**3. Cryoablation**

The first clinical surgical ablation for AF was introduced by Dr. James Cox in 1987, and was termed the Cox-Maze I. The successful 22 cases were reported in 1991 [2]. Over the subsequent years, the operation evolved into the Cox-Maze III or the cut-and-sew Maze [3], which has been applied extensively in clinical practice [4]. In the meantime, the introduction of ablation technology has significantly changed the attitude. Damiano et al. employed a combination of radiofrequency energy and cryoablation to replace several of the Cox-Maze III cut and sew lesions and termed this procedure as the Cox-Maze IV [5, 6]. Finally, the lesion sets of the

**Figure 1.** Scheme of the bi-atrial Cox-Maze procedure IV utilizing radiofrequency (RF) or cryoablation energy sources.

Khargi et al. reported that conventional cut-and-sew Cox-Maze III procedure is getting less frequently performed, and alternative sources of energy were predominantly used in all surgical ablation cases (92.0%), and almost always (98.4%) in concomitant procedures [9]. Cryoablation is employed as an alternative source of energy [10–12]. As compared to radiofrequency and cryoablation, other energy sources such as microwave, laser, and high-frequency ultrasound have proven less effective, and are not commercially available now [13–18].

It was documented that all AF is characterized by the presence of two or more large macroreentrant circuits in the atria simultaneously [19]. Haïssaguerre et al. first detected the focal triggers of atrial ectopic beats [20]. They noted that the ectopic foci are mainly (>90%) located in and

Cox-Maze IV have evolved to its current form [7, 8] (**Figure 1**).

64 Cardiac Arrhythmias

**2. Electrophysiologic basis of atrial fibrillation**

#### **3.1. Introduction of cryoablation**

The era of cryosurgery began with the development of automated cryosurgical equipment in the 1960s. Cooper et al. described cryosurgical resection of parenchymal organs using liquid nitrogen-refrigerated clamp in 1966 [22]. Cryosurgery has been an integral part of the surgical treatment of cardiac arrhythmias since the 1970s. With the recent technological development of cryoablation devices, the use of cryothermy in the treatment of cardiac arrhythmias is increasing.

Cryoablation is effective in producing electrical silent ablation lines, and can be used judiciously safely without injuring surrounding structures such as coronary arteries and valve tissue.

#### **3.2. Mechanisms of tissue injury in cryoablation**

Gage et al. described the mechanisms of tissue injury in cryosurgery [23]. The adverse effect of low temperature on cells begins as temperature falls into the hypothermic range. The function and structure of cells are stressed, and cell metabolism progressively fails. As the temperature goes further down and falls into the freezing range, water is crystallized, which causes more serious consequences than the earlier cooling. Ice crystal formation first occurs in the extracellular spaces, and with further cooling, it occurs within the cell. Intracellular ice formation requires temperatures colder than −40°C. Once intracellular ice is formed, it disrupts organelles and cell membranes, and cell death is practically certain.

The progress to a stable lesion can be divided into three phases: (1) freeze/thaw phase, (2) haemorrhagic and inflammatory phase, and (3) replacement fibrosis phase [24].

**1.** Freeze/thaw phase.

Intracellular and extracellular ice formation vary in size and location depending on tissue type, proximity to the cryoprobe, and the presence of blood flow during cryoablation. Ice crystals, themselves, do not cause mechanical disruption. They do not penetrate the cell membrane, but induce compression and distortion of adjacent cytoplasmic components [25, 26]. Irreversible injury to mitochondria is a consequence of increased membrane permeability during the thaw phase [27]. The damage to the mitochondrial membrane leads to membrane lipid peroxidation and enzyme hydrolysis. At this point, mitochondria become irreversibly deenergized [28]. In the heart, the application of cryoprobe to myocardium results in the formation of an elliptical hemispheroid lesion [29]. During the thawing, the myocytes get swollen and the myofilaments are extremely stretched.

**3.4. Cryoablation device**

pathway by freezing target tissues.

**3.5. Transmurality of cryoablation**

malleable probe on a 20 cm shaft. It utilizes nitrous oxide (N2

that provides a high flexibility [36] (**Figure 2**).

Cryothermal energy is delivered to myocardial tissue by using a cryoprobe. Cryoablation devices create an inflammatory response (cryonecrosis) that blocks the electrical conduction

Histopathological Change Following Cox-Maze IV Procedure for Atrial Fibrillation

There are two commercially available cryoablation probes for surgical treatment of cardiac arrhythmias. AtriCure Inc. (Mason, OH) has provided cryoICE probe, which uses a 10 cm

ral lesions that block propagation of atrial activation. The cryoFORM is a latest generation of cryoablation probe, which is made from stainless steel and has a corrugated surface, a design

Medtonic Inc. (Minneapolis, MN) has developed Cardioblate CryoFlex surgical ablation probes, which utilize argon-powered cryoablation (**Figure 3**). This is a malleable probe easily shaped by hand, and reaches temperature of approximately −150°C. This device is currently

Kettering et al. created a successful, a right atrial septal linear lesion with cryocatheter in pigs [37]. The bipolar voltage map demonstrated very low potentials along the ablation line and a sharply demarcated ablation area. However, they concluded that creating a transmural lesion and a complete conduction block remains an unsolved problem. Wadhwa et al. reported that successful transmurality was achieved with catheter cryoablation in the canine ventricle [38]. Masroor et al. reported that endocardial hypothermia was achieved with epicardial

**Figure 2.** Illustration of the flexibility of the cryoFORM ablation probe. The length of the active site of the malleable

**Figure 3.** Illustration of the Cardioblate CryoFlex ablation device (Reproduced with permission from Medtronic, Inc.).

probe surface is adjustable by the movable shaft cover (Reproduced with permission from AtriCure, Inc.).

approved for use in surgical ablation for AF in Europe but not in the United States.

O) to create continuous transmu-

http://dx.doi.org/10.5772/intechopen.72786

67

**2.** Haemorrhagic and inflammatory phase.

The second phase of myocardial injury following cryoablation is characterized by the development of haemorrhage [29], oedema, and inflammation [30], which are found within 48 hours after thawing. Harrison et al. reported the histologic changes following cryoablation to the atrioventricular node [31]. One week after the procedure, microscopy showed necrosis of myocardial cells and conduction fibres, a polymorphonuclear leukocytic infiltrate and marked haemorrhage in the peripheral lesion.

**3.** Replacement fibrosis phase.

The last phase in the evolution of a stable cryolesion is detected at 2–4 weeks after the cryoablation. At this point, the cryolesions consist of dense collagen and fat infiltration along with many small blood vessels. Harrison et al. reported that, 1 month after the procedure, the lesion had been replaced by dense fibrotic connective tissue [31].

#### **3.3. Electrophysiologic effects of cryoablation on the heart**

Jensen et al. developed an experimental myocardial injury model using cryoinjury in dogs [32]. Their histologic examination showed that the cellular pattern or healing myocardial cryolesions was similar to that of a healing myocardial infarction, but with less variability. Several papers reported that cryolesions have low arrhythmogenic potential in canine models [33–35].

Holman et al. reported the decrease of electrogram amplitude in cryolesions [33]. The decrease in amplitude reflects epicardial ice insulation or inhibition of myocardial electrical potential. More than 70% decrease in absolute amplitude from control potentials was predictive of cellular death. Klein et al. demonstrated that the cryolesions are sharply demarcated from normal myocardium and does not disrupt the surrounding anatomy [34]. The chronic cryolesion behaves electrophysiologically like an inert plug with no disruption of surrounding activation. Ventricular ectopic activity disappeared in cryolesions after 1 week of the cryoablation.

In conclusion, the cryothermal energy can create discrete, structurally intact, and electrically inert foci in the myocardium. That is, the electrophysiologic mechanism for a cryoablation is considered to be a useful therapeutic modality in the treatment of cardiac arrhythmias.

#### **3.4. Cryoablation device**

**1.** Freeze/thaw phase.

66 Cardiac Arrhythmias

**2.** Haemorrhagic and inflammatory phase.

**3.** Replacement fibrosis phase.

trate and marked haemorrhage in the peripheral lesion.

**3.3. Electrophysiologic effects of cryoablation on the heart**

the lesion had been replaced by dense fibrotic connective tissue [31].

Intracellular and extracellular ice formation vary in size and location depending on tissue type, proximity to the cryoprobe, and the presence of blood flow during cryoablation. Ice crystals, themselves, do not cause mechanical disruption. They do not penetrate the cell membrane, but induce compression and distortion of adjacent cytoplasmic components [25, 26]. Irreversible injury to mitochondria is a consequence of increased membrane permeability during the thaw phase [27]. The damage to the mitochondrial membrane leads to membrane lipid peroxidation and enzyme hydrolysis. At this point, mitochondria become irreversibly deenergized [28]. In the heart, the application of cryoprobe to myocardium results in the formation of an elliptical hemispheroid lesion [29]. During the thawing,

The second phase of myocardial injury following cryoablation is characterized by the development of haemorrhage [29], oedema, and inflammation [30], which are found within 48 hours after thawing. Harrison et al. reported the histologic changes following cryoablation to the atrioventricular node [31]. One week after the procedure, microscopy showed necrosis of myocardial cells and conduction fibres, a polymorphonuclear leukocytic infil-

The last phase in the evolution of a stable cryolesion is detected at 2–4 weeks after the cryoablation. At this point, the cryolesions consist of dense collagen and fat infiltration along with many small blood vessels. Harrison et al. reported that, 1 month after the procedure,

Jensen et al. developed an experimental myocardial injury model using cryoinjury in dogs [32]. Their histologic examination showed that the cellular pattern or healing myocardial cryolesions was similar to that of a healing myocardial infarction, but with less variability. Several papers reported that cryolesions have low arrhythmogenic potential in canine models [33–35].

Holman et al. reported the decrease of electrogram amplitude in cryolesions [33]. The decrease in amplitude reflects epicardial ice insulation or inhibition of myocardial electrical potential. More than 70% decrease in absolute amplitude from control potentials was predictive of cellular death. Klein et al. demonstrated that the cryolesions are sharply demarcated from normal myocardium and does not disrupt the surrounding anatomy [34]. The chronic cryolesion behaves electrophysiologically like an inert plug with no disruption of surrounding activation. Ventricular ectopic activity disappeared in cryolesions after 1 week of the cryoablation.

In conclusion, the cryothermal energy can create discrete, structurally intact, and electrically inert foci in the myocardium. That is, the electrophysiologic mechanism for a cryoablation is considered to be a useful therapeutic modality in the treatment of cardiac arrhythmias.

the myocytes get swollen and the myofilaments are extremely stretched.

Cryothermal energy is delivered to myocardial tissue by using a cryoprobe. Cryoablation devices create an inflammatory response (cryonecrosis) that blocks the electrical conduction pathway by freezing target tissues.

There are two commercially available cryoablation probes for surgical treatment of cardiac arrhythmias. AtriCure Inc. (Mason, OH) has provided cryoICE probe, which uses a 10 cm malleable probe on a 20 cm shaft. It utilizes nitrous oxide (N2 O) to create continuous transmural lesions that block propagation of atrial activation. The cryoFORM is a latest generation of cryoablation probe, which is made from stainless steel and has a corrugated surface, a design that provides a high flexibility [36] (**Figure 2**).

Medtonic Inc. (Minneapolis, MN) has developed Cardioblate CryoFlex surgical ablation probes, which utilize argon-powered cryoablation (**Figure 3**). This is a malleable probe easily shaped by hand, and reaches temperature of approximately −150°C. This device is currently approved for use in surgical ablation for AF in Europe but not in the United States.

#### **3.5. Transmurality of cryoablation**

Kettering et al. created a successful, a right atrial septal linear lesion with cryocatheter in pigs [37]. The bipolar voltage map demonstrated very low potentials along the ablation line and a sharply demarcated ablation area. However, they concluded that creating a transmural lesion and a complete conduction block remains an unsolved problem. Wadhwa et al. reported that successful transmurality was achieved with catheter cryoablation in the canine ventricle [38]. Masroor et al. reported that endocardial hypothermia was achieved with epicardial

**Figure 2.** Illustration of the flexibility of the cryoFORM ablation probe. The length of the active site of the malleable probe surface is adjustable by the movable shaft cover (Reproduced with permission from AtriCure, Inc.).

**Figure 3.** Illustration of the Cardioblate CryoFlex ablation device (Reproduced with permission from Medtronic, Inc.).

cryoablation on a beating heart model in pigs [39]. Schill et al. reported that the latest cryoablation probe produced transmural lesions in 97% of the arrested heart in an ovine model [40].

However, the transmurality created by surgical cryoablation in the human tissue has not been well studied.
