Left Ventricular Diastolic Dysfunction in Chronic Thromboembolic Pulmonary Hypertension

Abstract

<h3>Purpose</h3> Impairment of left ventricular (LV) relaxation is associated with increased mortality after surgical treatment of pulmonary hypertension (PH). We sought to describe the pathophysiology of LV diastolic dysfunction in a porcine model of chronic thromboembolic pulmonary hypertension (CTEPH). The reversibility of LV diastolic dysfunction was investigated in patients with CTEPH after pulmonary endarterectomy (PEA). <h3>Methods</h3> CTEPH was induced in 2-month-old Large White piglets (PH group, n=6) by ligation of the left pulmonary artery (PA) followed by weekly embolization of right lower lobe for 5 weeks using a strong tissue glue (N-acetyl cyanoacrylate). These animals were compared to sham-operated animals (controls, n=6). LV diastolic function was assessed using echocardiography and conductance catheter measurements. LV fibrosis was investigated at 6 weeks using red Sirius staining of myocardial tissues. Echocardiographic measurements for LV diastolic function were retrospectively analyzed in 102 patients, before and after PEA. <h3>Results</h3> Mean PA pressure was higher at 6 weeks in PH animals compared to controls (28.5 [28.0; 34.2] vs. 14.0 [12.5; 14.0] mmHg, p<0.01). Increased end-diastolic LV pressure was observed in PH group (21.9 [18.1; 22.7] vs. 12.2 [11.7; 13.8] mmHg, p=0.013), along with a marked decrease in the curve-fitting constant (c) and the maximum rate of LV filling (dV/dt_max), respectively by 49% (p=0.03) and 74% (p=0.014). Stiffness constant ß was strongly correlated with Doppler imaging index E/A (r=-0.94, p=0.015). Mean LV fibrosis score was significantly higher in PH group at 6 weeks (5.11±0.89% vs. 3.29±1.14%, p<0.01). Pre-operative impairment of LV filling pattern was remarkable in patients with CTEPH (E/A = 0.81±0.32; E/E'=6.42±2.84), and significantly improved at 7 days post PEA (+30%, p<0.001). At 6 months, E/A ratio was significantly higher (0.91 [0.75; 1.20] vs. 0.76 [0.66; 0.94], p=0.05) but remained abnormal, despite significant decrease in mean pulmonary vascular resistance (7.3 ±3.1WU vs. 3.8±1.5WU, p<0.001). <h3>Conclusion</h3> Impaired myocardial stiffness was associated with LV fibrosis in our piglet model of CTEPH. Mild LV diastolic dysfunction was observed at 6 months in patient with CTEPH despite significant decrease in RV pressure overload after PEA. Myocardial fibrosis may be responsible for persistent abnormal LV relaxation.