**3. Mechanical circulatory support**

MCS may be provided by VA-ECMO or the implantation of a temporary paracorporeal ventricular assistance device (VAD) and the choice depends on the knowledge about devices and shelf-available items. There's no manual or evidence-based decision-making protocol to choose one or another. Nevertheless, ECLS management may determinate success to discharge of patients experiencing PGD.

Advances in durable MCSs (LVADs) made its use reliable in patients with heart failure as a bridge to heart transplant, as well as postoperative support with ECLS in PGD HT to allow organ recovery. Although an LVAD is usually the choice for consistent outcomes in patients supported while waiting for a heart transplant, ECLS may be used in patients in whom LVADs, BiVADs, or TAH (total artificial hearts) are not reliable or available. It includes patients who are likely to receive a heart transplant within a short time period after listing.

ECLS use in heart transplant PGD continues to be the first line of support with some recent evidence of improved outcomes. There is some evidence on the use of short-term VAD but with limited results in a real-world setting [61]. Although further studies are necessary to understand the optimal role of ECLS in heart transplantation the objective of this chapter is to discuss its role in PGD, that accounts for 40–50% early mortality after heart transplantation according to studies using the International Society of Heart and Lung Transplantation (ISHLT) registry [5]. Mechanical circulatory support may be provided by VA-ECMO or implantation of a temporary VAD. In a recent analysis of 54 patients supported on ECMO for PGD in a large French center, 36 patients (67%) were weaned from the assisting device and 27 of the patients supported with ECMO (50%) were discharged from the hospital [62].

The overall conditional survival was 73% at 1 year and 66% at 5 years. The authors concluded that ECMO support is a reliable therapeutic option for severe, early graft failure after cardiac transplantation. Furthermore, patients treated with ECMO had the same 1-year conditional survival as patients who did not suffer from PGD. In this study, the authors found no difference in weaning when comparing peripheral ECMO and central ECMO (50%) but a higher rate of vascular complications (18%) in patients supported on peripheral ECMO.

Graft and cardiovascular dysfunction in ACHDR were the top two causes of early mortality and most likely related to the presence of elevated PVR, allosensitization, and longer donor organ ischemic times [30, 55–59]. The ACHDR were more likely to have longer-than-4-h ischemic times, peak panel-reactive antibody (PRA) class II >10%, and were found to have a higher rate of graft failure due to primary graft dysfunction. Thompson et al. showed that early graft survival was directly related to the number of HLA-DR (class-II) mismatches [59]. Graft dysfunction and postoperative bleeding are more likely to cause death in ACHDR compared to non-cardiac recipients (NCR) [49, 53, 60]. Because of graft dysfunction and young age, the re-transplant rate is higher among ACHDR compared to NCR [49, 55]. Improvement in the graft dysfunction rate in recent times can be attributed to better medical management of mild PGD with the use of levosimendan, nitric oxide, and phosphodiesterase inhibitors. The short-term survival for ACHDR is poorer as compared to NCR, and primary graft dysfunction remains a significant issue affecting short-term survival in ACHDR. The fact that the ACHDR who survives the first post-transplant year have better long-term survival than NCR indicates that perioperative mortality and morbidity is most likely the Achilles heel for cardiac transplantation in ACHDR [54]. Management of severe PGD with early intervention

and short-term mechanical support appears to have improved survival [5].

are likely to receive a heart transplant within a short time period after listing.

MCS may be provided by VA-ECMO or the implantation of a temporary paracorporeal ventricular assistance device (VAD) and the choice depends on the knowledge about devices and shelf-available items. There's no manual or evidence-based decision-making protocol to choose one or another. Nevertheless, ECLS management may determinate success to dis-

Advances in durable MCSs (LVADs) made its use reliable in patients with heart failure as a bridge to heart transplant, as well as postoperative support with ECLS in PGD HT to allow organ recovery. Although an LVAD is usually the choice for consistent outcomes in patients supported while waiting for a heart transplant, ECLS may be used in patients in whom LVADs, BiVADs, or TAH (total artificial hearts) are not reliable or available. It includes patients who

ECLS use in heart transplant PGD continues to be the first line of support with some recent evidence of improved outcomes. There is some evidence on the use of short-term VAD but with limited results in a real-world setting [61]. Although further studies are necessary to understand the optimal role of ECLS in heart transplantation the objective of this chapter is to discuss its role in PGD, that accounts for 40–50% early mortality after heart transplantation according to studies using the International Society of Heart and Lung Transplantation (ISHLT) registry [5]. Mechanical circulatory support may be provided by VA-ECMO or implantation of a temporary VAD. In a recent analysis of 54 patients supported on ECMO for PGD in a large French center, 36 patients (67%) were weaned from the assisting device and 27 of the patients supported with ECMO (50%) were discharged

**3. Mechanical circulatory support**

96 Advances in Extra-corporeal Perfusion Therapies

charge of patients experiencing PGD.

from the hospital [62].

The device of choice and timing of insertion varies among institutions, and the use of mechanical circulatory support tends to be more liberal for early support in high-volume centers with a potentially positive effect on graft recovery [63]. Although ECMO has been traditionally favored due to the ease installation, and the ability to provide oxygenation following a prolonged cardiopulmonary bypass, its use is associated with increased risk of bleeding, insufficient LV unloading, and the chance of intracardiac thrombosis in patients with minimal sistolic function [64, 65].

Takeda and colleagues from Columbia University performed an analysis of patients requiring mechanical support for PGD following heart transplant [66]. Of the 597 patients who received a heart transplant during the study period, severe PGD developed in 44 (7.4%). Within 24 h of transplant, 17 of these patients received support via a continuous-flow external VAD, and 27 received VA-ECMO support. The patients who received a VAD were more likely to have a longer support time, major bleeding requiring chest re-exploration, and renal failure requiring renal replacement therapy after surgery. In-hospital mortality was 41% for VAD patients and 19% for VA-ECMO patients. A total of 10 patients (59%) were weaned from VAD support, and 24 patients (89%) were removed from VA-ECMO support after adequate graft function recovery. The 3-year post-transplant survival was 41% in the VAD group and 66% in the VA-ECMO group, leading to the conclusion that for severe PGD, support with VA-ECMO appears to result in better clinical outcomes than VAD support. ECMO in patients with PGD or allograft failure due to other causes seems to be associated with better outcomes than ECMO support for other reasons. Tran and colleagues [67], from UCLA, demonstrated that patients requiring ECMO for graft failure after heart transplant had lower mortality (51.6%) when compared with patients who needed ECMO for other etiologies (69.1%).

ECLS/ECMO seems to be the best way to support PGD patients in almost all scenarios for many reasons. It can provide safe maximum flow and pulmonary support with different cannulation strategies—percutaneously, hybrid, or by central access. It is rapidly installed, and cost of disposable equipment is relatively inexpensive compared with other devices. In basic settings, veno-arterial (VA) ECMO is considered the main strategy. Central access is preferable due to fast installation, direct evaluation of the heart decompression, and easiest way to install a left-side drainage cannula in the left atrium or left ventricle if it remains distended.

A total of 16% of our PGD patients had a left cannula installed as a venting strategy to guarantee LV resting. Our preference is to use central VA ECMO. Patients may be extubated as any other heart surgery postoperatively after recovering from anesthesia. Cannulas may be positioned inferiorly through the thoracic wall and the chest fully closed to facilitate mobility and ambulation. Extubation may be done even if only the skin is closed—not sutured sternum. In this case, the care team has to ensure a sealed bandage around the cannulas to avoid pneumothorax formation.

Full support is sufficient when hemodynamic variables and microperfusion are normalized— VA ECMO usually provides normal oxymetric parameters if the patient is well supported. MAP goal usually is around 70, CVP < 15, SVO2 > 60%, serum lactate <2.0 mmol/L, and O2 saturation > 95%. Since the pulmonary flow is shunted throw the ECLS system, pulmonary artery pressures are expected to be very low, and most of the times cardiac index cannot be measured. Pulsatile waveforms are almost invisible or show a very low pulse pressure gradient (less than 20 mm Hg).

All patients had advanced heart failure and 2 (18.2%) patients were in a priority state before the transplantation. As for the etiology of the cardiomyopathy, 5 (45.4%) were due to Chagas disease, 3 idiopathic dilated cardiomyopathy, 1 from secondary to valvular cardiomyopathy, 1 had restrictive cardiomyopathy, and 1 was associated with peripartum cardiomyopathy.

Mechanical Circulatory Support (MCS) for Primary Graft Dysfunction (PGD)

http://dx.doi.org/10.5772/intechopen.76697

99

In our experience, the causes of PGD were not associated with severe rejection, as documented by routine endomyocardial biopsy in the first week, with only one patient presenting cellular rejection greater than 2R. Donors were predominantly male (n = 7; 63.6%) and had an average age of 26.6 ± 12.3 years (ranging from 15 to 48 years). The causes of death among donors included head trauma in 7 cases (63.6%), hemorrhagic stroke in 3 (27.3%), and cerebral tumor in 1. A total of 7 cases (63.6%) received continuous infusion of norepinephrine >0.1 mcg/kg/ min at the time of the retrieval. Retrievals took place in the same hospital of the implantation in 6 (54.5%) cases and at a distant center in the 5 remaining cases. The average ischemia time was 151 ± 82 min (ranging from 73 to 270 min), with 82.8 ± 14.2 min in the local retrievals and 233 ± 35.4 min in distant retrievals (p < 0.0001). The cold ischemia "limit" of 4 h was exceeded

In this group of patients, the use of ECMO met the desired goals, promoting cardiac recovery in most cases, with acceptable complication rates, considering the severity of the clinical condition of patients [71]. We were successful in removing the ECMO, with cardiac recovery in 81.8% of the patients after an average of 76 h. The main postoperative problems that we found were acute renal failure, stroke, and requirement for surgical revision of hemostasis. The first is a frequent complication [72] and is secondary to multiple insulting factors—shock, nephrotoxic drugs, and systemic venous congestion—and pre-transplant cardiorenal syndrome. Renal function recovered in all patients after a few sessions of hemodialysis, as described by Listijono et al. [73]. The last two are complications related to the requirement of anticoagulation during ECMO, which is difficult to control. Complicating factors are recent heart surgery, the presence of shock with concomitant hepatic dysfunction, and, eventually, disseminated intravascular coagulation. Excessive use of blood products complicates immunological sensitization, systemic congestion—including liver congestion, which increases bleeding—and pulmonary hypertension. The use of heparin-coated circuits, antifibrinolytics, careful surgical technique, maintenance of hemodynamic stability with systemic venous decompression, and synthetic derivatives of coagulation factors are important to minimize these complications. Although patients who developed stroke showed increased hospital mortality, those who

survived had full recovery of motor activity without limitation in their quality of life.

The aim of circulatory assistance in PGD is always cardiac recovery. Thus, the characteristics of the ideal device must comply with the following requirements: ability to be quickly installed, allowing the rapid re-establishment of cardiac output in order to maintain adequate tissue perfusion and reverse multiorgan dysfunction, reducing ventricular filling pressures, promoting myocardial protection with increased coronary flow, and having a low

None of the patients had PRAc—preformed antibodies calculated panel—above 10%.

in 2 (18.2%) patients.

**4. Conclusion(s)**

complication rate.

Usually, in the range of 3–7 days, it is possible to see some degree of heart recovery. Pulse pressure may rise above 20 mmHg, CI may be measurable through PAC, pulmonary pressures may rise, and the patient may be hemodynamically stable with a lower flow on ECLS system. At this point, the weaning protocol should require an echocardiographic evaluation to reassess biventricular function. In adults, patients showing aortic time-velocity integral (VTI) ≥10 cm, left ventricular ejection fraction (LVEF) >20–25%, and lateral mitral annulus peak systolic velocity (TDSa) ≥6 cm/s at minimal ECMO flow were all successfully weaned [68].

Although ECMO may provide adequate support, it has limitations such as insufficient LV unloading, limited time of support, and risks of thromboembolic and vascular complications. High pressures in left chambers may not be easily documented, and the patient may run with hemodynamic instability. Non-treatable low flow related to sequestration of stroke volume in the lungs, secondary of left chambers distention, and inability of the heart to decompress from ECMO post-load augmentation may be seen. A documented left-side heart high pressure requires an immediately strategy to unload left chambers and re-establish the desired flow. A drainage cannula in left atrium or ventricle that allows a fast connection on the ECMO circuit permits good drainage and is a feasible choice. It is important to note that, in this case, optimum flow will be achieved after a left-side drainage cannula insertion.

In case of recovery of the left ventricle's ability to unload, the left cannula may be removed before starting the weaning protocol or just reducing the ECMO to allow filing up the ventricle and considering weaning. Intra-aortic balloon pump has been documented, but in a different scenario setting, as a way to reducing systemic vascular resistance, helping to prevent LV distention, during the VA ECMO run [69]. More recently, in the largest US-based retrospective study, the addition of Impella to VA-ECMO for patients with refractory cardiogenic shock was associated with lower all-cause 30-day mortality, lower inotrope use, and comparable safety profiles as compared with VA-ECMO alone. This study reinforces the importance of LV decompression as an important factor to improve outcomes during VA ECMO in severe ventricular dysfunction [70].

If recovery is not noted on PGD, other strategies should be considered and palliative care may be an option. Although we were able to prolong ECMO support in an infant up to 44 days until recovery, a biventricular support including a durable VAD or a total artificial heart may be an option in selected patients. Since there is lack of evidence to support use of those alternatives on PGD, the selection of a device should be made according to the patient's clinical condition and the center's experience.

#### **3.1. Personal experience**

Between January 2007 and December 2013, a total of 71 heart transplantations were performed in patients with advanced heart failure and 11 (15.5%) of these patients presented PGD [71]. All patients had advanced heart failure and 2 (18.2%) patients were in a priority state before the transplantation. As for the etiology of the cardiomyopathy, 5 (45.4%) were due to Chagas disease, 3 idiopathic dilated cardiomyopathy, 1 from secondary to valvular cardiomyopathy, 1 had restrictive cardiomyopathy, and 1 was associated with peripartum cardiomyopathy. None of the patients had PRAc—preformed antibodies calculated panel—above 10%.

In our experience, the causes of PGD were not associated with severe rejection, as documented by routine endomyocardial biopsy in the first week, with only one patient presenting cellular rejection greater than 2R. Donors were predominantly male (n = 7; 63.6%) and had an average age of 26.6 ± 12.3 years (ranging from 15 to 48 years). The causes of death among donors included head trauma in 7 cases (63.6%), hemorrhagic stroke in 3 (27.3%), and cerebral tumor in 1. A total of 7 cases (63.6%) received continuous infusion of norepinephrine >0.1 mcg/kg/ min at the time of the retrieval. Retrievals took place in the same hospital of the implantation in 6 (54.5%) cases and at a distant center in the 5 remaining cases. The average ischemia time was 151 ± 82 min (ranging from 73 to 270 min), with 82.8 ± 14.2 min in the local retrievals and 233 ± 35.4 min in distant retrievals (p < 0.0001). The cold ischemia "limit" of 4 h was exceeded in 2 (18.2%) patients.

In this group of patients, the use of ECMO met the desired goals, promoting cardiac recovery in most cases, with acceptable complication rates, considering the severity of the clinical condition of patients [71]. We were successful in removing the ECMO, with cardiac recovery in 81.8% of the patients after an average of 76 h. The main postoperative problems that we found were acute renal failure, stroke, and requirement for surgical revision of hemostasis. The first is a frequent complication [72] and is secondary to multiple insulting factors—shock, nephrotoxic drugs, and systemic venous congestion—and pre-transplant cardiorenal syndrome. Renal function recovered in all patients after a few sessions of hemodialysis, as described by Listijono et al. [73]. The last two are complications related to the requirement of anticoagulation during ECMO, which is difficult to control. Complicating factors are recent heart surgery, the presence of shock with concomitant hepatic dysfunction, and, eventually, disseminated intravascular coagulation. Excessive use of blood products complicates immunological sensitization, systemic congestion—including liver congestion, which increases bleeding—and pulmonary hypertension. The use of heparin-coated circuits, antifibrinolytics, careful surgical technique, maintenance of hemodynamic stability with systemic venous decompression, and synthetic derivatives of coagulation factors are important to minimize these complications. Although patients who developed stroke showed increased hospital mortality, those who survived had full recovery of motor activity without limitation in their quality of life.


**About the Editor**

#### **V´ıctor Rolo**

V´ıctor is a Senior Researcher at the Forest Research Group of the University of Extremadura. He holds a Ph. D in Plant Biology and Production from the University of Extremadura. His past working experience includes postdoctoral positions at the University of Mendel (Czech Republic) and the University of Pretoria (South Africa), where he specialized in adaptive management and forest restoration. His research interests focus on assessing soil—plant components of forest and agroforestry systems to enhance their persistence and productivity in a changing environment. He uses experimental, observational and modelling methods in his research and has published several articles and book chapters.


**2. History and origin of CPPs**

The CPPs are initially discovered in 1965 when it was observed that histones and cationic polyamines such as polylysine stimulate the uptake of albumin by tumor cells in culture. It was shown that the conjugation of polylysine to albumin and other proteins enhances their transport into cells. Moreover, a comparison study of different homopolymers of cationic amino acids demonstrates that medium-length polymers of arginine enter cells more effective than similarlength polymers composed of lysine, ornithine, or histidine [11]. In 1988, it was discovered that the human immunodeficiency virus type 1 (HIV-1) encoded trans-acting activator of transcription (Tat) peptide which also translocates cell membranes and gains intracellular mammalian cells [12, 13]. Covalently the conjugation of Tat peptide to proteins or fluorescent markers allowed these molecules to gain into the cell. A few years later, another discovery was followed when polycationic peptide of natural (VP22 and AntP) and synthetic origin (transportan) was used for the delivery of genes, proteins, small exogenous peptide, or even nanoparticles. Furthermore, it was demonstrated that small domains in these peptides are often responsible for cellular entry [14]. Thus, these translocation sequences could be shortened to a few amino acids in comparison with the first Tat peptide, without affecting cell penetration efficiency [13]. Since that time, the list of synthetic CPPs has increased sharply, and the number continues to rise (**Table 1**). In the last decade, another peptide was described named maurocalcine (MCa), a 33 amino acid residue peptide that has been isolated from the venom of the Tunisian chactid scorpion *Scorpio maurus palmatus.* It folds according to an "inhibitor cystine knot" (ICK) motif and contains three disulfide bridges connected by the following pattern: C1–C4, C2–C5, and C3– C6 [15]. MCa acts on ryanodine receptors resulting in pharmacological activation. These receptors are calcium channels located in the membrane of the endoplasmic reticulum. They control Ca2+ release from internal stores and therefore a large number of cell functions [16, 17].

This peptide possesses vector properties when coupled to fluorescent streptavidin. This complex was shown to enter various cell types within minutes and in all cell types tested, a common feature of CPPs. A variety of mutants of MCa were then designed in order to unravel the most active residues for its pharmacological and penetration activities (**Figure 1**) [18, 19].