Results:

In the in vitro model, a rapid time-dependent loss of HMW multimers (>60% after 5 minutes and >90% after 30 minutes) was observed in both MCS-A and -B experiments. The loss of HMW multimers coincided with a loss of collagen-binding activity. Loss of HMW multimers and collagen-binding activity followed a similar time course in MCS-A and -B (p = 0.578 and p = 0.771 for HMW multimers and VWF:CB/VWF:Ag, respectively).

In the swine model (model 2 or dose-effect of pulsatility on VWF parameters) when combining all data points, a strong correlation was observed between arterial pulsatility and HMW multimer ratio (r = 0.73; p < 0.01). Of note, no significant increase AMP in LDH was observed during the time of the experiment (30 minutes), with no difference between the two devices (MCS-A or -B) in any of the locations (left ventricle or aorta). The swine model (model 3 or consequences of sequential changes of pulsatility on VWF parameters) showed that pulse pressure (PP) can be significantly and easily manipulated by relocating the same device (MCS-B) from one position to another (left ventricle vs. aorta and vice versa). The first low-pulsatility phase (phase 1:MCS in LV-1) was associated with a rapid and significant loss of HMW multimers (0.74 [IQR: 0.58-0.88], 0.51 [IQR: 0.38-0.60], and 0.39 [IQR: 0.22-0.48] at 5, 15, and 30 minutes, respectively vs. 0.90 [IQR: 0.84-1.10] at baseline; ANOVA p < 0.0001). After stopping the pump for 60 minutes (phase 2: native heart only-1) and restoring a low shear and a normal pulsatility, a complete recovery of HMW-multimer ratio (at 1.0 [IQR: 0.89-1.26]) was obtained. During the normal PP phase (phase 3: MCS in aorta), a decrease of HMW multimer ratio was also observed (0.87 [IQR: 0.69-1.04], 0.76 [IQR: 0.73-0.88], and 0.74 [IQR: 0.62-0.82] at 5, 15, and 30 minutes, respectively; ANOVA p < 0.0001).

In the patient with cardiogenic shock the study investigators observed that the PP during the first phase of CF-MCS was very low (<10 mm Hg). In the second phase, after PF-MCS implantation occurred, there was a high increase of PP (51 mm Hg [IQR: 42.5-54 mm Hg]). Then, during the last phase of dual support (CF-MCS + PF-MCS), a significant drop of PP (25 mm Hg [IQR: 20-30 mm Hg] vs. 51 mm Hg [IQR: 42.5-54 mm Hg], p < 0.01) occurred. Under CF-MCS (high shear and low pulsatility), a marked decrease of both VWF:Act/VWF:Ag and HMW-multimer ratio (0.6 and 0.3, respectively) were observed. Three hours after implantation, the PF-MCS support provided a rapid restoration of functional VWF with a complete normalization of both VWF:Act/VWF:Ag and HMW multimers and a parallel increase in VWFpp/VWF:Ag ratio from 1.0 to 2.2. During the 7 days of PF-MCS (low shear and normal pulsatility), VWF:Act/VWF:Ag and HMW multimers remained into the normal range (VWF:Act/VWF:Ag ratio = 1.11 [IQR: 1.04-1.22], HMW-multimers ratio = 0.87 [IQR: 0.78-0.98]). The hemodynamic and respiratory failure during PF-MCS required the addition of CF-MCS to PF-MCS (phase 3: high shear and low pulsatility). Upon initiation of PF-MCS, the investigators noted a recurrence of a functional VWF defect that remained stable over time (VWF:Act/VWF:Ag ratio = 0.51 [IQR: 0.47-0.55], HMW-multimers ratio = 0.10 [IQR: 0.07-0.10]). Under single PF-MCS support, a continuous increase inVWF:Ag occurred from 295 IU/dl just after implantation to 581 IU/dl after completing 7 days of PF-MCS. After implantation of additional CF to PF-MCS, VWF:Ag dropped to 369 IU/dl within the first day of dual support. Then, a progressive and milder rise of VWF:Ag was observed from 326 IU/dl in the second day to 491 IU/dl after completing 11 days of dual support. A progressive rise of VWFpp was noted under PF-MCS from 385 to 660 IU/dl between day 6 and day 12. After the addition of CF-MCS to PF-MCS, a progressive decrease of VWFpp occurred, from 660 IU/dl at day 13 to 363 IU/dl at day 23.