the pressure gradient between atrial and ventricular chambers. This phase is usually followed by an atrial contraction leading to further ventricle filling with no significant increase of enddiastolic ventricular pressures unless pathologic conditions, like CP, occur. In case of CP, given the reduced compliance of pericardium and its reduced stretching, diastolic pressures of the ventricles rapidly increase, and consequently, ventricular filling abruptly ceases during early to mid-diastole, when cardiac volume reaches the limit set by non-compliant pericardium. Thus, atrial emptying will be incomplete, leading to the increase of atrial and pulmonary/systemic venous pressure [4]. Systemic venous congestion results in hepatic congestion, peripheral edema, and ascites and, if long-standing, in cardiac cirrhosis and symptoms secondary to low cardiac output (**Figure 1**). As a matter of fact, although left ventricle (LV) ejection fraction is usually normal, the absolute reduction of diastolic filling, due to pericardial

#### **Figure 1.**

*Constrictive pericarditis physiology. During early to mid-diastole, ventricular filling (red arrows) is limited by pericardial thickness and incompliance (A) that resist to myocardial relaxation (white arrows) and, therefore, limiting ventricular preload to the early diastolic phase as showed by trans-mitral Doppler inflow pattern characterized by elevated and short "e"wave and a minor "a"wave (B) and sharp "y" descending wave at jugular vein pulse (C). Limitation to ventricular filling is, finally, associated to peripheral vein congestion as highlighted by dilation of inferior vena cava (D).*

reduced compliance, leads to reduced cardiac output and, consequently, to fatigue and reduced functional class. Finally, physiologic reduction of intrathoracic pressure during inspiration acts on lungs and pulmonary veins, as usual, but will not be transmitted to the heart (*heart-lungs decoupling*) because of the limited heart diastolic compliance (myocardial relaxation, after reaching maximal diastolic volume limited by pericardium incompliance, fails to increase linearly with respect to negative intrathoracic pressure that usually drives a suction phenomenon). Consequently, whereas in normal hearts, trans-mitral flow increases during inspiration, as a consequence of this suction phenomenon, in patients with CP, it is reduced because pulmonary veins have a negative pressure with respect to the left atrium, resulting in a reduction of forward blood flow, and, finally, to LV diastolic filling [5]. This phenomenon clearly does not apply to right ventricle (RV) because inspiratory negative pressure is not applied to systemic veins (originating outside of thorax), and consequently, venous pressure is not lower than right atrial pressure so that diastolic filling of RV is less reduced than LV during inspiration (**Figure 2**). This right-left mismatch and ventricle inter-dependence secondary to thickened non-compliant pericardium (expansion of one ventricle occurs at expenses of the other one because both are into a rigid pericardial envelope) explain the reason why, as explained before, during inspiration, LV filling decreases whereas RV filling increases with secondary leftward interventricular septal shift (*septal bounce*). Conversely, during expiration, pulmonary vein pressure increases, driving forward blood flow and, therefore, increasing trans-mitral flow.

#### **Figure 2.**

*Respiratory variations of ventricular filling pressures in constrictive pericarditis. During inspiration (left), thorax expansion is accompanied by a negative pressure transferred to lungs, pulmonary veins but not to the heart (because of uncompliant pericardium) and peripheral veins (outside of thorax). Pressure gradient from pulmonary veins to left atrium is reduced whereas gradient from vena cava to right atrium is increased (red arrow). Consequently, mitral inflow is reduced with respect to tricuspid flow and septum is shifted leftward (\*). During expiration (right), a positive pressure is transferred on pulmonary veins driving the increase of gradient from pulmonary veins to left atrium (red arrow) and the increase of mitral inflow with respect to tricuspid inflow. As a consequence, septum returns to neutral position.*

In this case, right ventricle filling, expressed as trans-tricuspid flow, decreases, and leftward interventricular septal deviation disappears [6].
